Alzheimer's Disease (AD) is characterized by its complex and heterogeneous etiology and gradual progression, leading to high drug failure rates in late-stage clinical trials. In order to better stratify individuals at risk for AD and discern potential therapeutic targets we employed a novel procedure utilizing cell-based co-regulated gene networks and polygenic risk scores (cbPRSs). After defining genetic subtypes using extremes of cbPRS distributions, we evaluated correlations of the genetic subtypes with previously defined AD subtypes defined on the basis of domain-specific cognitive functioning and neuroimaging biomarkers. Employing a PageRank algorithm, we identified priority gene targets for the genetic subtypes. Pathway analysis of priority genes demonstrated associations with neurodegeneration and suggested candidate drugs currently utilized in diabetes, hypertension, and epilepsy for repositioning in AD. Experimental validation utilizing human induced pluripotent stem cell (hiPSC)-derived astrocytes demonstrated the modifying effects of estradiol, levetiracetam, and pioglitazone on expression of APOE and complement C4 genes, suggesting potential repositioning for AD.

The authors have declared no competing interest.

This study was supported by the National Institute of Health (NIH) grants, U01AG068057, U19AG068753, U19AG079774, P30AG072978, RF1AG057519, R01AG069453, R56AG069130, U01AG032984, R01AG048927, U01AG062602, U01AG058654, RF1AG057768, and RF1AG054156. ROSMAP is supported by P30AG10161, P30AG72975, R01AG15819, R01AG17917, R01AG36042, U01AG46152, U01AG61356, R01AG082362, R56 AG078733, and K01AG062683. FHS is supported by National Heart, Lung and Blood Institute (75N92019D00031 and HHSN2682015000011). Collection of study data provided by the Rush ADC, Rush University Medical Center, Chicago was supported through funding by NIA grants P30-AG10161, P30-AG72975, R01-AG15819, R01-AG17917, U01-AG46152, and U01-AG61356, and funding from the Illinois Department of Public Health. We acknowledge Tony Tuck for the cell culture maintenance and support.

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 protocol, design, and performance of the current study were approved by the Boston University Institutional Review Board.

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.

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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).

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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

FHS data are available on the dbGaP website (https://www.ncbi.nlm.nih.gov/gap/; Study Accession ID: phs000056.v5.p3). ROSMAP resources can be requested at from the CommonMind Consortium portal (http://www.synapse.org). Data used in preparation of this article were obtained from the ADNI database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at the ADNI website (http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf).

http://www.synapse.org

http://adni.loni.usc.edu

https://www.ncbi.nlm.nih.gov/gap/