Genome-Wide Meta-Analysis Identifies Genetic Loci for Alzheimer’s

The study covered in this summary was published on medRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

• This study was the largest collaborative effort examining the genetics underlying cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD).

• The study identified six genetic locations associated with CSF biomarkers of AD. Two loci (CR1 and APOE) were associated with the CSF biomarker amyloid beta 42 (Aβ42), and four loci (BIN1, GMNC, C16orf95 and APOE) were associated with the CSF biomarker phosphorylated tau (pTau).

• The CR1, BIN1, and C16orf95 loci were novel associations.

• Other than APOE, no risk loci overlap was observed for Aβ42 and pTau.

• APOE and pTau pathologies seem to originate at least partly independently from each other. Aβ42 appears to be dominated by the effect of APOE, while pTau is influenced by multiple genetic components.

• CSF protein patterns suggest there may be multiple Aβ42- and pTau-related biologic pathways involved in the etiology of AD: amyloid, astrocyte, migration and processing, and migration and motility.

Why This Matters

• Genetic studies of patients with AD can contribute to understanding the pathophysiology of the disease. Larger studies may allow for greater precision in identifying genetic associations than smaller ones and potentially lead to treatments to delay or halt disease progression.

• In concordance with previous studies, Aβ42 and pTau showed the strongest association for APOE. APOE ɛ4 decreased amyloid beta levels and increased pTau levels, while APOE ɛ2 had the opposite effect.

• The fact that APOE and pTau pathologies seem to originate at least partially independently from each other is highly relevant biologic knowledge for the development of potential AD treatments.

• Study results suggest that different patient groups might benefit from distinct AD treatments, depending on the affected biologic pathway.

• These findings may partially explain the limited clinical efficacy of agents that aim to reduce beta-amyloid plaques.

Study Design

• Investigators retrospectively analyzed genotype data and CSF measurements from 16 European cohorts of 8074 individuals. Participants exhibited the full spectrum of cognitive decline that could possibly lead to AD. Measures of CSF proteins included important biomarkers for AD including Aß42, tau, and pTau.

• Investigators used two tools to estimate the heritability of single nucleotide polymorphisms (SNPs): linkage disequilibrium score regression, and genome-wide complex trait analysis.

• Linear regression was used to analyze the association between genetic single markers and CSF levels of Aβ42, tau, and pTau. Linear regression analyses were repeated for subgroups and stratified according to Aß42 status (normal or abnormal) and APOE4 gene status (carrier or noncarrier).

• After the discovery meta-analysis, which identified 1150 potential variants associated with CSF Aβ42 and tau, a replication meta-analysis was performed using data from 15 additional cohorts with 5042 samples.

• In the final phase, a combined meta-analysis of all 13,116 participants in both the discovery and replication groups was performed. Various additional analyses were also performed, including gene-based analysis and gene mapping. Phenome-wide association studies were performed for the top SNPs (rs4844610, rs429358, rs744373, rs9877502, rs4843559). CSF proteomic studies were also performed with the lead variants (rs9877502 and rs4843559) located near the GMNC gene. In the proteomic studies, 1282 proteins were included from one source, and 713 proteins were included from a second source.

• The genome-wide threshold for significance of P < 5 × 10⁻⁸ was used to defined genome-wide association study matches in the final meta-analysis.

• A gene set enrichment analysis of 83 variants (excluding APOE ɛ4 and APOE ɛ2) was performed to find molecular pathways enriched within each cluster.

Key Results

• Results for tau and pTau were highly correlated, so only results from pTau were reported.

• Researchers identified two loci (CR1 and APOE) for Aβ42 and four loci (BIN1, GMNC, C16orf95 and APOE) for pTau.

• The study confirmed the GMNC gene as a risk factor for CSF pTau levels.

• Three novel loci were identified: CR1 for CSF Aβ42 levels, and BIN1 and C16orf95 for CSF pTau levels.

Limitations

• The authors indicated no limitations of the study.

Disclosures

• The study was supported by a grant (European Alzheimer DNA BioBank) from the EU Joint Programme, Neurodegenerative Disease Research.

• Secondary research funding, including support of certain authors, was provided by numerous other sources.

• Of the 143 authors, 16 report competing interests of a commercial, public, or academic nature.

This is a summary of a preprint research study, “Genome-wide Meta-analysis for Alzheimer’s Disease Cerebrospinal Fluid Biomarkers,” written by Iris E. Jansen from Amsterdam University Medical Centers and colleagues and published on medRxiv.org. It is provided to you by Medscape. The study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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