Journal Article

Basic Science and Pathogenesis

Tosto, Giuseppe, Jiménez-Velázquez, Ivonne Z, Mez, Jesse, Lee, Annie J, Farrer, Lindsay A, Vardarajan, Badri N, Wang, Yanling, Lantigua, Rafael A, Chung, Jaeyoon, Schneider, Julie A, Brickman, Adam M, Kizil, Caghan, Mejia, Diones Rivera, Reyes-Dumeyer, Dolly, Medrano, Martin, Biber, Sarah A, Bennett, David A, Mayeux, Richard, Cui, Zuoqiao, Kukull, Walter A, Song, Zhengwei, Menon, Vilas, De Jager, Philip L

2024

Overview

Cardio and cerebrovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and clinical Alzheimer's Disease (AD), and over 70% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with a burden score of hypertension, diabetes, heart disease, and body mass index (BMI) by altering the normal astroglial-vascular mechanisms that underly amyloid clearance. Stroke, defined by history of a clinical stroke or brain imaging, is a moderately robust risk factor for AD and dementia. The goal here was to identify genes that interact with CVRFs, incorporating stroke as an additional factor, on AD in multi-ethnic cohorts. We conducted a genome-wide gene-CVRF score interaction analysis for AD, in 7,939 AD patients and 9,631 controls from eight multi-ethnic cohorts of non-Hispanic Whites, African Americans, and Hispanics including ADNI, NACC, NOMAS, WHICAP, EFIGA, and ROSMAP. A CVRF score was created from the first principal component of history of clinical stroke, hypertension, diabetes, and heart disease, and measured BMI. Gene-based interaction test was performed with the adaptive gene-environment interaction test. Results were summarized using a meta-analysis. We investigated the association of pathological AD, amyloid-β, or brain infarcts with gene expression and protein expression from the frontal cortex in ROSMAP using a generalized linear model. Age, sex, and the first three principal components were adjusted in the models. The interaction of CVRF score with FMNL2 on AD (p = 1.02E-05) was identified and additional genes were identified to interact with CVRF score, including SLC22A14 (p = 1.44E-06), AMMECR1L (p = 2.74E-06), PRG3 (p = 2.76E-06), CFAP99 (p = 5.22E-06), ADPGK-AS1 (p = 8.58E-06) and BRINP1 (p = 6.29E-06). ADPGK-AS1 and FMNL2 gene expressions were associated with pathological AD (p = 0.004 and p = 0.0002). FMNL2 and BRINP1 gene expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006). BRINP1 protein expression was associated with pathological AD (p = 0.0002) and was higher in the brains of patients with brain infarcts (p = 0.022). We identified novel candidate genes that interact with CVRFs on AD in multi-ethnic cohorts. Understanding the interplay between genes, CVRFs, and AD has the potential to reveal novel molecular targets for prevention and treatment for AD.

• Subject: Aged / Aged, 80 and over / Alzheimer Disease - genetics / Alzheimer Disease - pathology / Cohort Studies / Female / Genome-Wide Association Study / Humans / Male / Risk Factors