Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease
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AuthorRodríguez Rodríguez, Eloy; Sánchez Juan, Pascual; Vázquez Higuera, José Luis; Mateo Fernández, José Ignacio; Pozueta, Ana; Berciano Blanco, José Ángel; Cervantes, Sebastián; Alcolea, Daniel; Martínez Lage, P.; Clarimón, Jordi; Lleó, Alberto; Pastor, Pau; Combarros Pascual, Onofre
Aside from APOE, the genetic factors that influence in the progression from mild cognitive impairment (MCI) to Alzheimer´s disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on 8 non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring 6 or more risk alleles (second and third GRS tertiles) progressed 2-fold more rapidly to AD when compared with those with less than 6 risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.