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.

Custodio N.; Soto-Añari M.; Montesinos R.; Caipa M.P.; Ore-Gomez M.F.; Rivera-Fernandez C.; Reyes-Dumeyer D.; Tosto G. · Alzheimer's and Dementia (2022) · DOI: 10.1002/alz.066002

Resumen

Background: Alzheimer’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. Method: We 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. Result: 51 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). Conclusion: To 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).

Instituciones: Universidad Nacional de San Agustín de Arequipa; Universidad Católica San Pablo