Elsevier

Neurobiology of Aging

Volume 126, June 2023, Pages 103-112
Neurobiology of Aging

Independent role of Alzheimer's disease genetics and C-reactive protein on cognitive ability in aging

https://doi.org/10.1016/j.neurobiolaging.2023.02.006Get rights and content
Under a Creative Commons license
open access

Highlights

  • Apolipoprotein E (APOE) ε4 was associated with more pronounced cognitive decline over time.

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

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

  • 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 4 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 abbreviations

LOAD
Late-onset Alzheimer's disease
APOE
Apolipoprotein
GWAS
Genome-wide association studies
AD
Alzheimer's disease
SNP
Single-nucleotide polymorphism
ADNI study
The Alzheimer's Disease Neuroimaging Initiative
CSF
Cerebrospinal fluid
UKB
UK Biobank
APP
Amyloid precursor protein metabolism/Aß-formation
RCT
Reverse cholesterol transport
CRP
C-reactive protein
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
LD
Linkage Disequilibrium
ICD-10
International Statistical Classification of Diseases and Related Health Problems 10th Revision
VNR
Verbal number reasoning test
NM
Numeric memory test
VM
Visual memory test
RT
Reaction time test

Cited by (0)