Association Analysis Between Ischemic Stroke Risk Single Nucleotide Polymorphisms and Alzheimer's Disease

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Alzheimer's disease (AD) and ischemic stroke (IS) frequently co-occur, sharing risk factors and pathogenic mechanisms.
• The genetic overlap between IS risk and AD requires further investigation, particularly regarding specific gene polymorphisms.
• Understanding shared genetic underpinnings can illuminate disease pathways and identify novel therapeutic targets.

Purpose of the Study:

• To investigate the association between single nucleotide polymorphisms (SNPs) associated with ischemic stroke risk and the risk and severity of Alzheimer's disease.
• To explore the interaction between IS risk SNPs and apolipoprotein E (ApoE) ε4 status in relation to AD risk.
• To identify genetic markers from IS risk genes that may serve as predictors for AD.

Main Methods:

• Utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, including AD patients and normal controls.
• Identified IS risk SNPs from a large genome-wide association study (GWAS) meta-analysis.
• Performed SNP-based association analyses for AD risk, cerebrospinal fluid (CSF) biomarkers (Aβ42, t-tau, p-tau181), and neuroimaging data (hippocampal, whole brain, entorhinal cortex, mid-temporal volumes).
• Employed generalized multifactor dimensionality reduction (GMDR) to assess interactions between IS-risk SNPs and ApoE ε4.
• Explored protein-protein interactions (PPIs) using the STRING database.

Main Results:

• Five of seven studied IS-risk SNPs showed associations with AD risk indicators, including CSF biomarker levels and brain volumes.
• The T allele of SNP rs1487504 was linked to increased AD risk in individuals without the ApoE ε4 allele.
• A significant interaction between rs1487504 and ApoE ε4 was identified as an optimal model for predicting AD risk.
• SNP rs880315 (C allele) was associated with higher CSF Aβ42 levels, and SNP rs10774625 (A allele) with reduced entorhinal cortex volume in AD patients.

Conclusions:

• Ischemic stroke risk SNPs are significantly associated with both the risk of developing Alzheimer's disease and key AD biomarkers.
• These findings provide a genetic perspective on the relationship between IS and AD, highlighting shared genetic factors.
• IS risk SNPs represent a potential avenue for developing innovative predictive models for Alzheimer's disease.