Alzheimer's disease heterogeneity explained by polygenic risk scores derived from brain transcriptomic profiles

Year: 2023

Type: article

Abstract: INTRODUCTION: Alzheimer's disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity. METHODS: We conducted co-expression network analysis and identified gene sets (modules) that were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits including neuritic plaques (NPs) and neurofibrillary tangles (NFTs). We computed the module-based PRSs (mbPRSs) for each module and tested associations with mbPRSs for cognitive test scores, cognitively defined AD subgroups, and brain imaging data. RESULTS: Of the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning, respectively. They matched clinical subtypes and brain atrophy at specific regions. DISCUSSION: Our findings demonstrate that polygenic profiling based on co-expressed gene sets can explain heterogeneity in AD patients, enabling genetically informed patient stratification and precision medicine in AD. HIGHLIGHTS: Co-expression gene-network analysis in Alzheimer's disease (AD) brains identified gene sets (modules) associated with AD heterogeneity. AD-associated modules were selected when genes in each module were enriched for neuritic plaques and neurofibrillary tangles. Polygenic risk scores from two selected modules were linked to the matching cognitively defined AD subgroups (language and visuospatial subgroups). Polygenic risk scores from the two modules were associated with cognitive performance in language and visuospatial domains and the associations were confirmed in regional-specific brain atrophy data.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.13069

Authors: Jaeyoon Chung, Nathan Sahelijo, Toru Maruyama, Junming Hu, Rebecca Panitch, Weiming Xia, Jesse Mez, Thor D. Stein, the Alzheimer's Disease Neuroimaging Initiative, Andrew J. Saykin, Haruko Takeyama, Lindsay A. Farrer, Paul K. Crane, Kwangsik Nho, Gyungah R. Jun

Institutions: Boston University, Waseda University, Veterans Health Administration, Edith Nourse Rogers Memorial Veterans Hospital, VA Boston Healthcare System, Indiana University Indianapolis, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, Waseda Research Institute for Science and Engineering, University of Washington

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,000

Awards: G1033327480, G104586243, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, G1258278173, G1298807586, G1554142629, G1593117279, G1650819308, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, G1880935189, Alzheimer's Disease Neuroimaging Initiative, G2100670906, G2105457377, G2152643862, G2189010064, G2234218876, G2340207221, G2345704987, G2423387114, G2471646051, G2522063444, Gene discovery in PSP by transcriptome, neuropathology and sequence analysis, G2619161350, G2642611343, G2835601961, G29951154, Plasma AB as a Surrogate Genetic Marker for LOAD, G3025631564, G3036763132, Exploring the Role of the Brain Transcriptome in Cognitive Decline, G3130427885, G3130689503, G3131374986, G3146424788, G3216574877, G3284295768, Asian Cohort for Alzheimer's Disease (ACAD), G3553156159, G3710456697, Alzheimer Disease Genetic Architecture in African Americans, G3752451908, Pathway discovery, validation and compound identification for Alzheimer's disease, G3870774570, Alzheimers Disease Patient Registry, G3908963977, Einstein Aging Study, G4119534169, G4298864339, G43180419, G4440353152, G4475667458, G4501223628, G4800177743, G4860885537, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, G5207404921, G5209990037, Alzheimer's Disease Genetics Consortium, G528601746, G5365730499, EFFECTS OF TRAUMATIC BRAIN INJURY (TBI) AND POST TRAUMATIC STRESS DISORDER (PTSD) ON ALZHEIMER'S DISEASE (AD) IN VETERANS USING IMAGING AND BIOMARKERS IN THE AD NEUROIMAGING INITIATIVE (ADNI)", G5389965057, G5484535055, G5654639750, G5740349702, G5850682332, G613619302, G6173816828, G6194729725, G6210868510, G6371410416, G6412110892, G6447063303, Florida Alzheimer's Disease Research, Genetic Studies of Alzheimer Disease in Koreans, G6530347775, G6719828067, G6792506723, G6899163935, G6922373506, Genome wide association study of gene expression levels in Alzheimer's disease, G72415811, G7298697282, Tau and Neurodegeneration II: A therapeutic target, G7518927107, A Systems Approach to Targeting Innate Immunity in AD, G764699806, Genomic and Biological Studies of APOE ε2 in Alzheimer Disease, G7799614282, G781725486, G8228018387, G8281378126, G8289575266, G8337440805, G839208290, G8629123209, G8852128998, G8895907669, G8897063270, Precision Monitoring and Assessment in the Framingham Study: Cognitive, MRI, Genetic and Biomarker Precursors of AD & Dementia, G8957659042, G9000000449, G9000005508, G9000039018, G9000074849, G9000113025, G9000122335, G9000173373, G9000281821, G9000283702, G9000355711, Boston University Alzheimer's Disease Research Center, THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITE, Genetic Studies of Alzheimer's Disease in Jewish and Arab Populations, Alzheimer's Disease Neuroimaging Initiative (ADNI4), Alzheimer's Disease Research Centers, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), G920654007, Ultrascale Machine Learning to Empower Discovery in Alzheimers Disease Biobanks, G947960016, Mayo Alzheimer's Disease Research Center

OpenAlex ID: W4376132263