Background: Analyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) is important for identifying potential disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue-level eQTLs. Recent studies have explored brain cell type-specific eQTLs, but they lack a systematic analysis across various Alzheimer's disease (AD) GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type-specific eQTL datasets. In this study, we integrated brain cell type-specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level. Methods: To prioritize disease-causing genes, we used Summary Data-Based Mendelian Randomization (SMR) and Bayesian Colocalization (COLOC) to integrate AD GWAS summary statistics with cell-type-specific eQTLs. Combining data from five AD GWAS, three single-cell eQTL datasets, and one bulk tissue eQTL meta-analysis, we identified and confirmed both novel and known candidate causal genes. We investigated gene regulation through enhancer activity using H3K27ac and ATAC-seq data, performed protein-protein interaction and pathway enrichment analyses, and conducted a drug/compound enrichment analysis with the Drug Signatures Database (DSigDB) to support drug repurposing for AD. Results: We identified 27 candidate causal genes for AD using cell type-specific eQTL datasets, with the highest numbers in microglia, followed by excitatory neurons, astrocytes, inhibitory neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). PABPC1 emerged as a novel astrocyte-specific gene. Our analysis revealed protein-protein interaction (PPI) networks for these causal genes in microglia and astrocytes. We found the "regulation of aspartic-type peptidase activity" pathway being the most enriched among all the causal genes. AD-risk variants associated with candidate causal gene PABPC1 is located near or within enhancers only active in astrocytes. We classified the genes into three drug tiers and identified druggable interactions, with imatinib mesylate emerging as a key candidate. A drug-target gene network was created to explore potential drug targets for AD. Conclusions: We systematically prioritized AD candidate causal genes based on cell type-specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD-related genetic variants and facilitates the interpretation of AD GWAS results.

A.S. has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as several other NIA External Advisory Committees. He also serves as Editor-in-Chief of Brain Imaging and Behavior, a Springer-Nature Journal. S. L., T. R., P. B., D. C., D. B., N. T., K. N., S. C., M. C., Y. H., and T. P. have no interest to declare. The funders had no role in the study's design, the collection, analyses, or interpretation of data, the writing of the manuscript, or the decision to publish the results.

A.S. receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). K.N receives support from NIH grants (R01LM012535, U01AG072177, and U19AG0748790). U19AG074879). S.C was supported by ADNI Health Equity Scholarship (ADNI HESP) a sub-award of NIA grant (U19AG024904). S.L was supported by CLEAR-AD Diversity Scholarship of U19AG074879.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used ONLY openly available human data that were originally located at: GWAS summary statistics for Alzheimer's disease (AD) from [GCST007511](https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST007001-GCST008000/GCST007511/), [GCST013197](https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST013001-GCST014000/GCST013197/), [GCST90027158](http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90027001-GCST90028000/GCST90027158/), [GCST90012877](http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90012001-GCST90013000/GCST90012877/), and [GCST007320](http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST007001-GCST008000/GCST007320/). Publicly available summary statistics of MetaBrain eQTLs are available on the [MetaBrain website](https://www.metabrain.nl/). Fujita and Bryois Single-cell eQTL datasets are available from [Synapse (syn52335807)](https://www.synapse.org/), and [Zenodo (https://doi.org/10.5281/zenodo.5543734)](https://doi.org/10.5281/zenodo.5543734). The Mathys et al. (2023) snRNA dataset from the ROSMAP cohort is available from [Synapse (syn52293442)](https://www.synapse.org/). The publicly available dataset, including ATAC-seq (identifying open chromatin regions) and ChIP-seq (marking active enhancers (H3K27ac) and promoters (H3K4me3)) for each brain cell type, can be accessed through the UCSC Genome Browser session (hg19) at [the link](https://genome.ucsc.edu/s/nottalexi/glassLab_BrainCellTypes_hg19).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in this study are available upon reasonable request to the authors. The publicly available datasets used in this study can be accessed as follows: GWAS summary statistics for Alzheimer's disease (AD) from [GCST007511](https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST007001-GCST008000/GCST007511/), [GCST013197](https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST013001-GCST014000/GCST013197/), [GCST90027158](http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90027001-GCST90028000/GCST90027158/), [GCST90012877](http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90012001-GCST90013000/GCST90012877/), and [GCST007320](http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST007001-GCST008000/GCST007320/). Publicly available summary statistics of MetaBrain eQTLs are available on the [MetaBrain website](https://www.metabrain.nl/). Fujita and Bryois Single-cell eQTL datasets are available from [Synapse (syn52335807)](https://www.synapse.org/), and [Zenodo (https://doi.org/10.5281/zenodo.5543734)](https://doi.org/10.5281/zenodo.5543734). The Mathys et al. (2023) snRNA dataset from the ROSMAP cohort is available from [Synapse (syn52293442)](https://www.synapse.org/). The publicly available dataset, including ATAC-seq (identifying open chromatin regions) and ChIP-seq (marking active enhancers (H3K27ac) and promoters (H3K4me3)) for each brain cell type, can be accessed through the UCSC Genome Browser session (hg19) at [the link](https://genome.ucsc.edu/s/nottalexi/glassLab_BrainCellTypes_hg19).