Recent advances in the management of

Alzheimer’s disease

Presenter:- Dr Parthajyoti Neog, PGTModerator:- Dr. (Mrs.) Dolly Roy, Asso. Prof., SMCH

IntroductionHistoryClinical featuresPathophysiologyDiagnosisManagementRecent advancesConclusion

Alzheimer’s disease is defined as premature aging of the brain, usually beginning in mid-adult life and progressing rapidly to extreme loss of mental powers—similar to that seen in very, very old age.

Introduction

In Alzheimer’s disease, there is loss of neurons in that part of the limbic pathway that drives the memory process.

Loss of this memory function is devastating.

It is a progressive and fatal neurodegenerative disorder that results in impairment of the person’s ability to perform activities of daily living as well as a variety of neuropsychiatric symptoms and behavioral disturbances in the later stages of the disease.

Approximately 10% of all person over the age of 70 years have significant memory loss, and in more than half (60-70%) the cause is Alzheimer’s disease

In 1906, Dr. Alois Alzheimer, specifically identified a collection of brain cell abnormalities as a disease.

History

The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.

In the 1960s, scientists discovered a link between cognitive decline and the number of plaques and tangles in the brain.  

Emil Kraepelin

The medical community then formally recognized Alzheimer's as a disease and not a normal part of aging.

Alois Alzheimer's patient Auguste Deter in 1902. Hers was the first described case of what became known as Alzheimer's disease.

Stages of Alzheimer's disease A) Effects of ageing on memory but not AD

i) Forgetting things occasionally

ii) Misplacing items sometimes

iii) Minor short-term memory loss

iv) Forgetting that memory lapses

happened.

Clinical Features

B) Early stage Alzheimer's

i) Absent-mindedness

ii) Forgetting appointments

iii) Slight changes seen by close loved

ones

iv) Some confusion in situations outside

the familiar

C) Middle stage Alzheimer's

i) Deeper difficulty remembering

recently learned information

ii) Deepening confusion in many

circumstances

iii) Speech impairment

iv) Repeatedly initiating the same

conversation

D) Late stage Alzheimer's

i) More aggressive or passive

ii) Some loss of self-awareness

iii) Debilitating cognitive deficit

iv) More abusive, anxious, or

paranoid

a) Genetics

b) Cholinergic hypothesis

c) Amyloid hypothesis

d) Tau hypothesis

e) Other hypothesis

Pathophysiology

Genetic factors play an important role and about 15% of cases are familial.

Familial cases fall into two main groups: early-onset disease with autosomal dominant inheritance and a later-onset group whose inheritance is polygenic.

Genetics

Mutations in several genes have been described. The inheritance of one of the alleles of apolipoprotein ε (apo ε4) is associated with an increased risk of developing the disease (2–4 times higher in heterozygotes and 6–8 times in homozygotes).

Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2.

The oldest, on which most currently available drug therapies are based, is cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of theneurotransmitter acetylcholine.

Cholinergic hypothesis

The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.

Amyloid hypothesis

In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. 

Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. 

N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes.

N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6), also known as (TNFRSF21). 

DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. 

Exactly how disturbances of production and aggregation of the beta-amyloid peptide gives rise to the pathology of AD is not known. 

The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration.

Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis).

Tau hypothesis

Other hypothesis

Herpes simplex virus type 1 has been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.

Some studies have shown an increased risk of developing AD with environmental factors such as the intake of metals, particularly alluminium.

Some have hypothesised that dietary copper may play a causal role.

There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.

Biochemistry

Alzheimer's disease has been identified as

a protein misfolding disease (proteopathy), caused by plaque accumulation of abnormally folded amyloid beta protein, and tau protein in the brain. 

APP is critical to neuron growth, survival and post-injury repair. 

Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (Aβ). Aβ is a fragment from the larger amyloid precursor protein (APP).

APP is a transmembrane protein that penetrates through the neuron's membrane.

In Alzheimer's disease, an unknown enzyme in a proteolytic process causes APP to be divided into smaller fragments.

One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques.

Alzheimer's disease is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations.

Diagnosis

Advanced medical imaging with 

a) CT

b) MRI

c) SPECT

d) PET, can be used to help exclude

other cerebral pathology or

subtypes of dementia.

 

The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.

Challenging and gratifying despite the absence of a cure or a robust pharmacologic treatment.

Management

Focus is on long-term amelioration of associated behavioral and neurologic problems ， as well as providing caregiver support.

Building rapport with the patient, family members, and other caregivers is essential.

In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful.

Family members should emphasize activities that are pleasant while curtailing those that increase stress on the patient.

Kitchens ， bath rooms ， stairways ， and bed rooms need to be made safe ， and eventually patients will need to stop driving.

Loss of independence and change of environment may worsen confusion, agitation, and anger.

Communication and repeated calm reassurance are necessary.

Use of adult day care centers can be helpful.

Local and national support groups ， such as the Alzheimer's Association and the Family Caregiver Alliance ， are valuable resources. Internet access to these resources has become available to clinicians and families in recent years.

Cholinesterase inhibitors:-

a) Tacrine (1993),

b) Donepezil (1996),

c) Rivastigmine (2000), and

d) Galantamine (2001).

Drug Treatment

Tacrine: It is the first centrally acting anti-ChE to be introduced for AD.

In clinical trials tacrine produced significant improvement in memory, attention, praxis, reason and language.

However, it does not alter the course of underlying disease process.

Frequent side effects and hepatotoxicity have restricted its use.

Donepezil (1996): This is a cerebroselective and reversible anti-AChE drug.

The benefit is ascribed to elevation of ACh level in the cortex, especially in the surviving neurones that project from basal forebrain to cerebral cortex and hippocampus.

Because of long t½ (~70 hr), donepezil is administered once daily at bed time; a distinct advantage over rivastigmine and galantamine which need twice daily dosing. Moreover, it can be used even in relatively severe case of AD.

Donepezil is generally well tolerated and is not hepatotoxic.Dose: 5 mg OD HS (max 10 mg OD)

Rivastigmine (2000): This carbamate derivative of

physostigmine inhibits both AChE and BuChE. The carbamyl residue introduced by rivastigmine into

AChE molecule dissociates slowly resulting in inhibition of cerebral AChE for upto 10 hours despite the 2 hr plasma t½ of the drug.

Rivastigmine is indicated in mild to moderate cases of AD, but not in advanced disease.

Dose: Initially 1.5 mg BD, increase every 2 weeks by 1.5 mg/day upto 6 mg/BD

Galantamine (2001): It is a natural alkaloid which selectively inhibits cerebral AChE and has some direct agonistic action on nicotinic receptors as well.

It is well tolerated, but needs twice daily dosing.

Dose: 4 mg BD (max 12 mg BD)

N-methyl-D-aspartate receptor

(NMDA) antagonist.

a) Memantine: It appears to restore the function of damaged nerve cells and reduce abnormal excitatory signals by the modulation of the NMDA receptor activity.

It is indicated in moderate-to-severe AD, either to replace anti-AChEs or to supplement them.

Dose: Initially 5 mg OD, increase gradually upto 10 mg BD; stop if no clinical benefit in 6 months.

Piracetam : This cyclic GABA derivative has no GABA like activity and has been called ‘nootropic’ meaning a drug that selectively improves efficiency of higher telencephalic integrative activities.

Piracetam is not a vasodilator, does not affect total/regional CBF, but may reduce blood viscosity. In India and some other countries it has been promoted for cognitive impairment and dementia in the elderly as well as for mental retardation in children for over 30 years.

Side effects are minor: gastric discomfort, nervousness, excitement, insomnia, dizziness and skin rash.

Dose: 0.8–1 g TDS oral; children 20 mg/kg BD–TDS; 1–3 g i.m. 6 hourly in stroke/head injury.

Pyritinol (Pyrithioxine) : It consists of two pyridoxine molecules joined through a disulfide bridge, but has no vit B6 activity.

It is claimed to activate cerebral metabolism by selectively increasing glucose transport across blood-brain barrier and improving regional blood flow in ischaemic brain areas.

It has been promoted for: Sequelae of cerebrovascular accidents, head injury, prolonged anaesthesia. Infants and children with developmental disorders of CNS, delayed milestones. Concentration and memory defects, senility, organic brain syndromes.

However, therapeutic benefit, if any, is uncertain.

Dose: 100–200 mg TDS, children 50–100 mg TDS orally; 200–400 mg every 4–6 hours (max. 1 g/day) has been given i.v. for recovery from cerebral hypoxia due to cardiac arrest, anaesthesia, brain operations and stroke.

Side effects: Only mild g.i. upset was noted initially. Later skin rashes, itching and taste disturbances.

It has been withdrawn in some countries.

Dihydroergotoxine (Codergocrine): It is a semisynthetic ergot alkaloid having α adrenergic blocking property; claimed to increase cerebral blood flow selectively.

Dose of 1.0–1.5 mg TDS oral/sublingual or 0.3 mg i.m. OD, it has been recommended for MCI and dementia.

Therapeutic value is not established.

Citicoline: It is a compound derived from choline and cytidine, that is involved in biosynthesis of lecithin.

Citicoline is believed to improve cerebral function by increasing blood flow to the brain and enhancing cerebral metabolism.

In the absence of effective medicines and under promotional pressure, citicoline is being commonly prescribed for impaired brain function due to ischaemic stroke, parkinsonism, head injury, etc.

Dose: 0.5–1 g/day i.m. or i.v. inj, 200–600 mg/day oral in divided doses.

Ginkgo biloba: The dried extract of this Chinese plant contains a mixture of ginkgoflavon glycosides, which have PAF antagonistic action.

Since PAF has been implicated in cerebral thrombosis and infarcts, it is professed that G. biloba will prevent cerebral impairment in cerebrovascular insufficiency.

It has been promoted for a variety of cognitive and behavioural disorders in the elderly.

Dose: 40–80 mg TDS for a minimum period of 4 weeks.

Piribedil: It is a dopaminergic agonist claimed to improve memory, concentration, vigilance, giddiness and tinnitus in the elderly due to circulatory insufficiency.

Benefit is unsubstantiated. Minor efficacy in parkinsonism has also been reported.

Side effects are mild g.i. complaints.Dose: 50 mg OD, BD.

Recent Advances

1) Cholinesterase inhibitora) Phenserine: Phenserin treatments

increased cognition and regional cerebral metabolic rate for glucose in AD patients.

b) Dimebon: A cholinesterase inhibitor and also a NMDA-antagonist, showed improved cognitive and self-service functions while diminishing the psychopathic symptoms in AD patients.

c) Huperzine A: A Chinese herb with reversibly and selectively acetylcholinesterase inhibition activity, displayed good pharmacokinetics with a rapid absorption and a wide distribution in the body at a low to moderate rate of elimination.

Clinical trials have shown its cognitive enhancement in AD at a dose of 0.4 mg and seems to be a potential treatment option for AD.

d) Ladostigil : A multimodal drug, combined neuroprotective effects with monoamine oxidase (MAO) -A and -B and cholinesterase inhibitory activities in a single molecule, was tested and now in Phase II clinical trial.

e) PMS777: A new cholinesterase inhibitor with anti-PAF activity is also in clinical trial

a) β-secretase inhibitors: i) BACE (β- site APP cleaving enzyme): Lateral

ventricular injection of this inhibitor led to a significant dose- and time-dependent lowering of brain Aβ40 and Aβ42, a robust decreased sAPPβ and an increased sAPPα secretion.

ii) KMI-429: Injection of this inhibitor into the hippocampus of APP transgenic mice reduced Aβ production.

2) Aβ-targeting strategies

iii) GSK188909: Oral administration of this non-peptidic BACE1 inhibitor results in a significant reduction in the level of Aβ40 and Aβ42 in the brain of transgenic mice.

b) γ-secretase inhibitors

i) BMS-299897

ii) MRK-560.

iii) LY450139 dihydrate

c) α-secretase activators/modulators Since α-secretase and β-secretase compete

for the same substrate of APP, upregulation of α-secretase activity may decrease the amount of APP available for β-secretase, and thus decrease Aβ secretion and have therapeutic potential.

Many studies had indicated that members of the adamalysin family of proteins, mainly ADAM(A Disintegrin And Metalloproteinase) 10, ADAM 17 and ADAM 9, fulfill some of the criteria required of α-secretase.

i) Deprenyl: A neuroprotective agent used to slow AD progress, was shown to increase α-secretase activity by promoting ADAM10 and PKCα/ε translocation

d)M1 muscarinic agonists

M1 muscarinic receptors play a role in an apparent linkage of three major hallmarks of AD: Aβ peptide; tau hyperphosphorylation and loss of cholinergic function conductive to cognitive impairments.

i) Talsaclidine: It is a functionally selective muscarinic M1 agonist that stimulates non-amyloidogenic α-secretase processing in vitro.

In a double-blind, placebo-controlled, and randomized clinical study in AD patients, treatment with talsaclidine decreased CSF Aβ about 20% as compared with the baseline, suggesting its therapeutic potential.

ii) AF102B: another M1 agonist, also decreased CSF Aβ of AD patients.

iii) AF267B: On clinical trial.

e) Aβ-aggregation inhibitori) iAβ5p: This is the first drug was a β-sheet

breaker, which showed that intra hippocampal injection of it resulted in improved spatial memory and decreased amyloid plaque deposits.

ii) Tramiprosate: It is a compound that binds to soluble Aβ and inhibits the formation of neurotoxic aggregates that lead to amyloid plaque deposition in the brain.

f) ImmunotherapyPassive immunotherapy in AD patients with

repeated intravenous administration of human immunoglobulin against Aβ peptide resulted in stopped cognitive decline and slight improvement in functional scores.

i) LY2062430: On Phase I and II clinical trials.

ii) Bapineuzumab: After a phase II, multicenter, randomized, double-blind, placebo-controlled clinical trials it shows decreased total and phosphorylated tau levels in CSF without affecting Aβ level.

iii) AN1792A: Randomized, double-blind, placebo controlled, phase II clinical trial with this synthetic Aβ peptide in patients with mild to moderate AD was initiated, but the trial was later discontinued because of approximately 6% of the immunized AD patients(18/300) developed meningoencephalitis.

g) Aβ-degrading enzymes i) Neprilysin (NEP),

ii) Insulindegrading enzyme (IDE),

iii) Plasmin,

iv) Endothelin converting enzyme (ECE) 1

and 2,

v) Angiotensin-converting enzyme.

vi) Imatinib: A tyrosine kinase inhibitor, was shown to elevate AICD ( APP intracellular domain) in H4 human neuroglioma cells, and this was accompanied by concomitant increases of NEP protein, mRNA levels, and activity.

vii) Valproic acid: A widely used drug in the treatment of epilepsy, was capable of up-regulating NEP expression, seen in experimental rats.

Estrogen and green tea all could increase NEP activity and suggest their potential in AD treatment but there is a long way before their final clinical application.

h) Apolipoprotein E (ApoE) promotes Aβ clearance

The lipidated ApoE activates microglia and/or astrocyte to degrade Aβ. It decreased brain amyloid plaque burden and improved behavior functions in AD transgenic mice.

Bexarotene: Is a nuclear receptor modulator and ApoE activator, whether it is effective in AD prevention needs to be explored clinically.

i) Drugs influencing Aβ blood–brain barrier transport

The receptor for advanced glycation end products (RAGE) resides in the blood vessel wall cells and transport Aβ across the blood brain barrier from systemic circulation to facilitate their accumulation in brain.

In contrast to RAGE, low-density lipoprotein receptor-related protein-1 (LRP-1) mediates transport of Aβ peptide out of brain.

Thus inhibition of RAGE and/or activation of LRP-1 may be a therapeutic target for AD, but there are no clinical data available at present.

3) Drugs development based on the

metals hypothesis:There is increasing evidence that metal (mainly

Cu, Zn and Fe) metabolism is involved in the major phthophysiological events of AD: APP processing and tau hyperphosphorylation. Several chelators of Zn/Cu have been shown to inhibit Aβ aggregation in vitro and in vivo.

A phase II clinical trial with clioquinol, a metal-protein-attenuating compound that inhibits zinc and copper ions from binding to Aβ, led to improved cognitive function, decreased plasma Aβ42 level and zinc concentration as compared with control group.

Other metal chelators includs XH1, DP-109, PBT2.

PBT2 was an orally available, second generation 8-OH quinoline derivative of clioquinol, and is advancing as a disease-modifying candidate drug for Alzheimer’s disease.

4) HMG-CoA reductase inhibitors (the “statins”):

Clinical trial with atorvastatin for 1 year provides some clinical benefit in AD patients. Treatment with lovastatin resulted in decreased plasma Aβ level.

5) Monoamine oxidase inhibitorsMAO inhibitor deprenyl is an anti-Parkinson

drug used to inhibit dopamine degradation in the brain. Also as a neuroprotective agent, deprenyl has been used to slow the progress of neurodegenerative diseases such as AD for many years.

Rasagiline: Another MAO-B inhibitor is a bifunctional molecule which also has acetylcholinesterase inhibition activity.

6)Treatments based on tau pathology

a) Prevention of phosphorylation of tau

b) Prevention of the aggregation of tau

c) Prevention the misfolding of tau

d) Tau immunotherapy

Protein phosphatase (PP)-2A: It may increase dephosphorylation of tau. PP-2A also inhibits kinases such as MAPK (mitogen activated protein kinase), which phosphorylate tau.

a) Prevention of phosphorylation of tau

Cyclin-dependent kinase-5 (CDK5): It is a kinase suggested to phosphorylate tau in AD.

Transgenic mice in which CDK5 activity is activated (by overexpression of the p25 activator) in adult brain show evidence of a striking neurodegeneration with some tau pathology.

As report, inhibitors of CDK5 appear to have some influence on the development of pathology in some tau transgenic mice. There are as yet no reports of the use of CDK5 inhibitors in humans.

Glycogen synthase kinase (GSK)-3β: It has also been suggested as a drug target to inhibit tangle formation.

This kinase is blocked by

Lithium,

The M1 muscarinic agonist AF267B,

Propentofylline (PPF) and

SRN-003-556.

Recent studies using cell models have demonstrated that certain drug inhibitors are able to prevent tau protein aggregation and even dissolve the developed aggregates, which include-

b) Prevention of the aggregation of tau

Phenothiazines, Anthraquinones, Polyphenols, Thiacarbocyanine dyes, N-phenylamines, Thiazolyl-hydrazides, Rhodanines, Quinoxalines, Aminothienopyridazines etc.

c) Prevention the misfolding of tau i) Chaperones: The results from a

study by Dou and colleagues suggested that increasing the activation of molecular chaperones might prevent the misfolding of tau, which would then reduce the development of NFTs.

ii) Heat shock proteins: They have been shown to activate chaperones that prevent misfolding and even promote tau binding with microtubules.

7) Non-steroidal anti-inflammatory drugs (NSAIDs)

More than 20 epidemiological studies, some with a follow-up design and a good estimation of NSAIDs use via prescription data from pharmacies have suggested that the prolonged intake of NSAIDs may be associated with a reduced incidence of AD.

8) EstrogensMerlo et al. reported that estrogen can

activate matrix metalloproteinases-2 and −9 to increase beta amyloid degradation.

9)NicotinePublished studies in humans have reported the

effects of intravenous or subcutaneous nicotine administration on people with AD.

Significant improvements were reported in several cognitive tasks such as free recall, visual attention and perception and in mood although not on memory.

10) Melatonin

In AD patients, melatonin supplementation has been suggested to improve circadian rhythmicity, and to produce beneficial effects on memory.

11) Cell transplantation and gene therapy

In AD rat model, transplantation of cholinergic-rich tissue or peripheral cholinergic neurons ameliorates abnormal behavior and cognitive function. But no clinical trials in AD patients have been initiated with this method.

a) Endogenous nerve growth factor (NGF):

NGF administration rescues neurons from injury-induced cell damage and leads to associated memory improvements and thus NGF is good for gene therapy.

b) Besides NGF, another candidate for gene therapy is Aβ-degrading enzymes and the animal experiments are also positive. Clinical trials are not being initiated yet.

12) Other pharmacological therapies in clinical AD trails

a) Docosa-hexaenoic acid (DHA):

DHA is the most abundant omega 3 fatty acid in the brain. Data from animal models support the hypothesis that DHA maybe an effective treatment for AD by means of antiamyloid, antioxidant, and neuroprotective mechanisms.

b) Clioquinol: Metal chelation using clioquinol has been reported in a pilot study with 36 patients with AD to reduce the rate of cognitive loss in a double-blind, placebo-controlled, phase 2 clinical trial.

c) Resveratrol: Resveratrol, a red wine polyphenol, recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of AD pathology.

Exert its neuroprotective role through inhibition of Aβ aggregation, by scavenging oxidants and exerting anti inflammatory activities.

VaccinesAN-1792: Phase I studies of AN-1792 in humans

indicated that the vaccine was well tolerated, and a portion of the patients developed amyloid antibodies. As a result of these findings, a multicenter Phase IIa study in patients with mild-to-moderate Alzheimer’s disease was initiated.

Passive immunization: By using antibodies to Aβ4-10.

Intravenous immunoglobulin (IVIg): Initial results suggest that IVIg infusion may have long-term benefits for the treatment of cognitive decline in Alzheimer’s disease.149 A Phase II study is currently underway.150

The ultimate goal for Alzheimer’s disease pharmacotherapy is not merely to ameliorate symptoms, but to alter the onset or progression of the disease.

Conclusion

There are four drugs (donepezil, galantamine, rivastigmine, and memantine) currently approved for the treatment of Alzheimer’s disease, but the numerous complex and interrelated biochemical pathways underlying neurodegeneration in Alzheimer’s disease provide numerous potential targets for therapeutic intervention.

Several investigational compounds have demonstrated potential as therapeutic or preventive therapies and merit additional study. Gradual elucidation of the exact mechanisms of neurodegeneration will result in increasingly focused drug development efforts.

References1)Evaluating Prescription Drugs Used to Treat: Alzheimer's Disease Comparing

Effectiveness, Safety, and Price [PDF]. Consumer Reports Drug Effectiveness Review Project May 2012 [Retrieved 1 May 2013]. Consumer Reports.

2)Hong-Qi et al. Translational Neurodegeneration 2012, 1:21http://www.translationalneurodegeneration.com/content/1/1/21: Current advances in the treatment of Alzheimer’s disease: focused on considerations targeting Aβ and tau.

3)Current Strategies for the Treatment and Prevention of Alzheimer’s Disease, Primary Psychiatry | August 1, 2007 .

4) Goodman gilman’s The pharmacological basis of therapeutics, 12th edition.

5) Pharmacology and pharmacotherapeutics by R.S. Satoskar, 23rd edition.

6) Essential of Medical Pharmacology by K.D. Tripathi, 7th edition.