Title: Gene Expression and Biological Pathway Associations with Clinical Phenotypes in Alzheimer’s Disease

This project will examine how genetic variants, gene expression profiles, transcriptomic patterns, APOE status where available, and biological pathways are associated with Alzheimer’s disease and related cognitive, functional, and neuropathological phenotypes. The goal is to identify genomic and pathway-level factors that may help explain cognitive decline, daily functional changes, neuropathological burden, and vulnerability or resilience in Alzheimer’s disease and related neurodegenerative or cognitive aging conditions.

This study is a secondary analysis of existing coded/de-identified controlled-access data obtained through NIAGADS DSS. No new participants will be recruited, no participant contact will occur, and no new biospecimens or data will be collected. The requested datasets include Alzheimer’s disease sequencing data, oldest-old clinical and pathological data, microglia single-nuclei RNA-seq data, multi-brain-region mRNA-seq data from sporadic ALS, and genomic data related to cognitive ability. All analyses will comply with NIAGADS data use limitations, NIH Genomic Data Sharing Policy, NIA requirements, and Messiah University institutional oversight.

Analyses will evaluate associations between genetic or gene-level features and approved phenotypes, including AD diagnosis, case-control status, cognitive performance, general cognitive ability, functional status, daily activity measures, neuropathological findings, microglia-related expression profiles, brain-region-specific expression patterns, and disease stage where available. Methods may include quality control, phenotype harmonization, regression-based association testing, differential gene expression analysis, variant-to-gene annotation, gene-level aggregation, pathway enrichment, and aggregate or polygenic measures if appropriate. Models will adjust for relevant covariates such as age, sex, ancestry, relatedness, brain region, cell type, disease stage, batch effects, and technical factors. Only aggregate or summary-level results will be reported.

This project will use existing de-identified research data to study why some people develop Alzheimer’s disease or cognitive decline while others remain more resilient. The study will look at genetic information, gene activity, and biological pathways that may be related to memory, thinking ability, daily function, and brain changes seen in Alzheimer’s disease and related conditions.

No new participants will be recruited, and no new samples will be collected. The project will only use approved research data from NIAGADS. The goal is to better understand how inherited genetic differences and changes in gene expression may contribute to Alzheimer’s disease, cognitive decline, and functional changes in daily life. This research may help identify biological patterns that could support future studies on earlier detection, risk prediction, and better understanding of neurodegenerative diseases.

All data used in this project will be coded or de-identified. The study will not attempt to identify any individual participant, and results will only be reported in summary form.