ABSTRACT Late-onset Alzheimer's disease (LOAD) is the main cause of dementia; its causes accumulating evidence supports a strong genetic component underpinning its etiology. are still unknown but Hispanics (genetically admixed of European, African and Native American ancestry) show higher prevalence and incidence of LOAD than in non-Hispanic Whites; ancestry may explain the different frequencies of LOAD and other diseases across ethnic groups. To this end, we aim to elucidate the contribution of Native American ancestry to LOAD. Previous studies showed that ancestry is associated with many complex diseases although not extensively studied in LOAD. We show strong preliminary results supporting this observation. This study will recruit two Indigenous Amerindian populations, the Quechuas and Aymaras, in southern Peruvian Andes in collaboration with Prof. Nilton Custodio at the Instituto Peruano de Neurociencia (IPN). These populations show unique genetic and clinical features. 1) They show predominant Native American ancestry and very low prevalence (<5%) of APOE-ɛ4 allele (LOAD's main genetic risk factors). 2) They have surprisingly low frequencies of cardiovascular risk factors and diseases (CVRF/CVD) and we earlier showed that those with high burden of CVRF/CVD are at high risk for LOAD (Tosto et al. 2015). These features provide an unprecedented opportunity to identify genetic and non-genetic risk as well as protective factors for LOAD. In addition, this proposal responds to high-priority topic of interest for PAR-19-070 by fostering increased inclusion of underrepresented minorities in studies of health disparities and LOAD. We aim to recruit ~1,000 Aymara and Quechua in Puno and Arequipa, respectively, in addition to further expand an ongoing cohort of ~1,000 Lima mestizos (500 have already been collected with extensive demographic, clinical assessment and cognitive data). We will conduct extensive cognitive, sociodemographic and lifestyle assessment, cardiovascular profiling and blood collection for DNA extraction and biomarkers. We will leverage ongoing cohort studies of other Hispanic populations available at Columbia University (Caribbean Hispanics, Mexicans) for comparison and meta-analysis. We aim to: AIM 1) Identify cases of MCI and LOAD by recruiting and collecting biological samples and performing extensive cognitive assessment in Quechuas, Aymaras and Lima mestizos. AIM 2) Elucidate the association between LOAD and established risk factors (CVRF/CVD, blood biomarkers, lifestyle factors) in Peruvian and other Hispanic populations available at Columbia University. AIM 3) Perform GWAS and admixture mapping to identify genetic and ancestral loci associated with LOAD and their interplay with cardiovascular conditions, biomarkers and lifestyle factors.