Multi‐ethnic genome‐wide, gene‐based study identifies genes that interact with vascular risk factors in Alzheimer’s Disease (AD)

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Abstract Background Cardiovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and AD, and over 30% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with CVRFs (p = 6.6e‐07) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. The goal here was to identify additional genes that contribute to the interaction between CVRFs and AD. Method A collection of eight multi‐ethnic cohorts was explored to study genome‐wide gene‐CVRF score interaction analysis for AD, in 7,441 AD patients and 10,453 controls. The cardiovascular risk factors score (CVRF score) was created from a first principal component of the four vascular risk factors; self‐reported history of hypertension, diabetes, and heart disease, and measured body mass index. Gene‐based interaction test was performed using the adaptive gene‐environment interaction (aGE) test. Results were summarized using a meta‐analysis. We investigated the association of gene expression with pathological AD and AD phenotype (amyloid‐β, tau, or brain infarcts) in 1,092 samples from the frontal cortex in ROSMAP. The pathway enrichment analysis was performed on the differentially expressed genes. Age and sex were adjusted in the models. Result The previous interaction of CVRF score with FMNL2 (p = 3.64e‐07) was strengthened and additional genes were identified including BRINP1 (p = 2.45e‐06), CFAP99 (p = 3.3e‐06), and PRG3 (p = 3.71e‐06). FMNL2 encodes a formin‐related protein important in regulating actin and microtubules. FMNL2 and BRINP1 expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006, respectively). The expression level of BRINP1 interacted with brain infarcts on pathological AD (p = 0.02) and with amyloid‐β or tau on brain infarcts (p = 0.02 and p = 0.01, respectively). The pathways were relevant to cellular interactions between astrocytes and endothelia as well as the immune system reaction in the glio‐vascular niche. Conclusion The four novel genes are likely to be involved in the complex interaction between Alzheimer’s disease pathologies (amyloid and phosphorylated tau deposition) and cerebrovascular pathology, for example, at the glia‐vascular interface during AD progression. Understanding how these genes interfere with the mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain will be essential.

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