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

Abstract

SummaryAside 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 MCInonconverters. 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.

The Role of PICALM in Alzheimer’s Disease

“…Nevertheless, given that many common contributing genes (including PICALM) confer large effects in aggregate but small effects singly, more comprehensive analysis and studies with larger sample size are therefore needed to elucidate the genuine association between PICALM gene and AD risk in disparate ancestries. Similarly, it is worthy to note that the effects of concomitant presence of different alleles (such as PICALM and APOE4 [50], PICALM and BIN1 [55]) or SNPs, which is called multilocus genotype patterns (MLGPs), on the prediction effect of AD-related phenotype as well as reduction of sample sizes needed to detect therapeutic efficacy [56] may be more significant than single locus alone [57][58][59]. These MLGPs maybe naturally derived from epistatic genetic effect or being located in a haplotype block, providing an alternative analytical approach for LOAD genetic risk as well as an avenue for preclinical diagnosis of AD.…”

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

“…We examine select group of cognitive aging and AD risk alleles that may work in synergy to magnify cognitive decline in non-demented older adults. To date, previous work with additive risk panels [53,54] have been examined independently and lack integration with complex interactive networks between additive panels commonly linked to AD independently, in risk panels, and mechanisms related to cognitive impairment.…”

“…AD genetic risk scores have been associated with increased risk of late life cognitive impairment [55], AD risk [56], greater risk of conversion from MCI to AD [54,57,58], and discriminating an AD group from controls [59]. Research on genetic risk approaches have used several procedures for calculating risk scores.…”

“…Research on genetic risk approaches have used several procedures for calculating risk scores. For example, prior studies have used an explained variance-weighted genetic risk score [60], an odds ratio weighted risk score [53,54], large number of SNPs to create a polygenic risk score [61,62], weighted sum of the top risk scores [56], and an additive allelic risk score [11,53,63]. …”

A 22‐single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42

“…In addition, if genetic risk profiles are predictive of specific clinical characteristics such as onset age or speed of progression, this may aid decision making at the clinical and personal level. For example, a high score on an 8-SNP weighted genetic risk score (wGRSs) has been associated with a two times more rapid progression from mild cognitive impairment to AD [9].…”