Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease
Open accessAbstract
Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ɛ4 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 ɛ4 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 ɛ4 heterozygotes and 15 ɛ4 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 ɛ4 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 ɛ4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ɛ4 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.
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APOE4 is associated with increased Aβ deposition, but its influence on metabolic pathways may contribute to AD risk independently of Aβ.
“As such, APOE4 is associated with increased Aβ deposition but accumulating evidence suggests that its influence on metabolic pathways may contribute to disease risk independently of Aβ [3][4][5][6][7] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [3]
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APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
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- Authors
- Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Reiman, Eric M.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-03-13
- Volume
- 98
- Issue
- 6
- Pages
- 3334-3339
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC30654
- OpenAlex
- W2169096667
- Cited by
- 467
- References
- 7
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 7 · 2022: 3 · 2021: 12 · 2020: 15 · 2019: 12 · 2018: 16 · 2017: 14 · 2016: 9 · 2015: 8 · 2014: 24 · 2013: 22 · 2012: 19
- FWCI
- 15.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH57899-01A1, R01MH057899)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- APOE ε4, Alzheimer's disease prevention, cerebral metabolic rate of glucose, cognitively normal older adults, statistical power estimation, positron emission tomography, temporal lobe, posterior cingulate cortex, prefrontal cortex, parahippocampal gyrus, thalamus, basal forebrain
- MeSH terms
- Aged, Alzheimer Disease, Apolipoproteins E, Brain, Cognition, Female, Glucose, Heterozygote, Humans, Male, Middle Aged, Tomography, Emission-Computed, Apolipoprotein E4
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