Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum

dc.contributor.authorWen, Junhao
dc.contributor.authorYang, Zhijian
dc.contributor.authorNasrallah, Ilya M.
dc.contributor.authorCui, Yuhan
dc.contributor.authorErus, Guray
dc.contributor.authorSrinivasan, Dhivya
dc.contributor.authorAbdulkadir, Ahmed
dc.contributor.authorMamourian, Elizabeth
dc.contributor.authorHwang, Gyujoon
dc.contributor.authorSingh, Ashish
dc.contributor.authorBergman, Mark
dc.contributor.authorBao, Jingxuan
dc.contributor.authorVarol, Erdem
dc.contributor.authorZhou, Zhen
dc.contributor.authorBoquet-Pujadas, Aleix
dc.contributor.authorChen, Jiong
dc.contributor.authorToga, Arthur W.
dc.contributor.authorSaykin, Andrew J.
dc.contributor.authorHohman, Timothy J.
dc.contributor.authorThompson, Paul M.
dc.contributor.authorVilleneuve, Sylvia
dc.contributor.authorGollub, Randy
dc.contributor.authorSotiras, Aristeidis
dc.contributor.authorWittfeld, Katharina
dc.contributor.authorGrabe, Hans J.
dc.contributor.authorTosun, Duygu
dc.contributor.authorBilgel, Murat
dc.contributor.authorAn, Yang
dc.contributor.authorMarcus, Daniel S.
dc.contributor.authorLaMontagne, Pamela
dc.contributor.authorBenzinger, Tammie L.
dc.contributor.authorHeckbert, Susan R.
dc.contributor.authorAustin, Thomas R.
dc.contributor.authorLauner, Lenore J.
dc.contributor.authorEspeland, Mark
dc.contributor.authorMasters, Colin L.
dc.contributor.authorMaruff, Paul
dc.contributor.authorFripp, Jurgen
dc.contributor.authorJohnson, Sterling C.
dc.contributor.authorMorris, John C.
dc.contributor.authorAlbert, Marilyn S.
dc.contributor.authorBryan, R. Nick
dc.contributor.authorResnick, Susan M.
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorFan, Yong
dc.contributor.authorHabes, Mohamad
dc.contributor.authorWolk, David
dc.contributor.authorShen, Li
dc.contributor.authorShou, Haochang
dc.contributor.authorDavatzikos, Christos
dc.contributor.departmentRadiology and Imaging Sciences, School of Medicine
dc.date.accessioned2024-11-18T11:06:42Z
dc.date.available2024-11-18T11:06:42Z
dc.date.issued2024-10-05
dc.description.abstractAlzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .
dc.eprint.versionFinal published version
dc.identifier.citationWen J, Yang Z, Nasrallah IM, et al. Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum. Transl Psychiatry. 2024;14(1):420. Published 2024 Oct 5. doi:10.1038/s41398-024-03121-5
dc.identifier.urihttps://hdl.handle.net/1805/44565
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1038/s41398-024-03121-5
dc.relation.journalTranslational Psychiatry
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourcePMC
dc.subjectPersonalized medicine
dc.subjectPredictive markers
dc.subjectAlzheimer disease
dc.subjectCognitive dysfunction
dc.subjectAtrophy
dc.subjectMagnetic resonance imaging
dc.titleGenetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum
dc.typeArticle
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