BACKGROUND:Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS). METHODS:Three sets of summary statistics were included in our meta-GWAS of AD: an Spanish casecontrol study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inversevariance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of subthreshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study. FINDINGS:Using our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical ADcase control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10 -7 ), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10 -39 ). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12-4.18, p = 3.2×10 -10 ) increased risk compared to those with the 2% lowest risk (p = 5.9×10 -10 ). Using the PRS we identified APOE ɛ33 carriers with a similar risk as APOE ɛ4 heterozygotes carriers, as well as APOE ɛ4 heterozygote carriers with a similar risk as APOE ɛ4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10 -6 ); a 4-year median onset diff...
Alzheimer’s disease has a long asymptomatic phase that offers a substantial time window for intervention. Utilizing this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer’s disease pathology at pre-dementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer’s type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer’s type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 showed a higher probability of progressing to dementia of the Alzheimer’s type and a faster cognitive decline. CSF matrix metalloproteinase 10 increased the prediction accuracy of CSF Aβ42, P-tau181, and T-tau for conversion to dementia of the Alzheimer’s type. Including matrix metalloproteinase 10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aβ42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aβ42, P-tau181, and T-tau. Matrix metalloproteinase 10 was correlated with age in subjects with normal Aβ42, P-tau181, and T-tau levels. Our findings support the use of CSF matrix metalloproteinase 10 as a prognostic marker for dementia of the Alzheimer’s type and its inclusion to the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of matrix metalloproteinase 10 may reflect ageing and neuroinflammation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.