Polygenic risk of Alzheimer's disease in the Faroe Islands

Background and purpose The Faroe Islands are a geographically isolated population in the North Atlantic with a similar prevalence of Alzheimer's disease (AD) and all-cause dementia as other European populations. However, the genetic risk underlying AD and other dementia susceptibility has yet to be elucidated. Methods Forty-nine single-nucleotide polymorphisms (SNPs) were genotyped in 174 patients with AD and other dementias and 159 healthy controls. Single variant and polygenic risk score (PRS) associations, with/without APOE variability, were assessed by logistic regression. Performance was examined using receiver operating characteristic area under the curve (ROC AUC) analysis. Results APOErs429358 was associated with AD in the Faroese cohort after correction for multiple testing (odds ratio [OR] 6.32, 95% confidence interval [CI] 3.98-10.05, p = 6.31e(-15)), with suggestive evidence for three other variants: NECTIN2 rs41289512 (OR 2.05, 95% CI 1.20-3.51, p = 0.01), HLA-DRB1 rs6931277 (OR 0.67, 95% CI 0.48-0.94, p = 0.02) and APOE rs7412 [epsilon 2] (OR 0.28, 95% CI 0.11-0.73, p = 0.01). PRSs were associated with AD with or without the inclusion of APOE (PRS+APOE OR = 4.5, 95% CI 2.90-5.85, p = 4.56e(-15), and PRS-APOE OR = 1.53, 95% CI 1.21-1.98, p = 6.82e(-4)). AD ROC AUC analyses demonstrated a PRS+APOE AUC = 80.3% and PRS-APOE AUC = 63.4%. However, PRS+APOE was also significantly associated with all-cause dementia (OR = 3.39, 95% CI 2.51-4.71, p = 2.50e(-14)) with an AUC = 76.9%, that is, all-cause dementia showed similar results albeit less significant. Discussion In the Faroe Islands, SNP analyses highlighted APOE and immunogenomic variability in AD and dementia risk. PRS+APOE, based on 25 SNPs/loci, had excellent sensitivity and specificity for AD with an AUC of 80.3%. High PRSs were also associated with an earlier onset of late-onset AD.