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

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 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/ .

Authors

Institutions

Publication Details

Journal
Translational Psychiatry
Published
2024-10-05
DOI
https://doi.org/10.1038/s41398-024-03121-5
Citations
18
Primary Topic
Health, Environment, Cognitive Aging
Type
article
Field-Weighted Citation Impact
5.35
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Tammie L.S. Benzinger, Aristeidis Sotiras, Ashish Singh, Susan M. Resnick et al.
18 citations
Translational Psychiatry
Health, Environment, Cognitive Aging
5.35
article

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

Tammie L.S. Benzinger, Aristeidis Sotiras, Ashish Singh, Susan M. Resnick, Susan R. Heckbert, Duygu Tosun, Timothy J. Hohman, Ilya M. Nasrallah, Yong Fan, Gyujoon Hwang, Arthur W. Toga, Lenore J. Launer, Mohamad Habes, Jürgen Fripp, Andrew J. Saykin, Güray Erus, Jiong Chen, Christos A. Davatzikos, Hans Jörgen Grabe, David A. Wolk, Dhivya Srinivasan, Aleix Boquet-Pujadas, Jingxuan Bao, Colin Louis Masters, Luigi Ferrucci, Thomas R. Austin, Haochang Shou, Pamela LaMontagne, John C. Morris, Paul T. Maruff, Mark A. Espeland, Ahmed Abdulkadir, Zhen Zhou, Yuhan Cui, Katharina Wittfeld, Mark Bergman, Erdem Varol, Sylvia Villeneuve, R. Nick Bryan, Junhao Wen, Sterling C. Johnson, Murat Bilgel, Elizabeth Mamourian, Randy L. Gollub, Li Shen, Paul M. Thompson, Zhijian Yang, Yang An, Marilyn S. Albert, Daniel S. Marcus
article en
18 citations

Abstract

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 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/ .

Translational PsychiatryVol. 14(1)
University of Southern California (US), Indiana University Health (US), National Institutes of Health (US), University of Wisconsin–Madison (US), Harvard University (US), Johns Hopkins University (US), The University of Melbourne (AU), The University of Texas at San Antonio Health Science Center (US), University of California, San Francisco (US), University of Washington (US), Washington University in St. Louis (US), Florey Institute of Neuroscience and Mental Health (AU), Universitätsmedizin Greifswald (DE), Douglas Mental Health University Institute (CA), Johns Hopkins Medicine (US), MedStar Harbor Hospital (US), Massachusetts General Hospital (US), Alzheimer’s Disease Neuroimaging Initiative (US), Athinoula A. Martinos Center for Biomedical Imaging (US), Penn Center for AIDS Research (US), National Institute on Aging (US), Australian e-Health Research Centre (AU), CSIRO Health and Biosecurity (AU), Cognitive Neuroimaging Lab (FR), Artificial Intelligence in Medicine (Canada) (CA), Wake Forest University (US), McGill University (CA), Indiana University – Purdue University Indianapolis (US), Columbia University (US), University of Pennsylvania (US), Vanderbilt University Medical Center (US), University of Lausanne (CH)
Openalex Percentile: Top 4%
Health, Environment, Cognitive Aging
5.35
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.