Brain Cell-based Genetic Subtyping and Drug Repositioning for Alzheimer Disease.
Nathan SahelijoPriya RajagopalanLu QianRufuto RahmanDhawal PriyadarshiDaniel GoldsteinSophia I ThomopoulosDavid A BennettLindsay A FarrerThor D Steinnull nullLi ShenHeng HuangKwangsik NhoAndrew J SaykinChristos DavatzikosPaul M ThompsonJulia TcwGyungah R JunPublished in: medRxiv : the preprint server for health sciences (2024)
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.
Keyphrases
- insulin resistance
- genome wide
- copy number
- type diabetes
- metabolic syndrome
- dna methylation
- stem cells
- clinical trial
- genome wide identification
- glycemic control
- single cell
- cell therapy
- drug induced
- cardiovascular disease
- machine learning
- transcription factor
- endothelial cells
- cognitive decline
- emergency department
- oxidative stress
- white matter
- climate change
- genome wide analysis
- minimally invasive
- resting state
- multiple sclerosis
- randomized controlled trial
- risk assessment
- weight loss
- functional connectivity
- neural network
- induced pluripotent stem cells
- phase iii