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Alzheimer’s diseaseBy Ronald Steriti, NMD, PhD

Description

Alzheimer’s disease was first described in 1907 by Alois Alzheimer, a German psychiatrist. Henoted the pathologic hallmarks of the disease, including neurofibrillary tangles and senileplaques.

Symptoms

The symptoms of Alzheimer’s disease usually begin in the seventh to ninth decades of life,although early onset familial forms of the illness are well described (see below).

The most characteristic symptom of Alzheimer’s disease is a profound impairment of recentmemory. Individuals begin to misplace everyday items, such as the car keys or eyeglasses, andbecome disoriented and get lost in familiar surrounds (such as when driving on well-knownstreets). As the disease progresses they may experience mood swings with anxiety, depression oraggressive behavior. They often become uninterested in usual activities. In the terminal phasethere is apathy and an inability to communicate.

Neuropsychiatric symptoms that commonly accompany Alzheimer’s disease include:(Cummings 2001)

Agitation in 60% to 70% of patients

Apathy, 60% to 70%

Depression, 50%

Anxiety, 50%

Irritability, 50%

Delusional disorders and psychosis, 40% to 50%

Disinhibition, 30%

Hallucinations in 10%

Incidence

Alzheimer’s disease is the leading cause of dementia in the elderly and is the fourth leadingcause of death in developed nations (after heart disease, cancer and stroke). Up to 70% ofdementias are due to Alzheimer’s disease, with blood vessel disease (stroke and atherosclerosis)being the second most common cause.

As age advances, the risk of developing Alzheimer’s disease rises sharply. The frequency ofAlzheimer’s among 60-year-olds is about 1%. This incidence doubles approximately every 5years, becoming 2% at age 65, 4% at 70, 8% at 75, 16% at 80, and 32% at 85. It is estimated thatas many as two-thirds of those in their nineties suffer from some form of dementia. For those

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who aspire to live a very long life, dementia is a threat second only to death. Some believe thatdementia is a natural way to end life.

There are over 100,000 deaths per year related to Alzheimer’s disease. Four million people andtheir families suffer from this disease. Annual costs to the United States from Alzheimer’sdisease are over $60 billion. If a treatment that only delayed (not cured) the onset of the diseaseby five years, costs to society would decrease by about half and save $30 billion to $40 billioneach year in this country alone. (Martin 1999)

Course

Alzheimer’s disease leads to death within an average of 8 years after diagnosis, the last 3 yearsof which are typically spent in an institution. Besides memory loss, Alzheimer’s patients showdramatic personality changes, disorientation, declining physical coordination and an inability tocare for themselves. In the final stages, victims are bedridden, lose urinary and bowel control andare completely dependent on the care of others. Death is usually due to pneumonia or urinarytract infection.

Risk Factors

There are a wide range of risk factors associated with the development of dementia. Manyconsider Alzheimer’s disease to be caused by several different factors. The risk factors aresummarized below. (Stern, Gurland et al. 1994; Schofield, Tang et al. 1997; Kidd 1999)

Very likely advanced age, family history of Alzheimer’s or Parkinson’s disease,apolipoprotein E-4, head trauma, depression, reduced blood flow, stroke, estrogenimbalance, poor word fluency.

Likely emotional stress, toxic damage, alcohol abuse, nutrient deficiencies,neurotransmitter deficits, metabolic defects, under-activity, lower educationallevel, occupational electromagnetic exposure.

Possible aluminum exposure, latent viruses, sugar consumption, olfactory deficit, coronaryartery disease.

Diagnosis

Alzheimer’s disease is the most common cause of dementia. However, it is a diagnosis ofexclusion. The diagnosis is only 85% to 90% accurate and the diagnosis is only absolutelyconfirmed by brain biopsy after death. Brain biopsy is usually unacceptable prior to death, andother causes of dementia must be considered and eliminated before the diagnosis of Alzheimer’sis made.

Alzheimer’s-like symptoms can be manifested by a variety of different diseases including:

Space-occupying lesions in the brain, such as brain cancer and subduralhematoma.

Neurological damage, such as occurs after a stroke or with multiple infarctions.

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Other neurological disorders, such as Parkinson’s disease (a deficiency ofdopamine), Huntington’s disease, and multiple sclerosis.

Infectious diseases such as meningitis, late-stage syphilis, and AIDS.

Endocrine disorders, such as hypothyroidism and hypoglycemia.

Cardiovascular disorders, such as congestive heart failure and vascular disease.

Liver or kidney dysfunction.

Nutritional deficiencies of vitamin E, magnesium, and B vitamins (B12, folic acid, niacin andthiamin) can also produce symptoms which might be mistaken for dementia.

Assessment

Currently, the most respected standard for assessing the status of Alzheimer’s patients is theAlzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Memory, orientation,language and functionality are measured on a 70-point scale that increases (on average) by 7 to10 points per year as the patient’s cognition worsens. An improvement of 4 points (4 pointdecline in score) corresponds to a clinically significant reversal of symptoms of nearly half ayear.

The Mini-Mental Status Exam (MMSE) is frequently used for a quick clinical assessment infollowing patients with Alzheimer’s disease. The MMSE checks for orientation and simplethinking ability.

Labs

Standard lab tests for Alzheimer’s disease include:

CBC

Thyroid panel: T3, T4, TSH

Liver function tests

STD testing: VRDL for syphilis, HIV if young

EKG to assess heart function

EEG to differentiate focal vs. diffuse brain dysfunction

Vitamin B12 and folate levels

A CT or MRI of the head is usually ordered to determine if the symptoms arecaused by multi-infarct dementia or a subdural hematoma.

Several alternative lab tests may be helpful in evaluating patients with Alzheimer’s disease toguide treatments. These include:

A comprehensive hormone panel, including estrogen (E1, E2 and E3),progesterone, testosterone, and melatonin

Adrenal function test, including cortisol and DHEA

Oxidative stress levels

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Essential Fatty Acid Panel

Homocysteine, B6, B12, and folate levels

Markers of inflammation, including C-Reactive Protein (CRP)

Hair mineral analysis to assess heavy metal toxicity

A comprehensive vitamin panel (including vitamins A, C, E, and K and beta-carotene) should be considered.

Causes

The etiology (cause) of Alzheimer’s disease is unclear. Several mechanisms have been proposedwhich are described below.

Acetylcholine Depletion

The chemical defect in Alzheimer’s disease that produces the most striking symptoms isacetylcholine depletion which contributes significantly to loss of memory and loss of capacityfor attentiveness. Also, other brain transmitters, such as serotonin, GABA, somatostatin, andnorepinephrine, are reduced 50% or more.

The neurons in the cerebral cortex are the focal site of cellular degeneration in Alzheimer’s, butlower brain nuclei that send modulating neurotransmitters to the cortex are also severelyaffected. Neurons send signals to other neurons by releasing these chemicals into synapses. Butsignals are only effective when they have a beginning and an end. You can’t send Morse code byapplying constant pressure on a telegraph key. Acetylcholinesterase, the enzyme that breaksdown acetylcholine, ends the chemical signal that begins when acetylcholine is released into asynapse and then connects with a receptor.

The memory loss effect of acetylcholinesterase may be due to amplification of signals. Neuraldegeneration weakens or destroys the correct signal modulation so the correct neural messagesare unable to be delivered at the synapse. In Alzheimer’s disease, levels of acetylcholine may bedecreased by up to 90%. It has been found that giving young human subjects an anti-cholinergicagent (which counteracts acetylcholine), such as scopolamine, gives a profile similar toAlzheimer’s disease.

Beta-Amyloid

The most characteristic features of Alzheimer’s disease are senile plaques of beta-amyloidpeptide, neurofibrillary tangles involving tau protein, loss of synapses, and (ultimately) the deathof neurons. Although neurofibrillary tangles are more closely associated with neuronal deaththan beta-amyloid, the evidence is becoming convincing that beta-amyloid is the factor mostresponsible for starting the degenerative processes of Alzheimer’ disease.

Both neurofibrillary tangles and beta-amyloid senile plaques are due to protein abnormalities.The beta-amyloid peptide present in the core of senile plaques is a 42-amino acid chain producedby cleavage of a larger protein known as Amyloid Precursor Protein (APP). There are at least 3different types of beta-amyloid, depending on the site of RNA splicing/cleavage. AmyloidPrecursor Protein is normally found embedded in neural membranes and is thought to contribute

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to stabilizing the contact points between synapses. Some aggregates of beta-amyloid accumulatethroughout brain tissue in normal aging. Beta-amyloid is degraded by at least three enzymeswhich cleave it into smaller molecules. As it is cleaved and destroyed, more beta-amyloid isformed and accumulates. The damage begins when the beta-amyloid becomes concentrated insenile plaques and an inflammatory reaction with ongoing oxidative stress and free radicaldamage ensues.

Tau Protein

Neurons, and in particular the axons of neurons, use microtubules to transport substancesbetween the center of the neuron and its outer portions. The assembly and structural integrity ofmicrotubules are dependent upon several proteins, the most important of which is a proteincalled “tau”.

When tau is abnormally phosphorylated, it forms the paired helical filaments known asneurofibrillary tangles. Why this abnormal phosphorylation occurs is unknown, but the loss ofmicrotubule transport is particularly damaging in neurons that produce and release large amountsof neurotransmitters.

The large pyramidal neurons of the cortex and the forebrain (acetylcholine neurons amongothers) that are important for cognition have more microtubules than other neurons. These largeneurons also have the most neurofibrillary tangles in Alzheimer’s disease. This may explain thedecreases in cognitive ability that characterize Alzheimer’s disease.

Lipofuscin

Lipofuscin (age pigments) also accumulate in neurons and other cells as we age. Although muchdiscussion has ensued as to whether lipofuscin is involved in the pathogenesis of Alzheimer’sdisease, few neurologists today believe it is a central factor.

Free Radical Damage

Free radical damage (oxidative stress) is probably the most significant cause of biologic aging. Itis well-known that neurons are extremely sensitive to attacks by destructive free radicals. Thefollowing evidence supports the hypothesis of free-radical damage being a central cause inAlzheimer’s disease: (Christen 2000)

The brain lesions present in the brains of Alzhemier’s disease patients aretypically associated with attacks by free radicals (for example, damage to DNA,protein oxidation, lipid peroxidation, and advanced glycosylation end products)

Metals (such as iron, copper, zinc, and aluminum) are often present. These metalshave a catalytic activity which produces free radicals.

Beta-amyloid is aggregated and produces more free radicals in the presence offree radicals.

Beta-amyloid toxicity is eliminated by free radical scavengers.

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Apolipoprotein E is subject to attacks by free radicals, and apolipoprotein Eperoxidation has been correlated with Alzheimer’s disease. In contrast,apolipoprotein E can act as a free radical scavenger.

Alzheimer’s disease has been linked to mitochondrial anomalies affectingcytochrome-c oxidase. These anomalies may contribute to the abnormalproduction of free radicals.

Free radical scavengers (such as vitamin E, selegeline, and ginkgo biloba extract)have produced promising results in Alzheimer’s disease.

Inflammation

In Alzheimer’s disease, an inflammatory cascade begins in response to beta-amyloid. Theinflammatory response, involving cytokines and prostaglandins, occurs around beta-amyloid inthe neuron. This inflammatory process continues and accelerates the loss of neurons.

Inflammation is a protective response of the body that occurs during the process of repair. Thefour cardinal signs of inflammation are redness, swelling, heat and pain. The Russian biologistElie Metchnikoff, proposed that the purpose of inflammation was to bring phagocytotic cells tothe injured area in order to engulf invading bacteria. Both Metchnikoff and Paul Ehrlich (whodeveloped the humoral theory of immunity) shared the Nobel Prize in 1908.

Alterations in blood flow occur with inflammation, primarily to increase local circulation andspeed repair. The blood vessels become more permeable which allows protein-rich fluid(exudate) to collect between cells. This excess extravascular fluid is called edema.

The mechanism of inflammation is a complex interaction of chemical messangers. Arachadonicacid, via 5-lipoxygenase, forms leukotrienes that cause vasoconstriction, bronchospasm (i.e.,asthma), and increased permeability. Alternatively, arachadonic acid can form, viacyclooxygenase, prostaglandins which have similar actions and cause pain. Aspirin andindomethican inhibit cyclooxygenase which results in pain relief, but does not address theunderlying cause of the inflammation, or stop the actions of the leukotrienes.

Inflammation can be acute, as occurs after a physical injury, or chronic. There are several causesof chronic inflammation, including:

Persistent infections

Prolonged exposure to toxic elements

Autoimmune disease

Inflammation is considered to be an underlying cause of Alzheimer’s disease, primarily becauseamyloid-beta is an inflammatory protein. (Hull 1996; McGeer 1999)

C-reactive protein is a marker of inflammation that is associated with Alzheimer’s disease.(Iwamoto 1994)

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Advanced Glycation End Products

Glycation is a process central to aging. Advanced glycation end products (AGEs) are formedwhen glucose binds tightly to protein (the Maillard reaction) forming abnormal (glycated)complexes that progressively damage tissue elasticity. This process causes an increased stiffnessin the cardiovascular system leading to high blood pressure. Researchers are proposing thatAGEs may be part of Alzheimer’s disease and present the following evidence to support thishypothesis:

AGEs have been found in the neurofibrillary tangles of Alzheimer’s disease.

Polymerization of beta-amyloid peptide is significantly accelerated by cross-linking through AGEs in vitro.

Since lipofuscin is composed of protein and carbohydrate, glycation may beinvolved in lipofuscin formation more than oxidative stress or inflammation.

The inflammatory process is thought to be more important in the progression of neuronal damageeventually resulting in Alzheimer’s disease. Because of this, researchers are proposing thatAGEs may be a major contributor to the pathogenesis of Alzheimer’s disease. (Thome,Kornhuber et al. 1996; Munch, Mayer et al. 1997)

Aluminum Toxicity

The relevance of aluminum as a cause of Alzheimer’s disease is hotly debated. No mention of itis found in recent medical texts, although it is given considerable attention in books by holisticdoctors and naturopathic physicians. (Pizzorno and Murray 1995; Perlmutter 2000)

The hypothesis that aluminum is a cause of (or a risk factor in) the development of beta-amyloidplaques and neurofibrillary tangles and dementia in Alzheimer’s disease is based on studiesconducted in 1965 which showed that injection of experimental animals with aluminumcompounds induces the formation of neurofibrillary tangles. (Wisniewski and Wen 1992)Although aluminum has been found to concentrate in the senile plaques of Alzheimer’s patients,it has not been found to be consistently elevated in the brain or spinal fluid. (McDermott, Smithet al. 1979)

An article published in the journal Neurology found an astounding 250% increase risk ofAlzheimer’s disease in people drinking municipal water with high levels of aluminum for 10years or more. (McLachlan, Bergeron et al. 1996)

Aluminum has been found to inhibit choline transport and reduce neuronal cholineacetyltransferase. This may contribute to the acetylcholine deficiency, which is a key componentof Alzheimer’s disease. (King 1984)

A study published in the journal Lancet, used desferrioxamine, a chelator of aluminum, to treatAlzheimer’s patients. Desferrioxamine treatment led to significant reduction in the rate ofdecline of daily living skills. The mean rate of decline was twice as rapid for the no-treatmentgroup. (Crapper McLachlan, Dalton et al. 1991)

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Homocysteine

Homocysteine is an amino acid produced during protein digestion. It is now recognized as acritical risk factor for coronary artery disease and stroke. Elevated homocysteine levels in theblood dramatically increase the production of atheromatous plaques (a mixture of fat andcalcified inflammatory tissue that narrows and eventually blocks arteries.) Homocysteine levelsreflect the levels of vitamin B6, B12, and folic acid.

Homocysteine has been proposed as a marker for the early detection of cognitive impairment inthe elderly with the focus on Alzheimer’s disease. Several studies have found elevatedhomocysteine levels in Alzheimer’s patients. (Gottfries, Lehmann et al. 1998; McCaddon,Davies et al. 1998; Lehmann, Gottfries et al. 1999; Leblhuber, Walli et al. 2000; McCaddon,Hudson et al. 2001)

In a case-control study of 76 patients diagnosed with Alzheimer’s disease and 108 controls,serum homocysteine levels were found to be significantly higher and serum folate and vitaminB12 levels were lower in patients with Alzheimer’s disease. (Clarke, Smith et al. 1998)

A study of 52 patients with Alzheimer’s disease, 50 non-demented hospitalized controls, and 49healthy elderly subjects living at home found that patients with Alzheimer’s disease had thehighest serum methylmalonic acid and total homocysteine levels. The study also found, however,that the folate and B12 levels did not correlate between the three groups. (Joosten, Lesaffre et al.1997)

In a recent case-control study of 164 patients with clinically diagnosed Alzheimer’s diseaseincluding 76 patients with the diagnosis confirmed postmortem, mean total serum homocysteineconcentrations were found to be significantly higher than that of a control group of elderlyindividuals with no evidence of cognitive impairment.(Miller 1999)

Biopterin

Tetrahydrobiopterin is the cofactor in the hydroxylation of phenylalanine, tyrosine, andtryptophan leading to the eventual synthesis of the monoaminergic neurotransmitters, dopamine,norepinephrine, and serotonin.

A comparative study of the cerebrospinal fluid (CSF) and plasma of 30 patients withAlzheimer’s disease and of 19 healthy controls showed that the mean CSF biopterinconcentration in patients with Alzheimer’s disease was significantly less than in age-matchedcontrols. (Kay, Milstien et al. 1986)

A study of four patients with Alzheimer’s disease showed significantly reduced activity oftyrosine hydroxylase and tryptophan hydroxylase, and significantly reduced concentrations oftotal biopterin in the putamen and substantia nigra, although the total neopterin concentrationsdid not change significantly. (Sawada, Hirata et al. 1987)

5-Methyltetrahydrofolate and vitamin B12 appear to be required for the biosynthesis oftetrahydrobiopterin. Patients with senile dementia could possibly be benefited by theadministration of 5-methyltetrahydrofolate.(Hamon, Blair et al. 1986)

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Nutrition

Cobalamin (vitamin B12) deficiency is common in the elderly. Some authors propose thatcobalamin deficiency is a risk factor for Alzheimer’s disease. (Regland, Blennow et al. 1999)

A Japanese study of 64 patients with Alzheimer’s disease and 80 age-matched healthy adultsfound that the dietary behaviors of Alzheimer’s disease patients were markedly different. TheAlzheimer’s disease patients tended to dislike fish and green-yellow vegetables and took moremeats than controls. Nutrient analysis revealed that Alzheimer’s disease patients took lessvitamin C and carotene, and consumed significantly smaller amounts of omega-3polyunsaturated fatty acids (PUFAs) reflecting the low consumption of fish. These habits startedfrom 3 months to 44 years before the onset of dementia, suggesting these dietary abnormalitiesare not merely the consequence of dementia. (Otsuka 2000)

A study published in the journal Neuroepidemiology investigated the relationship betweenanimal product consumption and evidence of dementia in two cohort studies of 272 and 2,984subjects in California. The matched subjects who ate meat (including poultry and fish) weremore than twice as likely to become demented in comparison to their vegetarian counterparts(relative risk 2.18, p = 0.065). The discrepancy was further widened (relative risk 2.99, p =0.048) when past meat consumption was taken into account. (Giem, Beeson et al. 1993)

A study of 5,386 non-demented people found that high intakes of total fat, saturated fat, andcholesterol were associated with an increased risk of dementia. Fish consumption was inverselyrelated to the incidence of dementia and Alzheimer’s disease. (Kalmijn, Launer et al. 1997)

Genetics

Several forms of Alzheimer’s disease are genetic or inherited. These inherited forms are usuallyassociated with early-onset Alzheimer’s that occurs before the age of 50, and as early as 30. Lessthan 10% of all Alzheimer’s disease is on a genetic basis. These inherited forms have beenstudied in the families in which they have occurred and also in Downs’s syndrome (trisomy 21).All of these mutations, including the apolipoprotein E alleles, involve the metabolism of beta-amyloid in some way. So, even in the genetic forms, beta-amyloid remains central to thedevelopment of the disease.

Chromosome sites that have been implicated in Alzheimer’s disease include chromosome 21,19q, 12 and 1. Of the genetic types, the two most common are apolipoprotein E e4 allele andalpha-2-macroglobulin mutation. All the genetic types are inherited as autosomal dominantsexcept for apolipoprotein E e4 allele, in which each dose of the allele increases the risk fordeveloping the disease.

There are several families in which Alzheimer’s disease is very common. These includemutations of amyloid precursor protein, presenilin 1 or presenilin 2. One of the most extensivelystudied of these families is the Volga-German family. There have been multiple mutationsidentified involving these three proteins. They all lead to early-onset Alzheimer’s disease.

The genetic basis of Alzheimer’s was first studied in Downs’s syndrome which contains 3 copiesof chromosome 21 (trisomy 21). Recent research indicates myoinositol levels are related to

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chromosome 21. Pre-dementia levels of myoinositol are higher in Down’s syndrome and riseeven higher as dementia develops. (Huang, Alexander et al. 1999)

Apolipoprotein E

Late-onset Alzheimer’s is associated with the apolipoprotein E e4 allele. In persons homozygousfor the e4 allele, Alzheimer’s disease occurs 10 to 20 years earlier than in the general population.Persons having a double dose of the e4 allele (homozygous) have the most increased risk andthose having a single dose (heterozygous) have some increased risk. Heterozygotes (a singledose of the e4 allele) develop Alzheimer’s disease 5 to 10 years earlier than the generalpopulation. The other 2 alleles possible are e2 and e3, with e3 being the most common. Thealleles of apolipoprotein E vary in their affinity for beta-amyloid with e4 causing the mostproblems. The e4 allele increases its deposition and beta-pleated sheets of amyloid are seen.

The genetic test for apolipoprotein E alleles is easy to obtain. If you obtain this test and have oneor two copies of e4 allele, remember that this is not a guarantee you will develop Alzheimer’s,although it does increase your risk. Routine testing for e4 is not usually recommended because itis not causative or predictive of the occurrence of disease. However, if you know you arepositive for e4 allele, you would certainly want to institute aggressive preventive measures fordementia.

Alpha2-Macroglobulin

Alpha2-macroglobulin is another component of the senile plaque, along with beta-amyloid andother substances. Mutations here also increase the risk for developing Alzheimer’s disease. Thefrequency of occurrence of this mutation is somewhat less than for apolipoprotein E.

LDL Receptors

Mutations involving the LDL receptor (low density lipoprotein receptor) may also be important.This receptor binds both apolipoprotein E and alpha2-macroglobulin. LDL is a type of lipid orcholesterol, and cells, including neurons, contain receptor binding sites for LDL.

Conventional Treatment

At present, there is no true prevention for Alzheimer’s in conventional medicine but there areways to decrease the risk for developing the disease and also, possibly, slow the progression.Treatments include:

• Anti-cholinesterase inhibitors (such as tacrine and donepezil)

• Anti-inflammatories (NSAIDs and Cox-2 inhibitors)

• Estrogen replacement therapy

These various treatments target the pathways involved in the development of Alzheimer’sdisease. These pathways include oxidative stress, inflammation, estrogen hormone status,production of beta-amyloid, apolipoprotein E status, and cholinergic neuron depletion (withresulting decrease in acetylcholine levels). These are all possible avenues for treatment now or inthe future. At present, treatment, at best, slows progression of the disease. Future research will

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concentrate on slowing disease progression as well as lessening the burden on caregivers viapatient improvement. Following is a list of therapies from the medical literature that have beentried in the treatment of Alzheimer’s disease.

Acetylcholinesterase Inhibitors

Drug treatment with the acetylcholinesterase inhibitors (such as tacrine, donepizil, metrifonateand rivastigmine) is now begun after the disease has actually developed. This class of drugsincreases the amount of neurotransmitter acetylcholine at the nerve terminal by decreasing itsbreakdown by the enzyme cholinesterase. Remember that in Alzheimer’s disease the levels ofmultiple neurotransmitters, but especially acetylcholine, are decreased markedly. This loss ofacetylcholine occurs mainly in the cortical areas of the brain.

Acetylcholinesterase inhibitors have been shown to modestly improve memory and language anddecrease the emotional symptoms of apathy, anxiety, hallucinations, inappropriate behavior, andabnormal movement. None of these medications reverses the process and none is curative. Themost that can be hoped for at this point is some improvement in symptoms. These drugs arebegun after the disease has been diagnosed. Therefore, patients and their families should haverealistic expectations with these drugs and not expect dramatic improvement or a reversal of thedisease process. Less than half of patients show any benefit at all from acetylcholinesteraseinhibitors, even when there are no side effects.

DONEPEZIL

Donepezil (Aricept) is given for mild to moderate Alzheimer’s disease at a dose of 5 mg orally atbedtime for 6 weeks and then increased to a dose of 10 mg at bedtime if tolerated. Nausea anddiarrhea are the most common side effects. In patients with prior abnormally slow heart rate,asthma, or ulcer disease, a worsening of these processes can occur and should be watched for.However, their presence prior to treatment does not prevent the use of acetylcholinesteraseinhibitors.

A clinical trial with donepezil at 5 or 10 mg/day showed a 3.1 point ADAS-Cog improvement,with only 12% dropping out due to side effects. Patients on donepezil remain in a nonseveredisease state for a longer time. (Foster and Plosker 1999)

An article published in the French journal Encephale described the first large-scale study ofdonepezil at a daily dosage of 5 to 10 mg conducted over 14 weeks. The results show asignificant improvement in cognitive function in the treatment groups, compared to the placebogroups. The difference emerged after 3 weeks of treatment, lasted throughout the 12 weeks of thestudy, and was still very marked 3 weeks post-treatment discontinuation. The results of a secondstudy conducted over 30 weeks were similar. (Robert, Gokalsing et al. 1999)

Phase II clinical trials of donepezil have demonstrated that donepezil improves cognition, globalfunction, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, weregenerally mild in intensity, transient, and resolved during continued treatment with donepezil.(Doody 1999)

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A recent review of the clinical trials, however, concluded that donepezil produced only modestimprovements in cognitive function and that study clinicians had rated global clinical state morepositively in treated patients. Further, in two of the four studies, the patient's own rating of theirquality of life showed no benefit of donepezil compared with placebo. A variety of adverseeffects were recorded, with more incidents of nausea, vomiting, diarrhea, and anorexia in the 10mg per day group compared with placebo and the 5 mg per day group. (Birks, Melzer et al.2000)

TACRINE

Tacrine (Cognex) is another acetylcholinesterase inhibitor, although possible liver toxicity makesdonepezil the first choice.

Patients receiving 160 mg per day of tacrine in a 30-week double-blind, placebo-controlled studyshowed an ADAS-Cog improvement of 4.1 points if they completed the trial. But only 27% ofthe patients completed the trial, mostly because tacrine is so toxic to the liver and causes severeside effects. (Birks, Melzer et al. 2000)

Estrogen Replacement Therapy

Estrogen replacement therapy (ERT) is useful both in preventing Alzheimer’s disease as well asin treatment.

Studies of 2,529 women in the Leisure World Retirement Community cohort, 472 women in theBaltimore Longitudinal Study of Aging, and 1,124 women in a Manhattan cohort showed a 30%,50%, and 60% lower risk, respectively, for Alzheimer’s disease among postmenopausal womentaking estrogen-replacement therapy over those who were not. (Paganini-Hill and Henderson1994; Stern, Gurland et al. 1994; Paganini-Hill and Henderson 1996)

Animal experiments show that surgical removal of the ovaries can reduce choline uptake in thefrontal cortex and hippocampus by 24% and 34%, and cause a 45% decline in mRNA for NerveGrowth Factor (NGF) in the frontal cortex. Estrogen replacement reverses most of these effects.

Estrogen is an excellent neuroprotective agent and functions in a variety of ways, includingantioxidant mechanisms (decreasing oxidative stress), protection against toxicity from beta-amyloid, encouragement of neuronal dentritic growth, increasing Nerve Growth Factor (NGF),stimulation of neuronal axonal sprouting, and modulation of apolipoprotein E (ApoE)expression. All of these pathways involve the development of Alzheimer’s disease. (Yaffe,Sawaya et al. 1998)

Risks of estrogen replacement therapy include increased risk of carcinoma of the breast,development of blood clots in the legs or lungs (with oral estrogen only and not transdermal orpellets). Benefits additional to treating and preventing Alzheimer’s disease with estrogen includedecreased cardiovascular risk, longer lifespan, decreased osteoporosis risk, and decreased risk ofother cancers such as lymphoma and colon cancer. ERT, at present, is not available for men; but,in the future, trials with less feminizing agents (as 17-alpha-estradiol) may be considered.

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Anti-Inflammatory Drugs

NSAIDS

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) include drugs like aspirin, indomethicin(Indocin), ibuprofen (Motrin, Advil), relafen, and others. They all modulate inflammatorypathways but by a chemical mechanism slightly different from the Cox-2 inhibitors.

Recent research into the mechanism of NSAID use in Alzheimer’s disease found that it is morelikely to be through the suppression of microglial activity than by inhibiting the formation ofsenile plaques or neurofibrillary tangles. (Mackenzie and Munoz 1998)

A 50% reduction in risk against Alzheimer’s disease is seen in elderly arthritic patients who havebeen taking NSAIDs such as ibuprofen and indomethicin. Aspirin, however, was only effectivein dosages over 2.4 grams per day.

A clinical trial of 100 to 150 mg per day of indomethicin for 6 months resulted in a 14-pointADAS-Cog improvement among the 79% of patients who did not drop out due to gastrointestinalside effects. Inflammation apparently contributes significantly to the final neurodegenerativeprocesses which are initiated by beta-amyloid and neurofibrillary tangles.

In a population study in Cache County, Utah, 201 cases of Alzheimer’s disease and 4,425participants with no indication of cognitive impairment were identified, interviewed, and theirmedicine chest assessed. Compared with cognitively intact individuals, the AD cases hadsignificantly less reported current use of NSAIDs, aspirin, and histamine H2 receptorantagonists. (Anthony, Breitner et al. 2000)

A longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging,examined whether the risk of Alzheimer’s disease was reduced among reported users of aspirinor other nonsteroidal anti-inflammatory drugs (NSAIDs). The study found a decreased riskamong those with 2 or more years of NSAID use (relative risk = .40) compared with those withless than 2 years of use (relative risk = .65). Aspirin use did not decrease the risk (relative risk =.74), nor did acetaminophen (relative risk = 1.35). (Stewart, Kawas et al. 1997)

IBUPROFEN

Ibuprofen was used in a recent study of transgenic mice displaying widespread microglialactivation, age-related amyloid deposits, and dystrophic neurites. These mice were created byoverexpressing a variant of the amyloid precursor protein found in familial AD. Treatment withibuprofen produced significant reductions in interleukin-1beta and in the number and total areaof beta-amyloid deposits. (Lim, Yang et al. 2000)

COX-2 INHIBITORS

These are also anti-inflammatory drugs that decrease inflammation by a pathway different fromNSAIDs. They include medications like Celebrex. They have been shown to markedly decreasethe chemicals causing inflammation. These and the NSAIDs block the free radical attack onbrain tissue mediated by inflammation. (Scali, Prosperi et al. 2000)

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New Drug Research

Acetylcholinesterase Inhibitors

RIVASTIGMINE

Rivastigmine is an acetylcholinesterase inhibitor that has not yet been approved for use by theFDA. It has been found to be equally as effective as donepezil with comparable side effects, butthe ADAS-Cog improvement is 4.9 compared to 3.1 with donepezil. (Birks, Grimley Evans et al.2000; Wettstein 2000)

METRIFONATE

Metrifonate is an acetylcholinesterase inhibitor, not yet approved by the FDA, with research dataindicating it is equally effective to donepezil. Metrifonate has shown a 2.8 point ADAS-Cogimprovement, with very few side effects. Clinical trials with higher doses of metrifonate areunderway. (Wettstein 2000)

MAO-B Inhibitors

SELEGILENE

Selegilene (Eldepryl or Deprenyl) ia a drug approved for use in Parkinson’s disease thatirreversibly inhibits monoamine oxidase type B (MAO-B). Monoamine oxidase is an enzymethat inactivates the monoamine neurotransmitters norepinephrine, serotonin and dopamine.Selegilene is degraded in the liver into desmethyldeprenyl (the major metabolite), amphetamine,and methamphetamine which are eliminated in the urine. Side effects include nausea,hallucinations, confusion, dizziness, depression, agitation, and tremors.

In a study using vitamin E, selegilene, or both in Alzheimer’s disease, there was a modestimprovement in symptoms. (Sano, Ernesto et al. 1997)

In the Czech and Slovak Alzheimer’s disease Study Group using several well-acceptedmeasurements of mental function (including MMSE, Sternberg’s Memory Scanning Test, andothers), Selegilene had a long-term helpful effect on memory in mild to moderate Alzheimer’sdisease. This was thought to be due to selegilene’s effect on dopamine-rich prefrontal brainareas. (Filip and Kolibas 1999)

However, selegilene also has anti-apoptotic actions which may be helpful in Alzheimer’s diseasewhere cell death is important. Remember, apoptosis is the process of programmed cell death thatoccurs when cells are damaged. Apoptosis plays a role in the death of neurons in Alzheimer’sdisease as it does in all types of cell death. Limiting or reducing cell death in Alzheimer’s mayhelp prolong the life of needed neurons and possibly slow the disease process. (Gelowitz andPaterson 1999) (Suuronen, Kolehmainen et al. 2000)

Another study showed that selegilene protected cells from toxic effects of beta-amyloid.(Thomas 2000)

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Selegilene was shown to significantly increase the number of branching points and intersectionsin both apical and basal dendrites in deprenyl-treated monkeys compared to controls. The authorsof the study proposed that this may be the mechanism responsible for the enhancement ofcognitive functions in Alzheimer’s disease patients following deprenyl treatment.(Shankaranarayana Rao, Lakshmana et al. 1999)

A recent article suggested that stimulation of nitric oxide production could be central to theaction of selegilene. Deprenyl stimulates vasodilation and increases nitric oxide production inbrain tissue and cerebral blood vessels. Because nitric oxide modulates activities includingcerebral blood flow and memory, and reduced nitric oxide production has been observed in theAlzheimer’s disease brain, stimulation of nitric oxide production by deprenyl could contribute tothe enhancement of cognitive function in Alzheimer’s disease. (Thomas 2000)

Recent studies in rats show that the combination of selegilene with tacrine was remarkedly moreeffective than either agent alone. (Dringenberg, Laporte et al. 2000)

Nerve Growth Factor

Supplementing or increasing Nerve Growth Factor (NGF) may stimulate neuronal cell growth.This is an area of research, although no large trials have yet been done. (Gustilo, Markowska etal. 1999)

Secretase Inhibitors

Secretase inhibitors are an area of future research. These substances decrease levels of beta-amyloid by affecting its cleavage and metabolism. (Martin 1999)

Nicotine

Nicotine causes acetylcholine transmitter release and, therefore, is theoretically of benefit inAlzheimer’s disease with its decrease in acetylcholine levels. Some, but not all, studies haveshown a reduced incidence of Alzheimer’s disease among light smokers (fewer than 10cigarettes per day), but an increased incidence of the disease among heavy smokers (more than20 cigarettes per day).

A pilot study with six patients using nicotine patches (to avoid the effects of the other toxicchemicals in cigarette smoke) showed some improvement in a learning task, but no effect onglobal cognition or short-term memory. The scientific studies, however, are not conclusive.(Lopez-Arrieta, Rodriguez et al. 2001)

METANICOTINE

Metanicotine is less toxic than nicotine and causes nearly the same acetylcholine release.Metanicotine is currently under clinical studies for use in Alzheimer’s disease. (Park, Jang et al.2000)

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Vaccines

Although vaccine trials in rodents are promising and this work shows decreased behavioraleffects and brain damage from beta-amyloid with the vaccine, a usable human vaccine is notlikely in the near future. (Chapman 2000)

Innovative Drug Strategies

Hydergine

Hydergine (Ergoloid mesylates) is used in Europe for Alzheimer’s disease and other forms ofdementia. It acts as a mild vasodilator.

A meta-analysis of studies using Hydergine showed modest improvement for Alzheimer’ssymptoms, but only in dosages of 4 to 9 mg/day, rather than the typical dose of 3 mg/day.Hydergine increased the number of neuronal synapses and the plasticity of synaptic junctions ina rat study. However, when the dose is translated to human equivalents, about 2000 mg/daywould be required and has never been used in humans. (Bertoni-Freddari, Giuli et al. 1987)

In another study, Hydergine decreased hypoxia (a lack of oxygen) in the early stages ofAlzheimer’s disease but not in the late stages. In a PET scan analysis in multi-infarct dementia(not Alzheimer’s patients) and at a dose of 2.4 mg/day, Hydergine showed an improvement onthe PET scans. (Nagasawa, Kogure et al. 1990)

A recent meta-analysis of the published research on hydergine found significant treatment effectsin 13 of the trials that met the selection criteria. The overall review was very positive, despite thesmall number of trials. (Olin, Schneider et al. 2000)

Piracetam

Piracetam is a derivative of gamma-aminobutyric acid (GABA) that has been used in Europeancountries for the treatment of memory loss and other cognitive defects.

Several articles have explored the mechanism of piracetam. One study found that piracetam hadbeneficial effects on the fluidity of membranes from the hippocampus of Alzheimer’s diseasepatients. (Eckert, Cairns et al. 1999) Researchers have proposed that the mechanism of piracetamis due to it’s ability to alter the properties of cell membranes in the brain. (Muller, Eckert et al.1999)

A Phase IV study of piracetam in Hungary was conducted on 104 patients with cognitive declinefrom Alzheimer’s disease and/or cerebrovascular origin. Nearly all of the five factors of themodified Mini-Mental State Examination significantly increased, especially the factors ofmemory, and concentration-psychomotor speed. Despite this, statistical analysis of the resultsfound no relevant difference between the treatment and control groups. The degree of cognitiveimprovement was most pronounced in patients with depressive symptoms. (Tariska and Paksy2000)

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Memantine

Memantine is a derivative of an old anti-influenza drug, Amantidine, that has been used for thetreatment of dementia in Germany for more than twenty years. Memantine is a non-competitiveNMDA (N-methyl-D-aspartate) antagonist that blocks the action of glutamate, which can over-stimulate the nervous system and become toxic to nerve cells. Memantine has yet to be approvedby the FDA. (Kornhuber, Weller et al. 1994; Jain 2000)

Memantine was used to treat patients with moderately severe to severe primary dementia (49%of the Alzheimer type and in 51% of the vascular type) in a recent study published in theInternational journal Geriatric Psychiatry. 82 patients received 10 mg per day of memantine, and84 received a placebo. A positive response in the Clinical Global Impression of Change (CGI-C)was seen in 73% of those taking memantine, versus 45% for the placebo group, independent ofthe etiology of dementia. The results in the Behavioural Rating Scale for Geriatric Patients(BGP) subscore 'care dependence' were 3.1 points improvement under memantine and 1.1 pointsunder placebo. (Winblad and Poritis 1999)

Nefiracetam

One of the features of the Alzheimer brain is a loss of nicotinic acetylcholine receptors.Researchers have proposed that Nefiracetam may be useful in Alzheimer’s disease due to it’sability to stimulate nicotinic acetylcholine receptors. (Nishizaki, Matsuoka et al. 2000)

Nimodipine

Nimodipine, a calcium channel blocker, was found to be superior to placebo and Hydergine inOrganic Brain Syndrome. However, Alzheimer’s disease was not differentiated from the otherforms of dementia in this study. (Grobe-Einsler 1993)

Aminoguanidine

Aminoguanidine could be of value in reducing AGEs (Age-associated Glycosylation End-products) in Alzheimer’s disease. This therapy has shown some promise in small, isolatedstudies, but requires large clinical trials if merit is to be established with certainty. (Ramamurthy,P et al. 1999)

Innovative Surgery

Dr. Harry S. Goldsmith has developed a revolutionary surgical technique for the treatment ofAlzheimer’s disease. The technique that involves placing a part of the body called the“omentum” directly on the brain. The omentum is a layer of fat and blood vessels that cover theintestines. The omentum has several key factors that make this technique useful. It provokesangiogenesis (new blood vessel growth) and increases choline acetyltransferase, the enzymeresponsible for creating acetylcholine. (Goldsmith, Chen et al. 1973; Goldsmith, Griffith et al.1984; Goldsmith and Steward 1984; Goldsmith 1985; Goldsmith, McIntosh et al. 1987)

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Alternative Treatments

Acetylcholine Support

PHOSPHATIDYLCHOLINE (LECITHIN )

Lecithin (phosphatidylcholine) has a long history of use with Alzheimer’s disease.Phosphatidylcholine is a source of choline, the major component of acetylcholine, which isneeded for cell membrane integrity and to facilitate the movement of fats in and out of cells.

When given to animals, lecithin causes increased acetylcholine levels. Clinical trials, however,failed to show actual improvement. Alzheimer’s disease and other dementias do show increasedcholine levels which may indicate inadequate metabolism. Therefore, simply supplementing thelecithin would not necessarily help the metabolic defect in the cellular use ofphosphatidylcholine. (Peters and Levin 1979; Thal, Fuld et al. 1983; Little, Levy et al. 1985;Blusztajn, Liscovitch et al. 1987; Fitten, Perryman et al. 1990)

A recent review article analyzed 12 clinical trials using lecithin to treat Alzheimer’s disease (265patients), Parkinsonian dementia (21 patients), and subjective memory problems (90 patients).No trial reported any clear clinical benefit of lecithin for Alzheimer’s disease or Parkinsoniandementia. A dramatic result in favor of lecithin was obtained, however, in a trial of subjects withsubjective memory problems. (Higgins and Flicker 2000)

PANTOTHENIC ACID

The body uses choline and pantothenic acid (vitamin B5) to form acetylcholine. Pantothenic acidis also needed to produce, transport and release energy from fats.

Antioxidants

Oxidative stress is very important in the development of Alzheimer’s disease. Anti-oxidantsupplements help block this process.

“Beta-amyloid is aggregated and produces more free radicals in the presence of free radicals;beta-amyloid toxicity is eliminated by free radical scavengers.” (Grundman 2000; Grundman2000)

VITAMIN E

Researchers have shown that cultured cells are prevented from beta-amyloid toxicity with theaddition of vitamin E. (Grundman 2000)

Researchers at the University of Kentucky published a ground-breaking article showing thatvitamin E prevented the increase of polyamine metabolism in response to free radical mediatedoxidative stress caused by the addition of beta-amyloid to the rat neurons. (Yatin, Yatin et al.1999)

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Research conducted in Germany showed that both natural and synthetic vitamin E were moreeffective than estrogen (17-beta estradiol) in protecting neurons against oxidative death causedby beta-amyloid, hydrogen peroxide, and the excitatory amino acid glutamate. (Behl 2000)

Research conducted at the University of California, San Diego, School of Medicine studied theprotective effects of vitamin E in apolipoprotein E-deficient mice. Those treated with vitamin Edisplayed a significantly improved behavioral performance in the Morris water maze. Also, theuntreated mice displayed increased levels of lipid peroxidation and glutathione, whereas thevitamin E-treated mice showed near normal levels of both lipid peroxidation and glutathione.(Veinbergs, Mallory et al. 2000)

A study of 44 patients with Alzheimer’s disease and 37 matched controls showed that vitamin Elevels in the cerebral spinal fluid (CSF) and serum were significantly lower in Alzheimer’spatients. (Jimenez-Jimenez, de Bustos et al. 1997)

In the Alzheimer’s disease Cooperative Study, 2000 mg of vitamin E were given to Alzheimer’sdisease patients. This slowed the functional deterioration leading to nursing home placement.(Grundman 2000)

An article published in the New England Journal of Medicine described a double-blind, placebo-controlled, randomized, multi-center trial of patients with Alzheimer’s disease of moderateseverity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline(10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The baseline score on the Mini-Mental State Examinationwas higher in the placebo group than in the other three groups. Both vitamin E and segelinedelayed the progression of the disease with vitamin E acting slightly better than segeline (mediantime 670 vs. 655 days respectively.) (Sano, Ernesto et al. 1997)

A recent review of the published research on vitamin E for Alzheimer’s disease stated that,although there is insufficient evidence of efficacy of vitamin E, there is sufficient evidence ofpossible benefit to justify further studies. (Tabet, Birks et al. 2000) Researchers are suggestingthat the combination of vitamin E and donepezil be a current standard of Alzheimer’s diseasetherapy. (Doody 1999)

GINKGO BILOBA

Ginkgo biloba is the world’s oldest living tree. It has been traditionally used for improvingmemory and Alzheimer’s disease. It is a powerful antioxidant and also functions as a mildvasodilator (improves circulation), anti-inflammatory (via antioxidant effects), membraneprotector, anti-platelet agent and neurotransmitter modulator. (Perry, Pickering et al. 1999;Diamond, Shiflett et al. 2000)

Ginkgo was shown to protect neurons against toxicity induced by beta-amyloid fragments, with amaximal and complete protection at the highest concentration tested. Ginkgo also completelyblocked beta-amyloid-induced events, such as reactive oxygen species accumulation andapoptosis (cellular death). (Bastianetto, Ramassamy et al. 2000; Yao, Drieu et al. 2001)

A study of the effects of bilobalide, the main constituent of the non-flavone fraction of ginkgobiloba, provided the first direct evidence that bilobalide can protect neurons against oxidative

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stress. Bilobalide may block the apoptosis in the early stage and then attenuate the elevation of c-Myc, p53, and Bax genes and activation of caspase-3 in cells. (Zhou and Zhu 2000)

An article published in the journal Brain Research showed that pretreatment of nerve cells withisolated ginkgolides, the anti-oxidant component of ginkgo biloba leaves, or vitamin E,prevented the beta-amyloid-induced increase of reactive oxygen species (ROS). Ginkgolides, butnot vitamin E, inhibited the beta-amyloid-induced HNE (4-hydroxy-2-nonenal) modification ofmitochondrial proteins. (Yao, Drieu et al. 1999)

A 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multi-center study ofginkgo biloba at a dose of 120 mg (40 mg three times a day) was conducted and published in2000. The placebo group showed a statistically significant worsening in all domains ofassessment, while the group receiving ginkgo biloba was considered slightly improved on thecognitive assessment and the daily living and social behavior. No differences in safety betweenginkgo biloba and placebo were observed. (Le Bars, Kieser et al. 2000)

A similar 52-week, randomized double-blind, placebo-controlled, parallel-group, multi-centerstudy of ginkgo biloba by the same research team was published in 1997. The group treated withginkgo biloba had an ADAS-Cog score 1.4 points better than the placebo group (p=.04) and aGeriatric Evaluation by Relative's Rating Instrument (GERRI) score 0.14 points better than theplacebo group (p=.004). (Le Bars, Katz et al. 1997)

In an analysis of various studies and as measured by the ADAS-Cog, the 4 anti-cholinesterasesand ginkgo were equally effective in mild to moderate Alzheimer’s disease. Tacrine had a highdrop-out rate due to side effects. Most studies showed benefit from ginkgo but one did not. (vanDongen, van Rossum et al. 2000)

Extracts of ginkgo contain different amounts of the various active substances and are also ofvariable quality. A high-quality product, such as those made by Life Extension Foundation, isrecommended. (Kidd 1999)

VITAMIN C

An article published in the International journal Geriatric Psychiatry described a study ofAlzheimer’s disease patients in the region of Toulouse, France. Plasma vitamin E and C levelswere measured and consumption of raw and cooked fruit and vegetables was evaluated in orderto determine the mean vitamin C intakes. Mini Nutritional Assessment (MNA) and plasmaalbumin were used to measure nutritional status. The hospitalized Alzheimer’s subjects hadlower MNA scores and albumin levels but normal vitamin C intakes, but their plasma vitamin Cwas lower than that of community-living subjects. In the home-living Alzheimer subjects,vitamin C plasma levels decreased in proportion to the severity of the cognitive impairmentdespite similar vitamin C intakes. (Riviere, Birlouez-Aragon et al. 1998)

A prospective study of 633 persons 65 years and older examined the relation between use ofvitamin E and vitamin C and incidence of Alzheimer’s disease. After an average follow-upperiod of 4.3 years, 91 of the participants with vitamin information met accepted criteria for theclinical diagnosis of Alzheimer’s disease. None of the 27 vitamin E supplement users and noneof the 23 vitamin C supplement users had Alzheimer’s disease. There was no relation betweenAlzheimer’s disease and use of multivitamins. (Morris, Beckett et al. 1998)

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A study of ten patients with Alzheimer’s disease showed that one month supplementation of 400IU vitamin E and 1000 mg vitamin C significantly increased the concentration of both vitaminsin the plasma and cerebral spinal fluid. In contrast, supplementation with vitamin E aloneincreased its CSF and plasma concentrations but was unable to decrease lipoproteinoxidizability. (Kontush, Mann et al. 2001)

ACETYL-L-CARNITINE

There are multiple modes of action for acetyl-L-carnitine, including antioxidant effects,molecular chaperone effects, and others.

This agent possibly helps correct the acetylcholine deficit and has been tried in rodents.(Butterworth 2000) Double-blind studies have been done and showed some benefit. (Pettegrew,Levine et al. 2000)

Acetyl-L-carnitine was shown to protect neurons from the detrimental effects of beta-amyloid inthe cortex of rats.(Virmani, Caso et al. 2001)

In humans, a one-year controlled trial in early Alzheimer’s disease measured ADAS-Cog and theClinical Dementia Rating Scale in 229 patients. Acetyl-L-carnitine use slowed the clinicaldeterioration. This study concluded by recommending more research using both acetyl-L-carnitine plus a cholinesterase inhibitor (such as donepezil, tacrine, Rivastigmine orMetrifonate). (Thal, Calvani et al. 2000)

VITAMIN A

A recent study published in the European journal Neurology compared serum levels of beta-carotene and alpha-carotene, and vitamin A of 38 Alzheimer’s disease patients and 42 controls.They found that the serum levels of beta-carotene and vitamin A were significantly lower in theAlzheimer’s disease patient group. (Jimenez-Jimenez, Molina et al. 1999)

COENZYME Q10

CoQ10 is used in the mitochondrial production of energy in the electron transport chain. A rolefor mitochondrial dysfunction in neurodegenerative disease is gaining support. Studies haveimplicated mitochondrial defects in Alzheimer’s disease and use of CoQ10 has been suggestedfor this reason. However, the appropriate clinical studies using CoQ10 have not yet been done.(Beal 1999)

N-ACETYL-CYSTEINE

N-Acetyl-cysteine (NAC) is a precursor of glutathione, a powerful scavenger of free radicals.Glutathione deficiency has been associated with a number of neurodegenerative diseases,including Lou Gehrig’s and Parkinson’s disease.

A recent study showed that NAC significantly increased the glutathione levels and reducedoxidative stress in rodents treated with a known free-radical producer. (Pocernich, La Fontaine etal. 2000)

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NAC has been shown to protect mitochondrial respiration and neuronal microtubule structurefrom the toxic effects of HNE (4-hydroxy-2-nonenal), a reactive aldehyde product of lipidperoxidation. (Neely, Zimmerman et al. 2000)

FLAVONOIDS

A recent study showed that flavonoids have a protective effect on neurons exposed to oxidizedlipids in the form of low-density lipoprotein. (Schroeter, Williams et al. 2000)

NADH

A recent study examined the changed in the expression of genes encoding cytochrome c oxidaseand NADH dehydrogenase in the brains of 10 Alzheimer’s disease patients and 10 age-matchedcontrols. They found a decreased expression of the gene NADH-4 which may lead to a reductionin antioxidant activity of ubiquinone oxidoreductase. (Aksenov, Tucker et al. 1999)

Anti-Inflammatory Supplements

CURCUMIN

Curcumin, the active ingredient in the herb turmeric, is being investigated for use in Alzheimer’sdisease due to it’s potent anti-inflammatory action. (Joe 1997; Grilli 1999)

ESSENTIAL FATTY ACIDS

Essential fatty acids are found in oils including flax, borage, and fish oils. Fish oils contain EPA(eicosapentaenoic acid) and DHA (docosohexanoic acid), both of which are omega-3 oils.Essential fatty acids are important for healthy skin and hair. They also have significant anti-inflammatory action.

It has been proposed that a dietary deficiency of essential fatty acids could be a risk factor forAlzheimer’s disease. (Newman 1992; Newman 2000; Youdim, Martin et al. 2000)

Several small studies have explored the use of essential fatty acids in the treatment ofAlzheimer’s disease and found it to be beneficial. (Corrigan, Van Rhijn et al. 1991; Yehuda,Rabinovtz et al. 1996)

DHA

The neuron is composed of about 30% DHA (docosohexanoic acid), which is an important fattyacid in the neuronal membrane. Most of our DHA comes from fish consumption but also may betaken as a supplement. Low DHA has been found to be a risk factor for development ofAlzheimer’s disease. The decreased levels of DHA in later life could be related to decreasedsynthesis secondary to lower levels of delta 6-desaturase activity. (Horrocks and Yeo 1999;Kyle, Schaefer et al. 1999)

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EPA

A Japanese study found that administration of EPA (900 mg per day) in patients withAlzheimer’s disease improved MMSE significantly with maximal effects at 3 months and theeffects lasted 6 months. However, the score of MMSE decreased after 6 months. (Otsuka 2000)

GLA

Researchers have proposed that fish oils and GLA (gamma linolenic acid) may help preventAlzheimer’s disease by it’s anti-inflammatory effect of suppressing interleukin-1 production bymonocytes. (McCarty 1999)

Homocysteine

VITAMIN B12

Research has shown that low cobalamin (vitamin B12) levels are related to dementias in general.A common cause of cobalamin deficiency in elderly people is protein-bound cobalaminmalabsorption due to atrophic gastritis with hypo- or achlorhydria (low stomach acid). Often,however, the serum B12 levels are normal. The measurement of the metabolites homocysteineand/or methylmalonic acid is recommended as a more accurate assessment of cobalamin status.(Bopp-Kistler, Ruegger-Frey et al. 1999; McCaddon, Hudson et al. 2001)

Lower levels of vitamin B12 (below 200 pg/ml) in the blood are associated with dementiasymptoms. Because of this, and the absence of toxicity with use of vitamin B12, the argumenthas been voiced to raise recommended minimum serum levels of vitamin B12 and also liberallyadminister vitamin B12 to the elderly. “Vitamin B12 could play a role in the behavioral changesin Alzheimer’s disease.” (Eastley, Wilcock et al. 2000)

A study was recently conducted with outpatients at a geriatric memory clinic. Seventy-threeconsecutive outpatients with probable Alzheimer’s disease showed significant inverseassociations between vitamin B12 status and the behavioral and psychological symptoms ofdementia: irritability (p=0.045) and disturbed behavior (p=0.015). Of the 73 participants, 61patients had normal and 12 patients (16%) had subnormal (<200 pg/ml) vitamin B12 levels.(Meins, Muller-Thomsen et al. 2000)

A population-based longitudinal study of 370 nondemented persons, aged 75 years and older,conducted in Sweden found that subjects with low levels of B12 or folate had twice higher risksof developing Alzheimer’s disease over the 3-year period of the study. (Wang, Wahlin et al.2001)

FOLATE

Folate or folic acid derives its name from foliage (green plants). Folacin was first isolated fromspinach and other leafy green vegetables in 1941. Folic acid is needed for DNA synthesis and isalso needed to make SAMe (S-adenosyl methionine).

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A study of 126 patients, including 30 with Alzheimer’s disease, found that the levels of folate inthe cerebral spinal fluid (CSF) were significantly lower in late-onset Alzheimer’s diseasepatients. (Serot, Christmann et al. 2001)

A study published in the American Journal Medical Science found low levels of folate (alongwith deficiencies of thiamin and vitamin B12) in elderly individuals with senile dementia of theAlzheimer's type (22 subjects) as compared to the cognitively normal control group (41subjects.) (Renvall, Spindler et al. 1989)

SAME

SAMe (S-adenosyl methionine) is perhaps the safest and most effective antidepressant in theworld. SAMe is a precursor for glutathione, coenzyme A, cysteine, and taurine.

One study measured the levels of SAMe in postmortem brain of 11 patients with Alzheimer’sdisease. Decreased levels of S-adenosylmethionine (-67 to -85%) and its demethylated productS-adenosylhomocysteine (-56 to -79%) were found in all brain areas examined as compared withmatched controls (n = 14). (Morrison, Smith et al. 1996)

A review article of SAMe concluded that intravenous or oral administration of SAMe representsa possible treatment for Alzheimer's dementia, subacute combined degeneration of the spinalcord (SACD), and HIV-related neuropathies, as well as in patients with metabolic disorders suchas folate reductase deficiency. (Bottiglieri and Hyland 1994)

Nervous System Support

PHOSPHATIDYLSERINE

Phosphatidylserine is a major building block for nerve cells. Phosphatidylserine has been studiedfor use with Alzheimer’s disease and age-related mental decline. (Delwaide, Gyselynck-Mambourg et al. 1986; Crook, Petrie et al. 1992; Engel, Satzger et al. 1992)

In a study published in the journal Dementia, a six-month study of 70 patients with Alzheimer’sdisease divided into four groups indicated that phosphatidylserine treatment has an effect ondifferent measures of brain function. The improvements, however, were best documented after 8and 16 weeks and faded towards the end of the treatment period. (Heiss, Kessler et al. 1994)

INOSITOL

Inositol is required for the formation of cell membranes. It helps in transporting fats and affectsnerve transmission.

A double-blind controlled crossover trial examined use of inositol, at a dose of 6 grams per dayfor one month, in eleven patients with Alzheimer’s disease. Language and orientation improvedsignificantly more on inositol than on placebo (glucose). (Barak, Levine et al. 1996)

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VITAmIN K

A recent article published in the journal Medical Hypothesis proposes that vitamin K deficiencymay contribute to the pathogenesis of Alzheimer’s disease. The authors offer the following asevidence:

• A relative deficiency of vitamin K is common in aging men and women.

• The concentration of vitamin K is lower in the circulating blood of APOE4carriers than in that of persons with other APOE genotypes. The ApoE4genotype is associated with Alzheimer’s disease.

• Vitamin K has important functions in the brain, including the regulation ofsulfotransferase activity and the activity of a growth factor/tyrosine kinasereceptor (Gas 6/Axl).

• Vitamin K may also reduce neuronal damage associated with cardiovasculardisease.

The authors propose that vitamin K supplementation may have a beneficial effect in preventingor treating the disease. (Allison 2001)

IDeBENONE

Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), a cell membrane antioxidant andessential component of the mitochondrial electron transport chain which produces ATP (theenergy molecule of the body). The following mechanisms have been proposed for the use ofidebenone in Alzheimer’s disease:

Idebenone has been shown to stimulate nerve growth factor. (Nitta, Hasegawa etal. 1993; Nitta, Murakami et al. 1994; Yamada, Nitta et al. 1997)

Treatment with idebenone and alpha-tocopherol prevented learning and memorydeficits caused by beta-amyloid in rats. (Yamada, Tanaka et al. 1999)

Three hundred patients with Alzheimer’s disease were randomized to receive either placebo oridebenone, 30 mg three times per day, or 90 mg three times per day for six months. Statisticallysignificant improvement was noted in the total score of the Alzheimer’s disease AssessmentScale (ADAS-total), and in one cognitive parameter (ADAS-cog) in the idebenone 90 mg threetimes per day group, as compared to placebo. (Bergamasco, Scarzella et al. 1994; Anonymous2001)

An article in the journal Neuropsychobiology described the results of a double-blind, placebo-controlled multi-center study using idebenone in patients suffering from mild to moderatedementia of the Alzheimer type. A total of 300 patients were randomized to either placebo oridebenone 30 mg or 90 mg 3 times a day (n=100, each) and treated for 6 months. After month 6,idebenone 90 mg, showed statistically significant improvement in both the Total and CognitiveAlzheimer’s Disease Assessment Scales. (Weyer, Babej-Dolle et al. 1997)

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Natural Hormone Replacement

Estrogen replacement therapy (ERT) was discussed previously as conventional treatment for theprevention of Alzheimer’s disease. From a broader perspective, estrogen replacement is but onehormone in a complex system that includes three forms of estrogen (estrone, estradiol, andestriol), progesterone, testosterone, their precursors (DHEA and pregnenolone) and otherhormones (melatonin and cortisol). A comprehensive hormone panel is highly recommended todetermine which hormones are deficient or in excess and help guide appropriatesupplementation.

MELATONIN

Melatonin is a hormone that is released in mammals during the dark phase of the circadian cycle.Its production declines with age in animals and humans. The main use of melatonin is forinsomnia and to establish normal sleeping patterns after long air flights. The doses used in theresearch studies were higher than the 1 to 10 mg most persons use. Higher doses may causesleepiness, although no other serious side effects have been found with melatonin.

Melatonin is an antioxidant that has been shown to be highly effective in reducing oxidativedamage to the central nervous system. Melatonin also stimulates several antioxidant enzymes,including glutathione peroxidase and glutathione reductase. (Reiter, Cabrera et al. 1999)

Several studies have investigated the mechanism of action of melatonin in Alzheimer’s disease:

Melatonin was shown to significantly inhibit the release of free radicals inneuroblastoma cells. (Lahiri and Ghosh 1999)

Treatment of cells with high doses of melatonin have been found to decrease thesecretion of soluble beta-amyloid. (Lahiri 1999)

Melatonin prevented damage by beta-amyloid to neuroblastoma cells. (Pappolla,Chyan et al. 1999)

In a retrospective study, 14 Alzheimer’s disease patients received 9 mg melatonin daily for 22-35months. A significant improvement of sleep quality was found. (Brusco, Fainstein et al. 1999)

One study measured the melatonin levels in the cerebrospinal fluid (CSF) of 85 patients withAlzheimer’s disease and in 82 age-matched controls. In Alzheimer’s disease patients the CSFmelatonin levels were only one-fifth of those in control subjects.(Liu, Zhou et al. 1999)

A recent study examined the efficacy of melatonin in treatment of sleep and cognitive disordersof Alzheimer’s disease. Fourteen patients (8 females, 6 males, mean age 72 years) received 9 mggelatin melatonin capsules daily at bedtime for 22 to 35 months. Overall quality of sleep wasassessed from sleep logs filled in by the patients or their caretakers. At the time of assessment, asignificant improvement of sleep quality was found in all cases examined. Clinically, the patientsexhibited lack of progression of the cognitive and behavioral signs of the disease during the timethey received melatonin. (Brusco, Marquez et al. 2000)

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MUSIC THERAPY

A novel study assessed the effects of music therapy on the concentrations of melatonin,norepinephrine, epinephrine, serotonin, and prolactin in the blood of 20 male patients withAlzheimer’s disease at the Miami Veterans Administration Medical Center, Miami, Florida.Patients listened to 30- to 40-minute morning sessions of music therapy 5 times per week for 4weeks. Melatonin concentration in serum increased significantly after music therapy and wasfound to increase further at 6 weeks follow-up. Norepinephrine and epinephrine levels increasedsignificantly after 4 weeks of music therapy, but returned to pretherapy levels at 6 weeks follow-up. The authors concluded that increased levels of melatonin following music therapy may havecontributed to patients' relaxed and calm mood. (Kumar, Tims et al. 1999)

TRYPTOPHAN

Tryptophan is the precursor of serotonin and melatonin. It has been proposed that a dietary lackof tryptophan may make deficiencies of serotonin and melatonin common. (Maurizi 1990;Widner, Leblhuber et al. 2000)

In a double-blind, crossover study of 16 patients with dementia of the Alzheimer type and 16cognitively intact controls, subjects received either a tryptophan-free amino acid drink to induceacute tryptophan depletion, or a placebo drink containing a balanced mixture of amino acids. Oneach occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and theModified Mini-Mental State was administered at baseline and 4 hours later. Patients withdementia of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State after acute tryptophan depletion than after receiving placebo, while the comparisongroup showed no difference. (Porter, Lunn et al. 2000)

Adrenal Stress

The relationship between age-related memory loss and stress is central to the protocol used byDharma Singh Khalsa. Excessive stress from a modern life causes the adrenal glands to secreteexcessive amounts of cortisol eventually leading to adrenal fatigue. (Khalsa 1997)

DHEA

Alzheimer’s disease patients with higher DHEA levels did better on memory tests than thosewith lower DHEA levels. (Carlson, Sherwin et al. 1999) (Murialdo, Nobili et al. 2000)

Other data suggest that DHEA has a role in antioxidant status, Natural Killer (NK) cell immunefunction and other immune functions. This study showed low DHEA was a risk factor for thedevelopment of Alzheimer’s disease but did not show that replacing DHEA was of benefit.These studies still need to be done. (Hillen, Lun et al. 2000)

A study of adrenal secretion in 23 healthy elderly subjects, 23 elderly demented patients and 10healthy young subjects found a significant increase in cortisol levels during evening andnighttime in both groups of the aged subjects. In elderly subjects, particularly if demented, themean serum dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle weresignificantly lower than in young controls. (Magri, Terenzi et al. 2000)

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A cross-sectional study, called the Berlin Aging Study, found lower levels of DHEA-s in casesthat developed dementia of the Alzheimer type within 3 years as compared to matched controls.(Hillen, Lun et al. 2000)

Inhibition of AGE Formation

Central to the process of forming Advanced Glycation End Products (AGEs) is the presence ofsugar (glucose) which is central to the diagnosis of both diabetes and insulin insensitivity(referred to as Syndrome X). Appropriate lab tests would include the glucose tolerance test andinsulin levels. Appropriate treatment is covered in the section on diabetes.

VITAMINS B1 AND B6

Derivatives of vitamins B1 and B6 (thiamine pyrophosphate and pyridoxamine) have beenshown to decrease AGE formation. (Booth, Khalifah et al. 1996; Booth, Khalifah et al. 1997)

CARNOSINE

Carnosine is a multi-functional dipeptide made from a combination of the amino acids beta-alanine and L-histidine. Meat is the main dietary source of carnosine. High doses of carnosineare necessary for therapeutic effect because the body naturally degrades carnosine with theenzyme carnisoninase.

Copper and zinc are released during normal synaptic activity. However, in the presence of amildly acidic environment which is a characteristic of Alzheimer’s disease, they reduce to theirionic forms and become toxic to the nervous system. New research has shown that carnosine canbuffer copper and zinc toxicity in the brain. (Horning, Blakemore et al. 2000; Trombley, Horninget al. 2000)

Carnosine has also been shown, in vitro, to inhibit non-enzymic glycosylation and cross-linkingof proteins induced by reactive aldehydes, including aldose and ketose sugars, certain trioseglycolytic intermediates, and malondialdehyde (MDA, a lipid peroxidation product). Carnosinealso inhibits formation of MDA-induced protein-associated advanced glycosylation end products(AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde.(Munch, Mayer et al. 1997; Hipkiss 1998; Hipkiss, Preston et al. 1998; Preston, Hipkiss et al.1998)

Herbal Treatments

HUPERZINE A

Huperzine A is an alkaloid isolated from the Chinese herb Huperzia serrata.

In experiments using rats, Hyperzine A improved the decrease in acetylcholine activity in cortexand hippocampus. (Cheng 1996; Tang 1996; Bai, Tang et al. 2000; Camps, Cusack et al. 2000;Wang, Han et al. 2000)

Huperzine has also been found to protect against the toxic effects of beta-amyloid. (Xiao, Wanget al. 2000; Xiao, Wang et al. 2000)

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A double-blind, multi-center study of Huperzine A was conducted in China. Fifty patients weregiven 0.2 mg Huperzine and 53 patients were given placebo for eight weeks. About 58% (29/50)of patients treated with Huperzine showed improvements in their memory and cognitive andbehavioral functions. The efficacy of Huperzine was better than placebo (36%, 19/53) (p < 0.05).No severe side effect was found. (Xu and et al. 1995)

KUT

KUT is a Japanese herbal formula named “Kami-Umtan-To” that consists of 13 different herbs.KUT has been used since 1626 for neuropsychiatric problems. KUT has been shown to increasecholine acetyltransferase levels and nerve growth factor in cultured rat brain cells.

In a 12-month open clinical trial using KUT and estrogen, vitamin E and NSAIDs, the rate ofcognitive decline per year was measured using the Mini-Mental Status Exam (MMSE). Twentypatients with Alzheimer’s disease (MMSE score: 18.6 +/- 5.8) received extracts from originalKUT herbs, 7 Alzheimer’s disease patients (MMSE score: 21.3 +/- 2.8) were placed on thecombination therapy, and 32 patients served as controls (MMSE score: 20.8 +/- 5.6). The rate ofcognitive decline per year was significantly slower in the KUT group (1.4 points) and thecombination group (0.4 points) as compared to the 32 control patients who received no medicine(4.1 points). The efficacy of KUT alone was most noticeable after 3 months of use. (Arai, Suzukiet al. 2000)

Summary

The incidence of Alzheimer’s disease is increasing at an alarming rate along with the aging ofour population. The vast majority of Alzheimer’s disease is acquired or idiopathic (of unknowncause) by conventional medicine. There is much discussion about the cause of Alzheimer’sdisease and many consider that it may not be caused by a single agent. The causes discussed hereencompassed many diverse medical theories, including the biochemistry of acetylcholine andneurotransmitters, inflammation, oxidative stress and free radicals, and homocysteine. Recentadvances in lab testing may help identify the key areas in which to focus the therapies.

One interesting study showed that persons who had a love of reading and read frequently inchildhood had a very decreased incidence of Alzheimer’s disease. Regularly engaging in mentalactivity is necessary for preservation of brain function.

Most of the medical treatments listed here are used only after Alzheimer’s disease develops.Some, such as estrogen, vitamin B12, and antioxidants, are important in preventing dementiaalso.

Treatment Protocols

There are a vast number of choices in both drugs and nutritional supplements available forpatients with Alzheimer’s disease. A well-informed holistic or naturopathic medical doctor canbe of great help in ordering the appropriate lab tests and identifying the key supplements that willprovide the greatest benefit. The following are several of the supplements that have been coveredin this protocol along with standard daily dosages:

Acetylcholine support

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• Phosphatidylcholine derived from lecithin or capsulized with other cognitiveenhancers such as Cognitex

Antioxidants

• Ginkgo biloba, 120 mg in the morning or 60 mg three times daily

• Vitamin E, 2000 mg per day

• Vitamin C, 1,000 mg per day

• Acetyl-L-carnitine, 500 mg twice a day

• N-Acetyl cysteine, 500 mg twice a day

Anti-inflammatory

• Essential fatty acids (including omega-3 and omega-6 fatty acids, DHA, EPAand GLA). Dosage depends on the form.

• Curcumin (Turmeric), 400 mg three times a day

Homocysteine

• Vitamin B12, 1000 mcg a day or by injection

• Vitamin B6, 500 mg a day

• Folic acid, 400 mcg a day

• SAMe, 400-1600 mg a day, particularly if there are signs of depression

Nervous system support

• Methylcobalamin, the neurologically active form of vitamin B12; up to 5-10mg daily for brain aging

• Phosphatidylserine, 100 mg three times a day

Inhibit AGEs

• Carnosine, 1000 mg per day (minimum) should be considered

Based upon the results of appropriate lab testing (see the lab section at the beginning of thisarticle), the following may be used in addition:

• Hormone replacement therapy, preferably with natural forms of progesteroneand estrogen.

• DHEA supplementation. The usual dose is 10-50 mg in females and 40-100mg in males.

• Melatonin, 10 mg at bedtime, particularly if there is insomnia

Innovative drug strategies can include the following:

• Hydergine

• Piracetam

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Drug-Supplement Interactions

Ginkgo biloba

Ginkgo acts to thin the blood by reducing the ability of platelets (blood-clotting cells) to sticktogether. Care should be used when using Ginkgo with other agents that thin the blood, such asheparin, warfarin, aspirin, and some NSAIDs. (Harkness and Bratman 2000)

Vitamin E

Vitamin E has a long history of safe use. Vitamin E may add to the blood thinning effect ofaspirin and cause an increased risk of bleeding. Care should be taken when taking aspirin withvitamin E. (Harkness and Bratman 2000)

Vitamin K

Vitamin K directly counteracts the action of warfarin. Patients taking warfarin should seekqualified medical advice before taking vitamin K. (Harkness and Bratman 2000)

EPA and DHA

EPA and DHA have been shown to inhibit abnormal clotting in blood vessels. Care should beused with those taking anticoagulant medications such as warfarin.

References

Aksenov, M. Y., H. M. Tucker, et al. (1999). “The expression of several mitochondrial andnuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochromec oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer’s disease.”Neurochem Res 24(6): 767-74.

Allison, A. C. (2001). “The possible role of vitamin K deficiency in the pathogenesis ofAlzheimer's disease and in augmenting brain damage associated with cardiovascular disease.”Med Hypotheses 57(2): 151-5.

Anonymous (2001). “Idebenone - Monograph.” Altern Med Rev 6(1): 83-86.

Anthony, J. C., J. C. Breitner, et al. (2000). “Reduced prevalence of AD in users of NSAIDs andH2 receptor antagonists: the Cache County study.” Neurology 54(11): 2066-71.

Arai, H., T. Suzuki, et al. (2000). “[A new interventional strategy for Alzheimer's disease byJapanese herbal medicine].” Nippon Ronen Igakkai Zasshi 37(3): 212-5.

Bai, D. L., X. C. Tang, et al. (2000). “Huperzine A, a potential therapeutic agent for treatment ofAlzheimer's disease.” Curr Med Chem 7(3): 355-74.

Barak, Y., J. Levine, et al. (1996). “Inositol treatment of Alzheimer's disease: a double blind,cross-over placebo controlled trial.” Prog Neuropsychopharmacol Biol Psychiatry 20(4): 729-35.

32

Bastianetto, S., C. Ramassamy, et al. (2000). “The Ginkgo biloba extract (EGb 761) protectshippocampal neurons against cell death induced by beta-amyloid.” Eur J Neurosci 12(6): 1882-90.

Beal, M. F. (1999). “Mitochondria, NO and neurodegeneration.” Biochem Soc Symp 66: 43-54.

Behl, C. (2000). “Vitamin E protects neurons against oxidative cell death in vitro moreeffectively than 17-beta estradiol and induces the activity of the transcription factor NF-kappaB.”J Neural Transm 107(4): 393-407.

Bergamasco, B., L. Scarzella, et al. (1994). “Idebenone, a new drug in the treatment of cognitiveimpairment in patients with dementia of the Alzheimer type.” Funct Neurol 9(3): 161-8.

Bertoni-Freddari, C., C. Giuli, et al. (1987). “The effect of chronic hydergine treatment on theplasticity of synaptic junctions in the dentate gyrus of aged rats.” J Gerontol 42(5): 482-6.

Birks, J., J. Grimley Evans, et al. (2000). “Rivastigmine for Alzheimer's disease.” CochraneDatabase Syst Rev 4.

Birks, J. S., D. Melzer, et al. (2000). “Donepezil for mild and moderate Alzheimer's disease(Cochrane Review).” Cochrane Database Syst Rev 4.

Blusztajn, J. K., M. Liscovitch, et al. (1987). “Phosphatidylcholine as a precursor of choline foracetylcholine synthesis.” J Neural Transm Suppl 24: 247-59.

Booth, A. A., R. G. Khalifah, et al. (1996). “Thiamine pyrophosphate and pyridoxamine inhibitthe formation of antigenic advanced glycation end-products: comparison with aminoguanidine.”Biochem Biophys Res Commun 220(1): 113-9.

Booth, A. A., R. G. Khalifah, et al. (1997). “In vitro kinetic studies of formation of antigenicadvanced glycation end products (AGEs). Novel inhibition of post-Amadori glycationpathways.” J Biol Chem 272(9): 5430-7.

Bopp-Kistler, I., B. Ruegger-Frey, et al. (1999). “[Vitamin B12 deficiency in geriatrics].”Schweiz Rundsch Med Prax 88(45): 1867-75.

Bottiglieri, T. and K. Hyland (1994). “S-adenosylmethionine levels in psychiatric andneurological disorders: a review.” Acta Neurol Scand Suppl 154: 19-26.

Brusco, L. I., I. Fainstein, et al. (1999). “Effect of melatonin in selected populations of sleep-disturbed patients.” Biol Signals Recept 8(1-2): 126-31.

Brusco, L. I., M. Marquez, et al. (2000). “Melatonin treatment stabilizes chronobiologic andcognitive symptoms in Alzheimer’s disease.” Neuroendocrinol Lett 21(1): 39-42.

Butterworth, R. F. (2000). “Evidence for forebrain cholinergic neuronal loss in congenitalornithine transcarbamylase deficiency.” Metab Brain Dis 15(1): 83-91.

Camps, P., B. Cusack, et al. (2000). “Huprine X is a novel high-affinity inhibitor ofacetylcholinesterase that is of interest for treatment of Alzheimer's disease.” Mol Pharmacol57(2): 409-17.

33

Carlson, L. E., B. B. Sherwin, et al. (1999). “Relationships between dehydroepiandrosteronesulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimer's diseasepatients compared to healthy controls.” Horm Behav 35(3): 254-63.

Chapman, P. F. (2000). “Alzheimer's disease: model behaviour.” Nature 408(6815): 915-6.

Cheng, D. H. R. H. T. X. C. (1996). “Huperzine A, a novel promising acetylcholinesteraseinhibitor.” Neuroreport 8(1): 97-101.

Christen, Y. (2000). “Oxidative stress and Alzheimer disease.” Am J Clin Nutr 71(2): 621S-629S.

Clarke, R., A. D. Smith, et al. (1998). “Folate, vitamin B12, and serum total homocysteine levelsin confirmed Alzheimer disease.” Arch Neurol 55(11): 1449-55.

Corrigan, F. M., A. Van Rhijn, et al. (1991). “Essential fatty acids in Alzheimer's disease.” AnnN Y Acad Sci 640: 250-2.

Crapper McLachlan, D. R., A. J. Dalton, et al. (1991). “Intramuscular desferrioxamine in patientswith Alzheimer's disease.” Lancet 337(8753): 1304-8.

Crook, T., W. Petrie, et al. (1992). “Effects of phosphatidylserine in Alzheimer's disease.”Psychopharmacol Bull 28(1): 61-6.

Cummings, J. L. (2001). “Treatment of Alzheimer's disease.” Clin Cornerstone 3(4): 27-39.

Delwaide, P. J., A. M. Gyselynck-Mambourg, et al. (1986). “Double-blind randomizedcontrolled study of phosphatidylserine in senile demented patients.” Acta Neurol Scand 73(2):136-40.

Diamond, B. J., S. C. Shiflett, et al. (2000). “Ginkgo biloba extract: mechanisms and clinicalindications.” Arch Phys Med Rehabil 81(5): 668-78.

Doody, R. S. (1999). “Clinical profile of donepezil in the treatment of Alzheimer's disease.”Gerontology 45(Suppl 1): 23-32.

Doody, R. S. (1999). “Therapeutic standards in Alzheimer disease.” Alzheimer Dis Assoc Disord13 Suppl 2: S20-6.

Dringenberg, H. C., P. P. Laporte, et al. (2000). “Increased effectiveness of tacrine by deprenylco-treatment in rats: EEG and behavioral evidence.” Neuroreport 11(16): 3513-6.

Eastley, R., G. K. Wilcock, et al. (2000). “Vitamin B12 deficiency in dementia and cognitiveimpairment: the effects of treatment on neuropsychological function.” Int J Geriatr Psychiatry15(3): 226-33.

Eckert, G. P., N. J. Cairns, et al. (1999). “Piracetam reverses hippocampal membrane alterationsin Alzheimer's disease.” J Neural Transm 106(7-8): 757-61.

Engel, R. R., W. Satzger, et al. (1992). “Double-blind cross-over study of phosphatidylserine vs.placebo in patients with early dementia of the Alzheimer type.” Eur Neuropsychopharmacol2(2): 149-55.

34

Filip, V. and E. Kolibas (1999). “Selegiline in the treatment of Alzheimer's disease: a long-termrandomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer TypeStudy Group.” J Psychiatry Neurosci 24(3): 234-43.

Fitten, L. J., K. M. Perryman, et al. (1990). “Treatment of Alzheimer's disease with short- andlong-term oral THA and lecithin: a double-blind study.” Am J Psychiatry 147(2): 239-42.

Foster, R. H. and G. L. Plosker (1999). “Donepezil. Pharmacoeconomic implications of therapy.”Pharmacoeconomics 16(1): 99-114.

Gelowitz, D. L. and I. A. Paterson (1999). “Neuronal sparing and behavioral effects of theantiapoptotic drug, (-)deprenyl, following kainic acid administration.” Pharmacol BiochemBehav 62(2): 255-62.

Giem, P., W. L. Beeson, et al. (1993). “The incidence of dementia and intake of animal products:preliminary findings from the Adventist Health Study.” Neuroepidemiology 12(1): 28-36.

Goldsmith, H. S. (1985). “Abdominal omentum transfer and the nervous system.” Lancet1(8444): 1514.

Goldsmith, H. S., W. F. Chen, et al. (1973). “Brain vascularization by intact omentum.” ArchSurg 106(5): 695-8.

Goldsmith, H. S., A. L. Griffith, et al. (1984). “Lipid angiogenic factor from omentum.” Jama252(15): 2034-6.

Goldsmith, H. S., T. McIntosh, et al. (1987). “Vasoactive neurochemicals identified in omentum:a preliminary report.” Br J Neurosurg 1(3): 359-64.

Goldsmith, H. S. and E. Steward (1984). “Vascularization of brain and spinal cord by intactomentum.” Appl Neurophysiol 47(1-2): 57-61.

Gottfries, C. G., W. Lehmann, et al. (1998). “Early diagnosis of cognitive impairment in theelderly with the focus on Alzheimer's disease.” J Neural Transm 105(8-9): 773-86.

Grilli, M. M. M. (1999). “Nuclear factor-kappaB/Rel proteins: A point of convergence ofsignalling pathways relevant in neuronal function and dysfunction.” Biochemical Pharmacology57(1): 1-7.

Grobe-Einsler, R. (1993). “Clinical aspects of nimodipine.” Clin Neuropharmacol 16(Suppl 1):S39-45.

Grundman, M. (2000). “Vitamin E and Alzheimer disease: the basis for additional clinicaltrials.” Am J Clin Nutr 71(2): 630S-636S.

Grundman, M. (2000). “Vitamin E and Alzheimer disease: the basis for additional clinicaltrials(1).” Am J Clin Nutr 71(2 Part 2): 630S-6S.

Gustilo, M. C., A. L. Markowska, et al. (1999). “Evidence that nerve growth factor influencesrecent memory through structural changes in septohippocampal cholinergic neurons.” J CompNeurol 405(4): 491-507.

35

Hamon, C. G., J. A. Blair, et al. (1986). “The effect of tetrahydrofolate on tetrahydrobiopterinmetabolism.” J Ment Defic Res 30(Pt 2): 179-83.

Harkness, R. and S. Bratman (2000). Drug-Herb-Vitamin Interactions Bible, Prima Publishing.

Heiss, W. D., J. Kessler, et al. (1994). “Long-term effects of phosphatidylserine, pyritinol, andcognitive training in Alzheimer's disease. A neuropsychological, EEG, and PET investigation.”Dementia 5(2): 88-98.

Higgins, J. P. and L. Flicker (2000). “Lecithin for dementia and cognitive impairment (CochraneReview).” Cochrane Database Syst Rev 4.

Hillen, T., A. Lun, et al. (2000). “DHEA-S plasma levels and incidence of Alzheimer's disease.”Biol Psychiatry 47(2): 161-3.

Hipkiss, A. R. (1998). “Carnosine, a protective, anti-ageing peptide?” Int J Biochem Cell Biol30(8): 863-8.

Hipkiss, A. R., J. E. Preston, et al. (1998). “Pluripotent protective effects of carnosine, anaturally occurring dipeptide.” Ann N Y Acad Sci 854: 37-53.

Horning, M. S., L. J. Blakemore, et al. (2000). “Endogenous mechanisms of neuroprotection:role of zinc, copper, and carnosine.” Brain Res 852(1): 56-61.

Horrocks, L. A. and Y. K. Yeo (1999). “Health benefits of docosahexaenoic acid (DHA).”Pharmacol Res 40(3): 211-25.

Huang, W., G. E. Alexander, et al. (1999). “High brain myo-inositol levels in the predementiaphase of Alzheimer's disease in adults with Down's syndrome: a 1H MRS study.” Am JPsychiatry 156(12): 1879-86.

Hull, M. S. S. B. M. V. B. B. J. (1996). “Inflammatory mechanisms in Alzheimer's disease.” Eur.Arch. Psychiatry and Clin. Neuroscience 246(3): 124-128.

Iwamoto, N. N. E. O. J. A. H. (1994). “Demonstration of CRP immunoreactivity in brains ofAlzheimer's disease: Immunohistochemical study using formic acid pretreatment of tissuesections.” Neurosci. Lett. 177: 1-2.

Jain, K. K. (2000). “Evaluation of memantine for neuroprotection in dementia.” Expert OpinInvestig Drugs 9(6): 1397-406.

Jimenez-Jimenez, F. J., F. de Bustos, et al. (1997). “Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer's disease.” J Neural Transm 104(6-7): 703-10.

Jimenez-Jimenez, F. J., J. A. Molina, et al. (1999). “Serum levels of beta-carotene, alpha-carotene and vitamin A in patients with Alzheimer's disease.” Eur J Neurol 6(4): 495-7.

Joe, B. L. B. R. (1997). “Effect of curcumin and capsaicin on arachidonic acid metabolism andlysosomal enzyme secretion by rat peritoneal macrophages.” Lipids 32(11): 1173-1180.

Joosten, E., E. Lesaffre, et al. (1997). “Is metabolic evidence for vitamin B-12 and folatedeficiency more frequent in elderly patients with Alzheimer's disease?” J Gerontol A Biol SciMed Sci 52(2): M76-9.

36

Kalmijn, S., L. J. Launer, et al. (1997). “Dietary fat intake and the risk of incident dementia inthe Rotterdam Study.” Ann Neurol 42(5): 776-82.

Kay, A. D., S. Milstien, et al. (1986). “Cerebrospinal fluid biopterin is decreased in Alzheimer'sdisease.” Arch Neurol 43(10): 996-9.

Khalsa, D. S. (1997). Brain Longevity. New York, Warner Books.

Kidd, P. M. (1999). “A review of nutrients and botanicals in the integrative management ofcognitive dysfunction.” Altern Med Rev 4(3): 144-61.

King, R. G. (1984). “Do raised brain aluminium levels in Alzheimer's dementia contribute tocholinergic neuronal deficits?” Med Hypotheses 14(3): 301-6.

Kontush, A., U. Mann, et al. (2001). “Influence of vitamin E and C supplementation onlipoprotein oxidation in patients with Alzheimer’s disease.” Free Radic Biol Med 31(3): 345-54.

Kornhuber, J., M. Weller, et al. (1994). “Amantadine and memantine are NMDA receptorantagonists with neuroprotective properties.” J Neural Transm Suppl 43: 91-104.

Kumar, A. M., F. Tims, et al. (1999). “Music therapy increases serum melatonin levels inpatients with Alzheimer's disease.” Altern Ther Health Med 5(6): 49-57.

Kyle, D. J., E. Schaefer, et al. (1999). “Low serum docosahexaenoic acid is a significant riskfactor for Alzheimer's dementia.” Lipids 34(Suppl): S245.

Lahiri, D. K. (1999). “Melatonin affects the metabolism of the beta-amyloid precursor protein indifferent cell types.” J Pineal Res 26(3): 137-46.

Lahiri, D. K. and C. Ghosh (1999). “Interactions between melatonin, reactive oxygen species,and nitric oxide.” Ann N Y Acad Sci 893: 325-30.

Le Bars, P. L., M. M. Katz, et al. (1997). “A placebo-controlled, double-blind, randomized trialof an extract of Ginkgo biloba for dementia. North American EGb Study Group.” Jama 278(16):1327-32.

Le Bars, P. L., M. Kieser, et al. (2000). “A 26-week analysis of a double-blind, placebo-controlled trial of the ginkgo biloba extract EGb 761 in dementia.” Dement Geriatr Cogn Disord11(4): 230-7.

Leblhuber, F., J. Walli, et al. (2000). “Hyperhomocysteinemia in dementia.” J Neural Transm107(12): 1469-74.

Lehmann, M., C. G. Gottfries, et al. (1999). “Identification of cognitive impairment in theelderly: homocysteine is an early marker.” Dement Geriatr Cogn Disord 10(1): 12-20.

Lim, G. P., F. Yang, et al. (2000). “Ibuprofen suppresses plaque pathology and inflammation in amouse model for Alzheimer's disease.” J Neurosci 20(15): 5709-14.

Little, A., R. Levy, et al. (1985). “A double-blind, placebo controlled trial of high-dose lecithinin Alzheimer's disease.” J Neurol Neurosurg Psychiatry 48(8): 736-42.

37

Liu, R. Y., J. N. Zhou, et al. (1999). “Decreased melatonin levels in postmortem cerebrospinalfluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon4/4 genotype.” J ClinEndocrinol Metab 84(1): 323-7.

Lopez-Arrieta, J. M., J. L. Rodriguez, et al. (2001). “Efficacy and safety of Nicotine onAlzheimer's disease patients (Cochrane Review).” Cochrane Database Syst Rev 2.

Mackenzie, I. R. and D. G. Munoz (1998). “Nonsteroidal anti-inflammatory drug use andAlzheimer-type pathology in aging.” Neurology 50(4): 986-90.

Magri, F., F. Terenzi, et al. (2000). “Association between changes in adrenal secretion andcerebral morphometric correlates in normal aging and senile dementia.” Dement Geriatr CognDisord 11(2): 90-9.

Martin, J. B. (1999). “Molecular basis of the neurodegenerative disorders.” N Engl J Med340(25): 1970-80.

Maurizi, C. P. (1990). “The therapeutic potential for tryptophan and melatonin: possible roles indepression, sleep, Alzheimer's disease and abnormal aging.” Med Hypotheses 31(3): 233-42.

McCaddon, A., G. Davies, et al. (1998). “Total serum homocysteine in senile dementia ofAlzheimer type.” Int J Geriatr Psychiatry 13(4): 235-9.

McCaddon, A., P. Hudson, et al. (2001). “Analogues, ageing and aberrant assimilation ofvitamin B12 in Alzheimer's disease.” Dement Geriatr Cogn Disord 12(2): 133-7.

McCaddon, A., P. Hudson, et al. (2001). “Homocysteine and cognitive decline in healthyelderly.” Dement Geriatr Cogn Disord 12(5): 309-13.

McCarty, M. F. (1999). “Vascular nitric oxide, sex hormone replacement, and fish oil may helpto prevent Alzheimer's disease by suppressing synthesis of acute-phase cytokines.” MedHypotheses 53(5): 369-74.

McDermott, J. R., A. I. Smith, et al. (1979). “Brain aluminum in aging and Alzheimer disease.”Neurology 29(6): 809-14.

McGeer, E. G. M. P. L. (1999). “Brain inflammation in Alzheimer disease and the therapeuticimplications.” Current Pharmaceutical Design 5(10): 821-836.

McLachlan, D. R., C. Bergeron, et al. (1996). “Risk for neuropathologically confirmedAlzheimer's disease and residual aluminum in municipal drinking water employing weightedresidential histories.” Neurology 46(2): 401-5.

Meins, W., T. Muller-Thomsen, et al. (2000). “Subnormal serum vitamin B12 and behaviouraland psychological symptoms in Alzheimer's disease.” Int J Geriatr Psychiatry 15(5): 415-8.

Miller, J. W. (1999). “Homocysteine and Alzheimer's disease.” Nutr Rev 57(4): 126-9.

Morris, M. C., L. A. Beckett, et al. (1998). “Vitamin E and vitamin C supplement use and risk ofincident Alzheimer disease.” Alzheimer Dis Assoc Disord 12(3): 121-6.

Morrison, L. D., D. D. Smith, et al. (1996). “Brain S-adenosylmethionine levels are severelydecreased in Alzheimer's disease.” J Neurochem 67(3): 1328-31.

38

Muller, W. E., G. P. Eckert, et al. (1999). “Piracetam: novelty in a unique mode of action.”Pharmacopsychiatry 1: 2-9.

Munch, G., S. Mayer, et al. (1997). “Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide.” Biochim BiophysActa 1360(1): 17-29.

Murialdo, G., F. Nobili, et al. (2000). “Hippocampal perfusion and pituitary-adrenal axis inAlzheimer's disease.” Neuropsychobiology 42(2): 51-7.

Nagasawa, H., K. Kogure, et al. (1990). “Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography.” Tohoku J Exp Med 162(3):225-33.

Neely, M. D., L. Zimmerman, et al. (2000). “Congeners of N(alpha)-acetyl-L-cysteine but notaminoguanidine act as neuroprotectants from the lipid peroxidation product 4-hydroxy-2-nonenal.” Free Radic Biol Med 29(10): 1028-36.

Newman, P. E. (1992). “Could diet be one of the causal factors of Alzheimer's disease?” MedHypotheses 39(2): 123-6.

Newman, P. E. (2000). “Alzheimer's disease revisited.” Med Hypotheses 54(5): 774-6.

Nishizaki, T., T. Matsuoka, et al. (2000). “Presynaptic nicotinic acetylcholine receptors as afunctional target of nefiracetam in inducing a long-lasting facilitation of hippocampalneurotransmission.” Alzheimer Dis Assoc Disord 14(Suppl 1): S82-94.

Nitta, A., T. Hasegawa, et al. (1993). “Oral administration of idebenone, a stimulator of NGFsynthesis, recovers reduced NGF content in aged rat brain.” Neurosci Lett 163(2): 219-22.

Nitta, A., Y. Murakami, et al. (1994). “Oral administration of idebenone induces nerve growthfactor in the brain and improves learning and memory in basal forebrain-lesioned rats.” NaunynSchmiedebergs Arch Pharmacol 349(4): 401-7.

Olin, J., L. Schneider, et al. (2000). “Hydergine for dementia.” Cochrane Database Syst Rev 2.

Otsuka, M. (2000). “[Analysis of dietary factors in Alzheimer’s disease: clinical use ofnutritional intervention for prevention and treatment of dementia]. [Article in Japanese].” NipponRonen Igakkai Zasshi 37(12): 970-3.

Paganini-Hill, A. and V. W. Henderson (1994). “Estrogen deficiency and risk of Alzheimer'sdisease in women.” Am J Epidemiol 140(3): 256-61.

Paganini-Hill, A. and V. W. Henderson (1996). “Estrogen replacement therapy and risk ofAlzheimer disease.” Arch Intern Med 156(19): 2213-7.

Pappolla, M. A., Y. J. Chyan, et al. (1999). “Alzheimer beta protein mediated oxidative damageof mitochondrial DNA: prevention by melatonin.” J Pineal Res 27(4): 226-9.

Park, H., J. Jang, et al. (2000). “A concise synthetic pathway for trans-metanicotine analogues.”Arch Pharm Res 23(3): 202-5.

Perlmutter, D. (2000). BrainRecovery.com. Naples, FL, The Perlmutter Health Center.

39

Perry, E. K., A. T. Pickering, et al. (1999). “Medicinal plants and Alzheimer's disease: fromethnobotany to phytotherapy.” J Pharm Pharmacol 51(5): 527-34.

Peters, B. H. and H. S. Levin (1979). “Effects of physostigmine and lecithin on memory inAlzheimer disease.” Ann Neurol 6(3): 219-21.

Pettegrew, J. W., J. Levine, et al. (2000). “Acetyl-L-carnitine physical-chemical, metabolic, andtherapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatricdepression.” Mol Psychiatry 5(6): 616-32.

Pizzorno, J. E. and M. T. Murray (1995). Alzheimer's Disease. A Textbook of Natural Medicine.Seattle, WA, Bastyr College Publications.

Pocernich, C. B., M. La Fontaine, et al. (2000). “In-vivo glutathione elevation protects againsthydroxyl free radical-induced protein oxidation in rat brain.” Neurochem Int 36(3): 185-91.

Porter, R. J., B. S. Lunn, et al. (2000). “Cognitive deficit induced by acute tryptophan depletionin patients with Alzheimer's disease.” Am J Psychiatry 157(4): 638-40.

Preston, J. E., A. R. Hipkiss, et al. (1998). “Toxic effects of beta-amyloid(25-35) onimmortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine.” Neurosci Lett 242(2): 105-8.

Ramamurthy, B., H. o. o. P, et al. (1999). “An overview of carbohydrate-protein interactionswith specific reference to myosin and ageing.” Acta Physiol Scand 167(4): 327-9.

Regland, B., K. Blennow, et al. (1999). “The role of the polymorphic genes apolipoprotein E andmethylene- tetrahydrofolate reductase in the development of dementia of the Alzheimer type.”Dement Geriatr Cogn Disord 10(4): 245-51.

Reiter, R. J., J. Cabrera, et al. (1999). “Melatonin as a pharmacological agent against neuronalloss in experimental models of Huntington's disease, Alzheimer’s disease and parkinsonism.”Ann N Y Acad Sci 890: 471-85.

Renvall, M. J., A. A. Spindler, et al. (1989). “Nutritional status of free-living Alzheimer'spatients.” Am J Med Sci 298(1): 20-7.

Riviere, S., I. Birlouez-Aragon, et al. (1998). “Low plasma vitamin C in Alzheimer patientsdespite an adequate diet.” Int J Geriatr Psychiatry 13(11): 749-54.

Robert, P. H., E. Gokalsing, et al. (1999). “[Cholinergic hypothesis and Alzheimer's disease: theplace of donepezil (Aricept)].” Encephale(5): 23-7.

Sano, M., C. Ernesto, et al. (1997). “A controlled trial of selegiline, alpha-tocopherol, or both astreatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study.” N Engl J Med336(17): 1216-22.

Sawada, M., Y. Hirata, et al. (1987). “Tyrosine hydroxylase, tryptophan hydroxylase, biopterin,and neopterin in the brains of normal controls and patients with senile dementia of Alzheimertype.” J Neurochem 48(3): 760-4.

40

Scali, C., C. Prosperi, et al. (2000). “Brain inflammatory reaction in an animal model of neuronaldegeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer'sdisease.” Eur J Neurosci 12(6): 1900-12.

Schofield, P. W., M. Tang, et al. (1997). “Alzheimer's disease after remote head injury: anincidence study.” J Neurol Neurosurg Psychiatry 62(2): 119-24.

Schroeter, H., R. J. Williams, et al. (2000). “Phenolic antioxidants attenuate neuronal cell deathfollowing uptake of oxidized low-density lipoprotein.” Free Radic Biol Med 29(12): 1222-33.

Serot, J. M., D. Christmann, et al. (2001). “CSF-folate levels are decreased in late-onset ADpatients.” J Neural Transm 108(1): 93-9.

Shankaranarayana Rao, B. S., M. K. Lakshmana, et al. (1999). “Chronic (-) deprenyladministration alters dendritic morphology of layer III pyramidal neurons in the prefrontal cortexof adult Bonnett monkeys.” Brain Res 821(1): 218-23.

Stern, Y., B. Gurland, et al. (1994). “Influence of education and occupation on the incidence ofAlzheimer's disease.” Jama 271(13): 1004-10.

Stewart, W. F., C. Kawas, et al. (1997). “Risk of Alzheimer's disease and duration of NSAIDuse.” Neurology 48(3): 626-32.

Suuronen, T., P. Kolehmainen, et al. (2000). “Protective effect of L-deprenyl against apoptosisinduced by okadaic acid in cultured neuronal cells.” Biochem Pharmacol 59(12): 1589-95.

Tabet, N., J. Birks, et al. (2000). “Vitamin E for Alzheimer's disease (Cochrane Review).”Cochrane Database Syst Rev 4.

Tang, X. C. (1996). “Huperzine A (shuangyiping): a promising drug for Alzheimer's disease.”Zhongguo Yao Li Xue Bao 17(6): 481-4.

Tariska, P. and A. Paksy (2000). “[Cognitive enhancement effect of piracetam in patients withmild cognitive impairment and dementia].” Orv Hetil 141(22): 1189-93.

Thal, L. J., M. Calvani, et al. (2000). “A 1-year controlled trial of acetyl-l-carnitine in early-onsetAD.” Neurology 55(6): 805-10.

Thal, L. J., P. A. Fuld, et al. (1983). “Oral physostigmine and lecithin improve memory inAlzheimer disease.” Ann Neurol 13(5): 491-6.

Thomas, T. (2000). “Monoamine oxidase-B inhibitors in the treatment of Alzheimer's disease.”Neurobiol Aging 21(2): 343-8.

Thome, J., J. Kornhuber, et al. (1996). “[New hypothesis on etiopathogenesis of Alzheimersyndrome. Advanced glycation end products (AGEs)].” Nervenarzt 67(11): 924-9.

Trombley, P. Q., M. S. Horning, et al. (2000). “Interactions between carnosine and zinc andcopper: implications for neuromodulation and neuroprotection.” Biochemistry (Mosc) 65(7):807-16.

41

van Dongen, M. C., E. van Rossum, et al. (2000). “The efficacy of ginkgo for elderly peoplewith dementia and age-associated memory impairment: new results of a randomized clinicaltrial.” J Am Geriatr Soc 48(10): 1183-94.

Veinbergs, I., M. Mallory, et al. (2000). “Vitamin E supplementation prevents spatial learningdeficits and dendritic alterations in aged apolipoprotein E-deficient mice.” Eur J Neurosci12(12): 4541-6.

Virmani, M. A., V. Caso, et al. (2001). “The action of acetyl-L-carnitine on the neurotoxicityevoked by amyloid fragments and peroxide on primary rat cortical neurones.” Ann N Y Acad Sci939: 162-78.

Wang, H. X., A. Wahlin, et al. (2001). “Vitamin B(12) and folate in relation to the developmentof Alzheimer's disease.” Neurology 56(9): 1188-94.

Wang, L. M., Y. F. Han, et al. (2000). “Huperzine A improves cognitive deficits caused bychronic cerebral hypoperfusion in rats.” Eur J Pharmacol 398(1): 65-72.

Wettstein, A. (2000). “Cholinesterase inhibitors and Gingko extracts--are they comparable in thetreatment of dementia? Comparison of published placebo-controlled efficacy studies of at leastsix months' duration.” Phytomedicine 6(6): 393-401.

Weyer, G., R. M. Babej-Dolle, et al. (1997). “A controlled study of 2 doses of idebenone in thetreatment of Alzheimer's disease.” Neuropsychobiology 36(2): 73-82.

Widner, B., F. Leblhuber, et al. (2000). “Tryptophan degradation and immune activation inAlzheimer's disease.” J Neural Transm 107(3): 343-53.

Winblad, B. and N. Poritis (1999). “Memantine in severe dementia: results of the 9M-Best Study(Benefit and efficacy in severely demented patients during treatment with memantine).” Int JGeriatr Psychiatry 14(2): 135-46.

Wisniewski, H. M. and G. Y. Wen (1992). “Aluminium and Alzheimer's disease.” Ciba FoundSymp 169: 142-54.

Xiao, X. Q., R. Wang, et al. (2000). “Protective effects of huperzine A on beta-amyloid(25-35)induced oxidative injury in rat pheochromocytoma cells.” Neurosci Lett 286(3): 155-8.

Xiao, X. Q., R. Wang, et al. (2000). “Huperzine A and tacrine attenuate beta-amyloid peptide-induced oxidative injury.” J Neurosci Res 61(5): 564-9.

Xu, S. S. G. Z. X. W. Z. D. Z. M. X. W. A. Y. J. S. Z. M. L. T. Z. H. F. and et al. (1995).“Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease.”Chung Kuo Yao Li Hsueh Pao 16(5): 391-5.

Yaffe, K., G. Sawaya, et al. (1998). “Estrogen therapy in postmenopausal women: effects oncognitive function and dementia.” Jama 279(9): 688-95.

Yamada, K., A. Nitta, et al. (1997). “Orally active NGF synthesis stimulators: potentialtherapeutic agents in Alzheimer's disease.” Behav Brain Res 83(1-2): 117-22.

42

Yamada, K., T. Tanaka, et al. (1999). “Protective effects of idebenone and alpha-tocopherol onbeta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stressin beta-amyloid-induced neurotoxicity in vivo.” Eur J Neurosci 11(1): 83-90.

Yao, Z., K. Drieu, et al. (2001). “The Ginkgo biloba extract EGb 761 rescues the PC12 neuronalcells from beta-amyloid-induced cell death by inhibiting the formation of beta-amyloid-deriveddiffusible neurotoxic ligands.” Brain Res 889(1-2): 181-90.

Yao, Z. X., K. Drieu, et al. (1999). “Free radicals and lipid peroxidation do not mediate beta-amyloid-induced neuronal cell death.” Brain Res 847(2): 203-10.

Yatin, S. M., M. Yatin, et al. (1999). “Alzheimer's amyloid beta-peptide associated free radicalsincrease rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity:protective effect of vitamin E.” Neurosci Lett 263(1): 17-20.

Yehuda, S., S. Rabinovtz, et al. (1996). “Essential fatty acids preparation (SR-3) improvesAlzheimer's patients quality of life.” Int J Neurosci 87(3-4): 141-9.

Youdim, K. A., A. Martin, et al. (2000). “Essential fatty acids and the brain: possible healthimplications.” Int J Dev Neurosci 18(4-5): 383-99.

Zhou, L. J. and X. Z. Zhu (2000). “Reactive oxygen species-induced apoptosis in PC12 cells andprotective effect of bilobalide.” J Pharmacol Exp Ther 293(3): 982-8.