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. 2023 May;19(5):1983-1993.
doi: 10.1002/alz.12831. Epub 2022 Nov 17.

APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease

Angelina J Polsinelli  1   2 , Paige E Logan  1   2 , Kathleen A Lane  3 , Mohit K Manchella  4 , Sára Nemes  1 , Apoorva Bharthur Sanjay  1 , Sujuan Gao  2   3 , Liana G Apostolova  1   2
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APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease

Angelina J Polsinelli et al. Alzheimers Dement. 2023 May.

Abstract

Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD).

Method: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center.

Results: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001).

Conclusion: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants.

Highlights: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.

Keywords: APOE ε4; cognitive decline; early-onset Alzheimer's disease; late-onset Alzheimer's disease; sex differences.

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Conflict of interest statement

CONFLICTS OF INTEREST

Declaration of interest for A.J.P., P.E.L, K.A.L, M.K.M., S.N., A.B.S., and S.G.: none. L.G.A. has received personal compensation in the range of $500 to $4999 for serving as a Consultant for National Institutes of Health (NIH), Florida Dept of Health, NIH Biobank, Eli Lilly, and GE Healthcare. L.G.A. has received personal compensation in the range of $500 to $4999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai and serving on a Scientific Advisory or Data Safety Monitoring board for Two Labs. L.G.A. has received personal compensation in the range of $5000 to $9999 for serving as a Consultant for Biogen, serving on a Scientific Advisory or Data Safety Monitoring board for IQVIA, and serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. L.G.A. has received personal compensation in the range of $10,000 to $49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for the Alzheimer’s Association. An immediate family member of L.G.A. has stock in Semiring, Cassava Neurosciences, and Golden Seed. The institution of L.G.A. has received research support from Roche, National Institute on Aging (NIA), Alzheimer’s Association, AVID radiopharmaceuticals, and Life Molecular Imaging. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Diagram outlining exclusion steps for sample with corresponding number of participants and observations excluded
FIGURE 2
FIGURE 2
Significant effects of APOE ε4 and sex on cognitive decline within early onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) for (A) Montreal Cognitive Assessment (MoCA), (B) Craft Story, Immediate Recall, (C) Craft Story, Delayed Recall (D) Multilingual Naming Test (MINT), (E) Semantic Fluency, (F) Trail Making Test A (TMT A), and (G) Trail Making Test B (TMT B)
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