Precision Medicine in Alzheimer’s Disease: Phenotype Investigation, Medication Effects and Variant Analysis in Cell Type Specific Subgroups

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by cognitive decline and dementia and has few clinically approved treatments. The clinical and neuropathological heterogeneity of AD suggests the existence of AD subgroups with unique mechanisms and implies the need for cell‐type specific subtyping and treatments. The goal of this project was to investigate the differential effects of medications on cognitive tests in eight previously defined brain cell type‐based polygenic risk scores (PRS).MethodMedication usage information, imputed genotypes, phenotypic data and cognitive test scores were collected for 487,409 participants from the UK Biobank to use in the analysis of the different PRS groups. We determined the characteristics of the PRS used by comparing 16 phenotypes in high and low risk subjects. Association between four cognitive test scores (fluid intelligence, reaction time, prospective memory, and pairs matching) and medication status (treated vs. untreated) was determined using logistic regression. Cognitive scores were rank‐transformed for the analysis, and the logistic regression was performed separately for high‐risk and low‐risk genetic groups. Genome‐wide association studies (GWAS) were used to detect genetic variants linked to medication usage. This analysis was repeated for all, high risk and low risk samples, using only medications that demonstrated a significant association with improved cognitive function during follow up examination.ResultPhenotypic variation was wide among different PRS groups. Genetically different PRS groups shared phenotypic characteristics, suggesting that different underlying mechanisms lead to similar outcomes. Six medications were significantly associated (P<0.05) with improved cognitive function during follow‐up examination. Atenolol, a high blood pressure medication, was associated with the largest gain, with an improvement on the effect of cognitive function by 67% in the high‐risk compared to the low‐risk subjects from an astrocyte genetic subtype (Ast‐M9). The atenolol GWAS focused on the Ast‐M9 high risk group identified two genome wide significant variants at the same locus. These were previously shown to be associated with phenotypes related to blood pressure and were known eQTLs.ConclusionOur findings suggest potential novel implications for genetic subtype‐driven treatment options for AD. Further research is needed to validate these associations that may explain differential effects of medications in AD‐subtypes.