Available online 22 February 2023

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APOE ε4 was associated with more pronounced cognitive decline over time

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PRS-LOAD including all variants (except APOE) predicted cognitive level

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PRS-LOAD including 17 high-effect variants predicted cognitive decline

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Immune PRS-LOAD predicted cognitive aging independent of C-reactive Protein.

Abstract

Apolipoprotein E (APOE) ε4, the strongest genetic risk factor for late onset Alzheimer's Disease (LOAD), has been associated with cognitive decline independent from AD pathology, but the role for other LOAD risk genes in normal cognitive aging is less studied. We examined the effect of APOE ε4 and several different polygenic risk scores (PRS) for LOAD on cognitive level and decline in aging, using longitudinal data from the UK Biobank. While PRS-LOAD including all variants (except APOE) predicted cognitive level, APOE ε4 and PRS-LOAD based on 17 non-APOE gene variants with strong association to AD (p<5e-8) predicted age-related decline in verbal numeric reasoning. The effect on decline were partly driven by four variants involved in the immune system. Those variants also predicted serum levels of the inflammatory marker C-reactive protein (CRP), but CRP did not mediate the effect on decline. Those findings suggest genetic variations in immune functions play a role in aspects of cognitive aging, that may be independent of LOAD pathology as well as systemic inflammation measured by CRP.

Keywords

Alzheimer's disease

Cognitive aging

Polygenic risk scores

APOE

serum CRP

pathway-based PRS-LOAD

List of abbreviationsLOAD

Late-onset Alzheimer's disease

GWAS

Genome-wide association studies

SNP

Single-nucleotide polymorphism

ADNI study

The Alzheimer's Disease Neuroimaging Initiative

APP

Amyloid precursor protein metabolism/Aß-formation

RCT

Reverse cholesterol transport

PRS-LOAD

Genome-wide polygenic risk score for Late-onset Alzheimer's disease

APP PRS-LOAD

Amyloid precursor protein metabolism/Aß-formation pathway polygenic risk score

Tau PRS-LOAD

Tau protein binding pathway polygenic risk score

Lipids PRS-LOAD

Lipids metabolism pathway polygenic risk score

RCT PRS-LOAD

Reverse cholesterol transport pathway polygenic risk score

Immune PRS-LOAD

Immune response pathway polygenic risk score

ICD-10

International Statistical Classification of Diseases and Related Health Problems 10th Revision

VNR

Verbal number reasoning test

© 2023 The Author(s). Published by Elsevier Inc.