Genome-wide significant risk factors for Alzheimer’s disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment

Abstract

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054–1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029–2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

“…To date, except for CLU and APOE, few of the identified genetic risk variants in case-control GWAS for AD have shown a consistent effect on disease progression in MCI patients [42]. Our study now adds to this list PLCG2 as a strong protector of cognitive function at the MCI stage.…”

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

“…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.…”

From Polygenic Scores to Precision Medicine in Alzheimer’s Disease: A Systematic Review

“…Rodriguez-Rodriguez et al compared those in the 1 st and 3 rd tertile of PRS (OR: 1.32, 95% CI: 0.57-3.06). Neither of the hazard models used by Lacour et al and Andrews et al produced significant results (Lacour HR: 1.18, 95% CI: 0.37-2.0; Andrews HR: 1.05, 95% CI: 0.86-1.29) [29,37]. However, Andrews et al found their PRS was associated with an increased risk of transitioning from normal cognition to dementia (HR = 4.19, 95% CI: 1.72-10.20) [37].…”

“…The findings for MCI conversion prediction are more mixed. Of the three studies reporting negative results, two had relatively low power [11,29]. Almost all the studies exploring PRS prediction accuracy report that there is some overlap between cases and controls at high polygenic risk.…”

“…Eight studies assessed the ability of PRS to predict MCI to AD conversion. Three studies did not report statistically significant results [11,29,37]. Rodriguez-Rodriguez et al compared those in the 1 st and 3 rd tertile of PRS (OR: 1.32, 95% CI: 0.57-3.06).…”