Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease

Cross-sectional positron emission tomography (PET) studies find that cognit ively normal carriers of the apolipoprotein E (APOE) epsilon4 allele, a com mon Alzheimer's susceptibility gene, have abnormally low measurements of th e cerebral metabolic rate for glucose (CMRgI) in the same regions as patien ts with Alzheimer's dementia. In this article, we characterize longitudinal CMRgI declines in cognitively normal epsilon4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently te st the potential of candidate therapies for the prevention of Alzheimer's d isease. We studied 10 cognitively normal epsilon4 heterozygotes and 15 epsi lon4 noncarriers 50-63 years of age with a reported family history of Alzhe imer's dementia before and after an interval of approximately 2 years. The epsilon4 heterozygotes had significant CMRgI declines in the vicinity of te mporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahi ppocampal gyrus, and thalamus, and these declines were significantly greate r than those in the epsilon4 noncarriers. In testing candidate primary prev ention therapies, we estimate that between 50 and 115 cognitively normal ep silon4 heterozygotes are needed per active and placebo treatment group to d etect a 25% attenuation in these CMRgI declines with 80% power and P = 0.00 5 in 2 years. Assuming these CMRgI declines are related to the predispositi on to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study tho usands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.