Year: 2026
Type: preprint
Abstract: The apolipoprotein E ε4 ( APOE ε4) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet its associated protein changes across biofluids, brain regions, and cell types remain incompletely understood. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimer’s Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). To characterise APOE ε4 effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and patient induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. In plasma, APOE ε4 carriers shared a proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this plasma signature discriminated carriers from non-carriers in an independent CSF cohort, and mediation analysis resolved a subset of these proteins into those lying upstream and downstream of AD. Carriage was also associated with greater neuropathological burden, reflected in higher Braak stages and CERAD scores. However, only limited APOE ε4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor concordance between the transcriptome and proteome. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE ε4-associated changes. These findings show that APOE ε4 is associated with a consistent proteomic signature across plasma and CSF, but its effects in the brain differ across cell types and brain regions.
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Epidemiologic Study of Neural Reserve and Neurobiology of Aging, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, Exploring the Role of the Brain Transcriptome in Cognitive Decline, Identifying, validating and targeting AD susceptibility networks in monocytes, Pathway discovery, validation and compound identification for Alzheimer's disease, G4356727394, Exploring the Role of the Brain Epigenome: Cognitive Decline and Life Experiences, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, Alzheimer's Disease Genetics Consortium, G5627134285, G578809140, AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers, G5952929075, Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targets, Cognitive Decline and Dementia: Life Experiences and the Brain Histone Epigenome, Discovery of Novel Proteomic Targets for Treatment of Alzheimer's Disease, Deconstructing and modeling the single cell architecture of the Alzheimer brain, Rush Alzheimer's Disease Research Center
OpenAlex ID: W7207836190