Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience
Keenan A. Walker, Yang An, Abhay Moghekar, Ruin Moaddel, Michael R. Duggan, Zhongsheng Peng, Qu Tian, Luke C. Pilling, Shannon M. Drouin, Mark A. Espeland, Stephen R. Rapp, Kathleen M. Hayden, Aladdin H. Shadyab, Ramon Casanova, Madhav Thambisetty, Peter R. Rapp, Dimitrios Kapogiannis, Luigi Ferrucci, Susan M. Resnick
Abstract
Abstract Background Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOE ε4 carriers to maintain normal cognitive functioning in older adulthood. Methods APOE ε4 carriers and APOE ε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß 42/40 ) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOE ε4 carriers, examined whether these associations generalized to APOE ε3 homozygotes, and replicated these findings in the UK Biobank. Results A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε 4 carriers). Compared to resilient APOE ε4 carriers, non-resilient APOE ε4 carriers had lower Aß 42/40 /tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε 4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOE ε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOE ε4 carriers (protein*genotype interaction- P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOE ε4 carriers in the UK Biobank validation sample ( N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOE ε4 carriers. Conclusions We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε 4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.