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Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

ABSTRACT: Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

SUBMITTER: Reiman EM

PROVIDER: S-EPMC6997393 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Reiman Eric M EM Arboleda-Velasquez Joseph F JF Quiroz Yakeel T YT Huentelman Matthew J MJ Beach Thomas G TG Caselli Richard J RJ Chen Yinghua Y Su Yi Y Myers Amanda J AJ Hardy John J Paul Vonsattel Jean J Younkin Steven G SG Bennett David A DA De Jager Philip L PL Larson Eric B EB Crane Paul K PK Keene C Dirk CD Kamboh M Ilyas MI Kofler Julia K JK Duque Linda L Gilbert John R JR Gwirtsman Harry E HE Buxbaum Joseph D JD Dickson Dennis W DW Frosch Matthew P MP Ghetti Bernardino F BF Lunetta Kathryn L KL Wang Li-San LS Hyman Bradley T BT Kukull Walter A WA Foroud Tatiana T Haines Jonathan L JL Mayeux Richard P RP Pericak-Vance Margaret A MA Schneider Julie A JA Trojanowski John Q JQ Farrer Lindsay A LA Schellenberg Gerard D GD Beecham Gary W GW Montine Thomas J TJ Jun Gyungah R GR

Nature communications 20200203 1

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alz ...[more]

PMID: 32015339

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Project description:Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia.

Dataset Information

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Publications

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Similar Datasets

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