Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

Abstract

SummaryCerebrovascular damage coexists with Alzheimer’s disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, andAPOEε4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes:KIRREL3rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001),KIRREL3rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), andEXOC6Brs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g.KIRREL3TT/CT or GG/GT carriers andEXOC6BGG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially inKIRREL3andEXOC6Bgenotype carriers.