TY - JOUR
T1 - Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum
AU - Wen, Junhao
AU - Yang, Zhijian
AU - Nasrallah, Ilya M.
AU - Cui, Yuhan
AU - Erus, Guray
AU - Srinivasan, Dhivya
AU - Abdulkadir, Ahmed
AU - Mamourian, Elizabeth
AU - Hwang, Gyujoon
AU - Singh, Ashish
AU - Bergman, Mark
AU - Bao, Jingxuan
AU - Varol, Erdem
AU - Zhou, Zhen
AU - Boquet-Pujadas, Aleix
AU - Chen, Jiong
AU - Toga, Arthur W.
AU - Saykin, Andrew J.
AU - Hohman, Timothy J.
AU - Thompson, Paul M.
AU - Villeneuve, Sylvia
AU - Gollub, Randy
AU - Sotiras, Aristeidis
AU - Wittfeld, Katharina
AU - Grabe, Hans J.
AU - Tosun, Duygu
AU - Bilgel, Murat
AU - An, Yang
AU - Marcus, Daniel S.
AU - LaMontagne, Pamela
AU - Benzinger, Tammie L.
AU - Heckbert, Susan R.
AU - Austin, Thomas R.
AU - Launer, Lenore J.
AU - Espeland, Mark
AU - Masters, Colin L.
AU - Maruff, Paul
AU - Fripp, Jurgen
AU - Johnson, Sterling C.
AU - Morris, John C.
AU - Albert, Marilyn S.
AU - Bryan, R. Nick
AU - Resnick, Susan M.
AU - Ferrucci, Luigi
AU - Fan, Yong
AU - Habes, Mohamad
AU - Wolk, David
AU - Shen, Li
AU - Shou, Haochang
AU - Davatzikos, Christos
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - Alzheimer’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 APOEε4, 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/.
AB - Alzheimer’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 APOEε4, 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/.
UR - http://www.scopus.com/inward/record.url?scp=85205758659&partnerID=8YFLogxK
U2 - 10.1038/s41398-024-03121-5
DO - 10.1038/s41398-024-03121-5
M3 - Article
C2 - 39368996
AN - SCOPUS:85205758659
SN - 2158-3188
VL - 14
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 420
ER -