Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

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Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer's disease

10.21203/rs.3.rs-149163/v3 ◽

2021 ◽

Author(s):

Atul Kumar ◽

Maryam Shoai ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

John Hardy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Genetic Variants ◽

Cognitive Change ◽

Mediation Effect ◽

Polygenic Risk Score ◽

Preclinical Ad ◽

Polygenic Scores

Abstract Background: Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability.Methods: In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 260 b-amyloid (Ab) negative cognitively unimpaired (CU) individuals, 121 Ab-positive CU (preclinical AD), 50 Ab-negative mild cognitive impairment (MCI) patients, and 127 Ab-positive MCI patients (prodromal AD). Results: The polygenic score (PGS) for intelligence (p = 2.9e-02, beta = 0.1) was protective in CU and MCI participants regardless of Ab status, while polygenic risk score for AD (p = 8.2e-03, beta = -0.12) was correlated with rate of cognitive impairment and was partially mediated by Ab-pathology (mediation effect 20 %). There was no influence of education PGS, implying that educational achievement and rate of cognitive impairment are unrelated.Conclusions: Genetic variants associated with intelligence mitigate cognitive decline independent of Ab-pathology, but the effects of genetic variants associated with AD are partly mediated by Ab-pathology.

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Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-021-99310-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atul Kumar ◽

Maryam Shoai ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

John Hardy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Genetic Variants ◽

Statistical Significance ◽

Cognitive Change ◽

Rate Of Change ◽

Polygenic Risk Score ◽

Preclinical Ad ◽

Polygenic Scores

AbstractCognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years. We included 260 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 121 Aβ-positive CU (preclinical AD), 50 Aβ-negative mild cognitive impairment (MCI) patients, and 127 Aβ-positive MCI patients (prodromal AD). Statistical significance was determined at Bonferroni corrected p value < 0.05. The PGS for intelligence (beta = 0.1, p = 2.9e−02) was protective against decline in MMSE in CU and MCI participants regardless of Aβ status. The polygenic risk score for AD (beta = − 0.12, p = 9.4e−03) was correlated with the rate of change in MMSE and was partially mediated by Aβ-pathology (mediation effect 20%). There was no effect of education PGS on cognitive measures. Genetic variants associated with intelligence mitigate cognitive decline independent of Aβ-pathology, while effects of genetic variants associated with AD are partly mediated by Aβ-pathology.

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Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01199-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Joseph S. Reddy ◽

Mariet Allen ◽

Charlotte C. G. Ho ◽

Stephanie R. Oatman ◽

Özkan İş ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genome Wide Association Study ◽

Transcriptome Profiling ◽

Brain Regions ◽

Common Finding ◽

Amyloid Angiopathy ◽

Genome Wide ◽

A Genome ◽

Male Sex

AbstractCerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

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