Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer’s disease

E Rodríguez-Rodríguez,A Lleó,D Alcolea,O Combarros,P Sánchez-Juan,P Martínez-Lage,J Clarimón,J Berciano,S Cervantes,J L Vázquez-Higuera,P Pastor,I Mateo,A Pozueta

doi:10.1007/s00702-012-0920-x

Abstract

Aside from APOE, the genetic factors that influence 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 eight 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 26.3months) 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 six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six 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.

Highlights

There has been a lot of interest in the detection of predictors of conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD) using neuroimaging methods, CSF biomarkers and cognitive tests (Jack et al, 2010; Landau et al, 2010; Davatzikos et al, 2011)
Summary Aside from APOE, the genetic factors that influence in the progression from mild cognitive impairment (MCI) to Alzheimers 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

Summary

Introduction

There has been a lot of interest in the detection of predictors of conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD) using neuroimaging methods, CSF biomarkers and cognitive tests (Jack et al, 2010; Landau et al, 2010; Davatzikos et al, 2011). While the ε4 allele of APOE is the major genetic risk factor for AD, recent genome-wide association studies (GWASs) have identified several susceptibility loci for AD (Harold et al, 2009; Lambert et al, 2009; Seshadri et al, 2010; Hollingworth et al, 2011; Naj et al, 2011), but most of these risk alleles have shown only a modest effect (odds ratios between 0.88 and 1.23). Previous studies have shown that combining multiple loci with modest effects into a global genetic risk score (GRS) might improve identification of persons who are at risk for common complex diseases, such as coronary heart disease (Ripatti et al, 2010), type 2 diabetes (Cornelis et al, 2009), rheumatoid arthritis (Karlson et al, 2010), or multiple sclerosis (De Jager et al, 2009). We investigated the relationship between 8 non-APOE AD risk alleles (ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179), considered individually and as cumulative GRS, with two goals: first to characterize the conversion risk from MCI to AD, and to investigate the velocity of progression in MCI-converters to AD

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