Basic Science and Pathogenesis

Genetic studies have identified more than 80 loci associated with Alzheimer disease (AD), with APOE recognized as a major risk factor. Understanding the complete genetic landscape representation across ancestries in Alzheimer disease (AD) studies is critical to advance our ability in solving AD for everyone. Cuban Americans have a substantial European ancestral background alongside African and Amerindian ancestries. This study aims to determine whether these established AD risk loci Cuban Americans, which could enhance our understanding of the genetic architecture of AD.

The CA dataset includes TOPMED imputed data from 239 individuals (119 AD, 120 cognitively unimpaired) ascertained through the Cuban American Alzheimer's Disease Initiative (CuADI). For association analysis, we employed a mixed-model regression approach (SAIGE) where we controlled for age, gender, population substructure (first three principal components), and relatedness.

Association analysis in Cuban Americans replicated SORL1 (rs74685827), CR1 (rs6656401), ADAM17 (rs72777026), and RASGEF1C (rs113706587) as risk loci for AD with odds ratios of 5.71 (p = 0.02), 1.70 (p = 0.048), 1.81 (p = 0.024), and 1.87 (p = 0.032), respectively. Conversely, SPI1 (rs3740688) and ADAMTS1 (rs2830489) were found as protective loci with odds ratios of 0.60 (p = 0.007) and 0.66 (p = 0.049). Importantly, the APOE4 was significantly associated with AD (OR=2.94, p = 1.37×10^-4) showing an effect size similar to those observed in European populations.

This study replicated the associations of SORL1, CR1, ADAM17, RASGEF1C, SPI1, and ADAMTS1 with AD risk and protection are found in Cuban Americans. The large effect of the APOE4 aligns with its established role in AD pathogenesis across different populations. These results enhance our overall understanding of the genetic underpinnings of AD and support the advancement of targeted research and therapeutic interventions.