Native American Ancestry is associated with lower risk of Alzheimer’s Disease: results from the Genetic of Alzheimer’s disease in Peruvian Populations (GAPP) study.

Abstract

AbstractBackgroundAlzheimer’s Disease Related Dementias (ADRD) is not equally distributed among racial and ethnic groups. The APOE‐ɛ4 allele alone does not explain the different frequency of the disease. In fact, Hispanics (HI) and African Americans e4 non‐carriers still show a two‐to‐four‐fold higher incidence of ADRD, compared with non‐Hispanic Whites. Ancestry is an understudied yet a critical aspect of health disparities, as it may explain observed differences in frequency of ADRD across ethnic groups. We recently launched a genetic study in Peruvians, whose genome is characterized by large Native‐American ancestry proportions (higher than other HI populations such as Caribbean Hispanics or Mexicans), and studied the association between Ancestry, APOE‐e4 and ADRD.MethodWe recruited 264 Peruvians across three main sites in Peru (Lima, Arequipa, Puno). Genotyping was conducted on GSA Illumina platform, and, after QC, global ancestries (Native American [NAT], European [EUR], African [AFR]) were estimated using the Human Genome Diversity Project as reference (Figure 1). Number of APOE‐e4 alleles were entered as predictor along with proportion of global ancestries in regression models, adjusting for age, sex and education. AD status was employed as main outcome; episodic memory scores were used as secondary outcomes in healthy controls.Result51 were diagnosed with AD, 213 were healthy controls (mean age 72 years old). Average ancestry was estimated to be 73.0% NAT, 23.8% EUR, 3.2% AFR. APOE‐e4 was found associated with AD (OR [95%CI] = 4.09 [1.98‐8.47], p<0.001). NAT ancestry proportion was found protective at trend in the whole cohort (OR = 0.73[0.50‐1.06], p = 0.096). When restricted to e4 non‐carriers, NAT ancestry was found significantly associated with lower AD risk (OR = 0.57[0.36‐0.91], p = 0.019). Consistently, higher NAT ancestry was associated with better episodic memory scores in healthy controls (e.g. delayed recall: betastandardized = 0.26, p<0.001).ConclusionTo our knowledge, this is the largest collection of individuals with predominant Native American ancestry showing protective effect towards ADRD. This is particularly evident in those individuals not carrying the APOE‐e4 allele. APOE is confirmed as strong risk factor for ADRD (larger than other HI populations).