Integrated genetic analysis of Alzheimer's disease and stroke subtypes: insights from LDSC, PLACO, and MR studies

This study aimed to evaluate the genetic relationship between Alzheimer's disease (AD) and stroke, including its subtypes.

The Linkage Disequilibrium Score Regression (LDSC) for heritability and genetic correlations, Polygenic Likelihood Ratio under a Composite Null Hypothesis (PLACO) method for pleiotropic loci and locus, and Functional maps and annotations from genome-wide association studies (FUMA) for function analysis of multi-effect loci, multi-marker analysis of genoMic annotation (MAGMA) for gene tissue specificity, Mendelian Randomization (MR) analyses for causal relationships between AD and five stroke subtypes were performed through Single Nucleotide Polymorphism (SNP) heritability enrichments and causal associations were analyzed using comprehensive GWAS data.

Manhattan plots revealed pleiotropic SNPs mainly on chromosomes 11 and 19, with additional loci on chromosomes 1, 2, and 3 for specific subgroups. Key genes like DEDD, UFC1, USP21, affecting both AD and stroke subtypes, were enriched in brain tissues, highlighting shared mechanisms. Stratified LD score regression showed overlaps in brain regions such as substantia nigra and spinal cord. MR analysis indicated AD as a risk factor for LAS and AS but protective for cerebral embolism stroke (CES), supported by consistent causal effect estimates without publication bias. This study reveals that AD shares genetic factors with multiple stroke subtypes, notably in brain tissues, impacting their etiology and potential treatments.

Overall, our study revealed that AD shares genetic factors with multiple stroke subtypes, notably in brain tissues. MR analysis indicates AD is a risk factor for LAS and AS, but protective for CES.