Elucidating the neuropathological and molecular heterogeneity of amyloid beta and tau in Alzheimer's disease through machine learning and transcriptomic integration
Year: 2026
Type: article
Study design: Observational Study
Abstract: Discerning functional brain network variations related to neuropathological aggregates in Alzheimer's disease (AD), including amyloid-beta (Abeta) and phosphorylated tau (p-tau), is crucial for understanding their link to cognitive decline and underlying molecular mechanisms. However, these variations are often confounded by normal aging-related changes, complicating interpretation. To address this challenge, we first defined Alzheimer's continuum cases (Abeta positive (A+), n = 129) and normal elderly (Abeta negative (A-), n = 160) using cerebral spinal fluid amyloid levels, and then applied a novel deep learning approach to resting-state connectivity using functional magnetic resonance imaging (fMRI) of the 289 subjects to disentangle A+-specific dimensions in brain network alterations from those shared with A- individuals. The identified A+-specific dimensions were further refined to predict individual Abeta and p-tau levels separately. We observed that resulting brain signatures, defined from A+-specific dimensions for predicting these two CSF biomarkers, were both attributed to the right superior temporal and anterior cingulate cortices and associated with attention and memory domains. When linking the brain signatures to gene expression data from a public transcriptomic atlas, we found that the brain signatures were associated with molecular pathways involving synaptic dysfunction and disruptions in pathways containing activity of excitatory neurons, astrocytes, and microglia. For A--shared dimensions, the Aβ-linked brain signature involved the left fusiform and right middle cingulate cortices, correlating with the language cognitive measurement and language-related molecular pathways. The p-tau-linked signature predominantly involved the right insula and inferior temporal cortices, correlating with the aging-related molecular pathways. Collectively, our findings provided new insights in understanding of Alzheimer's continuum pathological biomarkers.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.71757
Institutions: Lehigh University, Stanford Medicine, Stanford University, Children's National, George Washington University, Pennsylvania State University, New York University, Hospital de Sant Pau, Biomedical Research Networking Center on Neurodegenerative Diseases, Centro de Investigación Biomédica en Red, Institut de Recerca Sant Pau, The University of Texas at Austin
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Funders: U.S. Department of Defense, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, F. Hoffmann-La Roche, Meso Scale Diagnostics, BioClinica, Novartis Pharmaceuticals Corporation, Northern California Institute for Research and Education, Eisai, Servier, H. Lundbeck A/S, IXICO, National Institutes of Health, Genentech, Canadian Institutes of Health Research, National Institute on Aging, National Heart, Lung, and Blood Institute
Awards: G1012222616, Identifying neural circuits vulnerable during Alzheimer's progression, Assess Neural Circuits and Subtypes Underlying Dimensions of Neuropsychiatric Symptoms in Alzheimer's Disease, G1298807586, Alzheimer's Disease Research Center, G1554142629, G1593117279, DS-ARC: A Remote Digital Cognitive Assessment for Down Syndrome-Associated Alzheimer's Disease, G1650819308, G1880935189, G2100670906, G2152643862, G2189010064, The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome, G2340207221, G2471646051, G2522063444, G3131374986, G3553156159, G3710456697, G3752451908, G3870774570, G3908963977, G3966393351, G4119534169, G43180419, G4475667458, G4501223628, Clinical trials to prevent Alzheimer's Disease in Down Syndrome, G4800177743, G5172452523, G5207404921, G5209990037, G528601746, G5324093878, G5365730499, G5654639750, Alzheimer's Disease Neuroimaging Initiative, G5740349702, G5850682332, G613619302, G6173816828, G6210868510, G6371410416, G6412110892, G6447063303, G6719828067, G6792506723, G6899163935, G6948409098, G72415811, G7298697282, Tau pathology in Down syndrome and Alzheimer's, G764699806, G7799614282, G781725486, G8228018387, G8281378126, G839208290, Biological Correlates of Alzheimer in Down Syndrome., G8852128998, G8895907669, G8897063270, G8957659042, Multidisciplinary Research Training in Sleep Science
OpenAlex ID: W4403540618