Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent alzheimer's disease

Eric M. Reiman, Richard J. Caselli, Kewei Chen, Gene E. Alexander, Daniel Bandy, Jennifer Frost

Research output: Contribution to journalArticle

386 Scopus citations

Abstract

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ε4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal ε4 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 test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal ε4 heterozygotes and 15 ε4 noncarriers 50-63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The ε4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the ε4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ε4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

Original languageEnglish (US)
Pages (from-to)3334-3339
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number6
DOIs
StatePublished - Mar 13 2001

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