Predictability of polygenic risk score for progression to dementia and its interaction with APOE ε4 in mild cognitive impairment

Abstract

Background: The combinatorial effect of multiple genetic factors calculated as a polygenic risk score (PRS) has been studied to predict disease progression to Alzheimer's disease (AD) from mild cognitive impairment (MCI). Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE gene. These studies may have missed the APOE genotype-specific predictability of PRS for disease progression to AD.

Methods: We analyzed 732 MCI from the Alzheimer's Disease Neuroimaging Initiative cohort, including those who progressed to AD within 5 years post-baseline (n = 270) and remained stable as MCI (n = 462). The predictability of PRS including and excluding the APOE region (PRS+APOE and PRS-APOE) on the conversion to AD and its interaction with the APOE ε4 carrier status were assessed using Cox regression analyses.

Results: PRS+APOE (hazard ratio [HR] 1.468, 95% CI 1.335-1.615) and PRS-APOE (HR 1.293, 95% CI 1.157-1.445) were both associated with a significantly increased risk of MCI progression to dementia. The interaction between PRS+APOE and APOE ε4 carrier status was significant with a P-value of 0.0378. The association of PRSs with the progression risk was stronger in APOE ε4 non-carriers (PRS+APOE: HR 1.710, 95% CI 1.244-2.351; PRS-APOE: HR 1.429, 95% CI 1.182-1.728) than in APOE ε4 carriers (PRS+APOE: HR 1.167, 95% CI 1.005-1.355; PRS-APOE: HR 1.172, 95% CI 1.020-1.346).

Conclusions: PRS could predict the conversion of MCI to dementia with a stronger association in APOE ε4 non-carriers than APOE ε4 carriers. This indicates PRS as a potential genetic predictor particularly for MCI with no APOE ε4 alleles.