Genomic Characterisation of the Relationship and Causal Links Between Vascular Calcification, Alzheimer’s Disease, and Cognitive Traits

Biomedicines, Journal Year: 2025, Volume and Issue: 13(3), P. 618 - 618

Published: March 3, 2025

Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, underlying mechanisms are unclear. Here, we investigate shared genetic causal relationships of calcification—coronary artery (CAC) abdominal aortic (AAC)—with Alzheimer’s disease (AD), five traits. Methods: We analyse large-scale genome-wide association (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), gene-based analysis. Results: Our findings reveal nominally significant positive correlation CAC AD, which becomes non-significant after excluding APOE region. AAC demonstrate negative correlations with performance educational attainment. MR found no AD traits, except for bidirectional borderline-significant fluid intelligence scores. Pairwise-GWAS analysis identifies SNPs (posterior probability [PPA]3 < 0.5). However, find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, gene analyses revealing genes in regions, APOE, TOMM40, NECTIN2, APOC1. Moreover, identify suggestively 0.5) chromosomes 1, 6, 7, 9 implicating genes, NAV1, IPO9, PHACTR1, UFL1, FHL5, FOCAD. Conclusions: Current limited associations loci, at region, highlight complex interplay neurodegenerative processes. Given APOE’s roles lipid metabolism, neuroinflammation, integrity, its involvement may disorders, pointing to potential targets further investigation.

Language: Английский

Genetic and Lifestyle Risks for Coronary Artery Disease and Long-Term Risk of Incident Dementia Subtypes

Circulation, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

BACKGROUND: Shared genetic and lifestyle risk factors may underlie the development of both coronary artery disease (CAD) dementia. We examined whether an increased for CAD is associated with long-term developing all-cause, Alzheimer’s, or vascular dementia, investigated differences in potentially modifiable mid- to late-life period attenuate this risk. METHODS: A prospective cohort study 365 782 participants free from dementia at least 5 years after baseline assessment was conducted within UK Biobank cohort. Genetic assessed using a genomewide polygenic score (PRS) modified version American Heart Association’s Life’s Essential 8 Lifestyle Risk Score (LRS). Higher values scores were deemed represent Primary outcomes incident diagnoses obtained electronic health records. Secondary neuroimaging phenotypes measured 32 028 recalled magnetic resonance imaging. Sensitivity analyses test extent by which biological behavioral contributed observed associations. RESULTS: total 8870 cases all-cause over median 13.9-year follow-up. Both (LRS) modestly elevated (subhazard ratio per SD increase, 1.10 [1.08, 1.12], P <0.001, PRS 1.04 [1.02, 1.06], =0.006, LRS). This appeared largely attributable underlying ratio, 1.16 [1.11, 1.21], <0.001 1.15 [1.09, 1.22], LRS), because Alzheimer’s found demonstrate moderate associations alone 1.09 [1.06, 1.13]; <0.001). LRS have additive rather than interactive effect PRS, individuals highest tertiles ≈70% more likely develop during follow-up compared those lowest 1.71 [1.39, 2.11]; substantially attenuated low baseline, however, regardless (40% 50% reduction versus high tertile tertile; all). In subset assessments, demonstrated ≈25% greater volume white matter hyperintensities tertiles, but showed little difference gray hippocampal volumes. identified between hyperintensity burden whereas some seemingly paradoxical relationships. CONCLUSIONS: Individuals who are genetically predisposed also face old age. reduced demonstrating healthy profiles earlier lifespan, particularly be caused pathology.

Language: Английский