In Context

850 www.thelancet.com/neurology Vol 9 September 2010

Preventing Alzheimer’s disease: could a new kind of trial be the key?With an epidemic of Alzheimer’s disease lying in wait, some researchers are calling for a new era of prevention research—research in which people with a particular genetic fate would be vital participants. Adrian Burton reports.

Alzheimer’s disease (AD) aff ects one in ten people over 65 years of age and about half of people over 85. With people living longer than ever, the number of patients with AD could double every 20 years, potentially leading to a fi nancially overwhelming epidemic. Against this backdrop, some researchers are calling for a fundamental change in the way AD preventive treatment trials are done and in the evidence that bodies such as the US Food and Drug Administration should accept before licensing treatments. But who would have thought that much of this change would depend on a few people living in a remote part of South America?

“Now is the time to launch the era of Alzheimer’s prevention research”, says Eric Reiman (Banner Alzheimer’s Institute [BAI], Phoenix, AZ, USA), a leading voice in the call for change under the fl ag of the Alzheimer’s Prevention Initiative. “Currently, it takes too many cognitively normal people, too much money, and too much time—longer than the life of a drug product’s patent—to evaluate presymptomatic AD treatments in a randomised trial using clinical end-points. We need to establish the means to evaluate a range of promising pre-symptomatic treatments using AD biomarkers that are reasonably likely to predict a clinical benefi t [if we are to] fi nd a treatment that works as quickly as possible, [and create] an accelerated regulatory approval pathway.”

AD trials have suff ered from serious problems. Most have involved people who are close to developing or already showing the fi rst signs of the disease—when it might be too late for a treatment to have much eff ect—and

those involving clearly presymptomatic people have been encumbered by the numbers of participants required (only one in ten people might naturally develop AD by 65 years of age). Furthermore, regulatory bodies require that clinical benefi t be shown before a treatment is approved, meaning that preventive trials in presymptomatic people would need to run for years, incurring huge fi nancial burdens.

Reiman and his colleagues at the BAI suggest something quite diff erent should be done: that promising treatments should be tested in presymptomatic trials lasting just 2 years in groups of people who are very likely to develop AD, that a range of AD biomarkers be simultaneously followed over this period, and that the extent to which their movement predicts the clinical benefi t a treatment might have be recorded.

But are there any such biomarkers? And do such people exist? “Right now, we have several potential biomarkers for tracking changes over time in AD”, explains Pierre Tariot, also of the BAI. “These include fl uordeoxyglucose-PET (FDG-PET) measure ments of the decline in cerebral glucose metabolism, MRI measure ments of regional or whole brain shrinkage, recently developed PET methods for the assessment of amyloid plaque burden, and cerebrospinal fl uid

(CSF) measurements of amyloid β42, total tau and phosphotau levels, alone or in combination.”

And, sadly, people who have genetic defects that put them at much greater risk of developing AD do exist. About 2–3% of the population, carry two copies of the APOE ε4 allele and are 20 times more likely to develop AD in old age. Putting together a registry of APOE ε4 homozygous people would provide one—albeit geographically spread out—population in which to undertake these new trials.

Further, about 500 families world-wide are known to carry a dominant mutation of the presenilin-1 gene—the E280A PS1 allele—that almost certainly leads to early-onset AD in those who inherit it. The largest so-called extended family with this mutation lives in Antioquía in northwestern Colombia; all are thought to be the descendents of a single person. Those who carry the mutation develop AD at around 48 years of age. About 40% of the aff ected kindred live in or close to the city of Medellín, whereas the others live in mountain villages in what is even now a genetically isolated region. However, the misfortune of these people provides a relatively large, localised population in which the proposed trials could be done—and perhaps ultimately help them. 1235 present members of this kindred have now been genotyped and over 480 have been identifi ed as carriers of the mutation; about 1000 carriers might eventually be identifi ed. Trials in this population would involve people as young as 18–25 years of age.

Although doing trials that would require monitoring by neuroimaging or CSF collection from people living in

“We must urgently fi nd a way to increase the speed with which we evaluate Alzheimer’s disease treatments or we will be engulfed by a wave of disease that is travelling much faster than our present trials system”

For more on the Alzheimer’s Prevention Initiative see

Biomark Med 2010; 4: 3–14

In Context

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For more on Lopera’s work see JAMA 1997; 277: 793–99

a remote part of Colombia might not immediately seem feasible, Francisco Lopera (University of Antioquía), who discovered their plight in the early 1980s, allays concerns: “We are looking for options that promise the best possibilities of success. In Medellín we have good capacity to undertake functional magnetic resonance studies, and within 18 months we will have Pittsburgh compound B-PET and FDG-PET capabilities. We will select those patients who live close by for the imaging part of the study, but we could bring in residents who live further away if required. Some would have to stay overnight, but we can book them into hotels in Medellín if necessary.”

Lopera also explains that CSF samples could be collected in local health clinics, and that a network of family members armed with trial plans and mobile phones is already in place, liaising between participants and researchers to make sure everyone attends appointments and knows what is happening next. “[These families] have been participating for 15 years in studies with little hope”, says Lopera. “Seeing that [this project] off ers the hope of a solution they will surely continue to be involved.”

However, even the most promising of potential AD drugs and anti-amyloid vaccines have failed to produce the desired results in more traditional trials. Could researchers honestly hope these drugs and vaccines would fare any better as presymptomatic treatments? “There is a growing concern that many of these treatments might be too little too late to have a profound eff ect by the time people have symptoms and extensive brain pathology”, explains Tariot. “If a treatment appears to have an anti-amyloid eff ect or another promising mechanism of action, and if it is suffi ciently safe, it should be considered in presymptomatic trials whether or not it works in clinically aff ected patients.”

Certainly, deciding which of the two potential trial populations should receive which treatment raises some

problems. “Although many of the treatments to try have already been shown safe in other populations, safety in the homozygous APOE ε4 group would not necessarily be the same as safety in the Colombian group”, warns Francisco Wandosell (CIBERNED-Universidad Autónoma de Madrid, Spain). “For example, the diff erence in the age of these two experimental populations means their physiology is diff erent, and certainly [the Colombian group] is still of reproductive age, so the researchers will have to take some care deciding which treatment each group can receive. Secondly, APOE ε4 is still only a risk factor, meaning that the number of homozygous people enrolled in a particular trial needs to be high enough to ensure an accurate statistical analysis.”

“These trials are an excellent idea and off er a singular opportunity, though they must obviously adhere to ethical regulations”, remarks Jesús Ávila, of the Centro de Biología Molecular Severo Ochoa (CSIC-Universidad Autónoma de Madrid, Spain). “And unfortunately there might be a problem of keeping people involved in ever-changing trials. If a treatment were seen to be doing little in terms of the biomarkers followed, the researchers could drop it and start with another using the same participants. But staying involved would require much self-sacrifi ce on the part of these people. Another problem is that the authorities may not license a treatment based on biomarker evidence alone; they may still want clinical evidence. Convincing them might be tough—but what other hope do these homozygous carriers of APOE ε4 or E280A PS1 carriers have?”

Reiman concedes these challenges, and also recognises that any fi ndings made in these groups of genetically at-risk people might not be generalisable to the larger population. However, the sense behind considering the fi rst use of investigational treatments in people at the highest imminent risk of AD is hard to counter, and if regulatory agencies were to become convinced

that the movement of one or more biomarkers predicted clinical benefi t reasonably well, this might provide a way to test many candidate treatments and seek the accelerated approval of those that show promise. If predicted clinical benefi ts eventually became a reality, the benefi t could be enormous.

“Initiatives such as this should be seen as an urgent priority”, remarks Facundo Manes (Favaloro University, Buenos Aires, Argentina). “We must urgently fi nd a way to increase the speed with which we evaluate AD treatments or we will be engulfed by a wave of disease that is travelling much faster than our present trials system. If these proposed trials can be performed and help us fi nd something that delays the onset of AD by even 5 years we could halve the number of people who at any one time have the disease. Imagine if we could delay it for longer, or even indefi nitely. The debt the world would owe to these populations of tragically affl icted people would be incalculable.”

Adrian Burton

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