Persons inheriting autosomal dominant mutations causing familial Alzheimer disease (familial AD, or FAD) are essentially certain to develop the illness at a young age that is predictable, at least to some extent. Known mutations in the genes encoding for Presenilin-1 (PSEN1
), Amyloid Precursor Protein (APP
), and Presenilin-2 (PSEN2
) result in FAD, an aggressive illness with a more rapidly progressive course than that of late onset Alzheimer's disease (LOAD). FAD accounts for 2% or less of all AD cases. The identification of the genes responsible for this form of the disease has contributed greatly to our understanding of AD in general. Characterization of the normal and abnormal function of the proteins encoded by these genes contributed greatly to the prevailing “amyloid hypothesis” of AD pathogenesis(1
). The pathogenic forms of these genes all lead to aberrant metabolism of the amyloid precursor protein, favoring the production of cleavage products more prone to aggregation (particularly the 42-amino acid length beta-amyloid peptide, or Aβ42). Many of these mutations have been transfected into mice, producing useful animal models that recapitulate many, though not all, disease characteristics. In addition to leading to breakthroughs in our understanding of the mechanisms of AD pathogenesis, the study of persons with or at-risk for FAD has provided insights into the cognitive(2
), and biochemical changes(7
) occurring in the earliest stages of the illness. These observations are likely to enhance our ability to diagnose and possibly treat LOAD in its presymptomatic stage. In this paper we discuss the advantages to performing studies for the prevention of AD in the population at-risk for FAD as well as the many challenges to such an endeavor.
With the aging of the baby boomers in the U.S. and with increasing longevity worldwide, the specter of Alzheimer's Disease (AD) as a major public health crisis is looming. Barring major advances in stem cell therapy and neural regeneration, it may be impossible to reverse established disease once it is present. Halting, slowing the progression of, or preventing AD altogether are likely to be more tractable goals. In part due to competing mortality in the aged population, it has been estimated that delaying the onset of AD by 5 years would result in a 50% reduction of AD cases in a generation(9
). Therefore, efforts to develop treatments that are effective in preventing AD are of high priority.
It is difficult to definitively establish the efficacy of an intervention in the prevention of AD. Much of the information we have regarding whether or not certain interventions may be helpful in the primary prevention of AD comes from retrospective epidemiological observations(10
). Such studies yield important clues as to what types of interventions might be studied further, but they do not offer definitive proof that an intervention causes the observed effect. This level of proof requires the completion of prospective, randomized, double blind, placebo-controlled studies. Such studies of prevention in AD are challenging for several reasons. It is currently difficult to establish a priori
who in a population will ultimately develop AD and over what time frame. Therefore one must study hundreds or thousands of persons for many years in order to guarantee that a significant number in any treatment arm will develop (or would
have developed) AD so that meaningful conclusions can be drawn(11
). For example it has been estimated that it would require between 3,000 and 6,000 total subjects to detect a 30% reduction in the occurrence of AD over 5 years assuming a 5 - 10% cumulative incidence of the disease(13
). Such large and long duration studies are prohibitively costly and prone to high drop-out rates. This large scale approach has nonetheless been employed by including the development of dementia or other cognitive variable as outcome measures in controlled studies of interventions thought to have wider health benefits. Examples of this approach include the now-terminated Women's Health Initiative Study that looked at the preventative effects of estrogen and/or a progestational agent(14
) and the on-going study of selenium and vitamin E in the prevention of prostate cancer (15
Another method used during the drug development process that may be adapted to prevention protocols is the use of small short-duration studies in which alternative outcome measures such as changes in cognition, biochemical markers, or imaging variables are the primary outcome measures. Until such measures have been validated and accepted as surrogate disease markers by the U.S. Food and Drug Administration, however, alternative methods will be required.
In recent years, there have been significant advances in our understanding of clinical, genetic, imaging, and biochemical markers that predict who is more likely to develop clinical AD in the near future. Such indices may be used to identify a sub-group, or “enriched” population at increased risk for the development of AD that might be entered into prevention trials(16
). The “oldest old,” persons with amnestic mild cognitive impairment (MCI), persons with medial temporal lobe atrophy on magnetic resonance imaging (MRI), people carrying the ε4 allele of the Apolipoprotein E gene, or persons with other “risk factors” have been proposed as populations at increased risk for developing AD that might be identified and enrolled in prevention trials. Though these strategies might reduce the size of the population and the duration required for prevention studies, these measures are still imperfect predictors of the subsequent development of AD. Inclusion of persons who are not destined to develop AD in prevention trials increases the number of people required and the duration over which they need to be followed. This adds to the costs of such studies and requires unnecessary exposure of persons who will not develop the disease to potential risks of the intervention. Therefore, alternative mechanisms by which potential preventative therapies can be more efficiently tested should be considered.