Sleep Disturbance and Cognitive Function in Alzheimer’s Disease: The Shared Genetic Basis

Sleep disturbances (SD) are linked to cognitive function (CF) and Alzheimer’s disease (AD), but the genetic mechanisms, especially in non-European populations, are underexplored. With the goal to further the understanding of the genetic architecture of AD and promote the development of early prediction of AD, this research will use large-scale data to investigate the genetic basis underlying SD and CF in AD.
Objectives
1. Identify unique and shared genetic basis of SD and CF in AD.
2. Examine the associations between genetic liability and measurement of SD and CF in AD progression.
Study Design
Objective 1 will be a genome wide association study (GWAS).
Objective 2 will be a polygenic risk score (PRS) study.
Analysis Plan
We will combine the genotype data from NIAGADS with phenotype data from the NACC to conduct the proposed projects. Specifically, we propose to use the Alzheimer’s Disease Research Centers (ADRC) GWAS Datasets ADC1-15 to maximize the sample that matches with NACC phenotypes (SD, CF, and AD).
Analyses will follow the established Ricopili protocol (https://sites.google.com/a/broadinstitute.org/ricopili/). First, we will conduct quality control (QC) checks on genotype data following standard protocols. Second, we will conduct data imputation where genetic variants were not genotypes using Michigan Imputation Server following standard protocols using the 1000 Genomes Phase 3 Reference data.
For objective 1, we will conduct the phenotype-specific GWAS on SD, CF, and AD. We will then run cross-phenotype meta-analysis to examine the shared genetic basis of sleep disturbance and cognitive function in AD.
For objective 2, we will construct PRSs for SD, CF and AD using PRS-CSx approach. Linear and logistic regressions will be used to examine the associations between PRS and measurements of SD and CF, and AD. Cox proportional hazard regression will be used to examine the association between SD PRS and longitudinal CF changes in AD progression.
Outcomes, such as summary statistics of GWAS and constructed PRSs, will be submitted to NIAGADS.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive deterioration. It affects approximately 34 million people worldwide, yet reliable early prediction methods remain elusive. Prior research has implicated the impact of sleep disturbance on cognitive decline and AD pathophysiology. However, few studies have explored the genetic correlation between sleep disturbance and cognitive function in the context of AD, especially among non-European populations. To address these research gaps, the proposed research will employ bioinformatic and computational techniques to analyze largescale databases to further understand the unique and shared genetic variants that contribute to sleep disturbance and cognitive function in AD. This exploration of the genetic correlation between sleep disturbance and cognitive function in AD will inform future research to improve early detection of AD risk in individuals with pre-clinical symptoms and prediction of cognitive deterioration through AD development and progression.