Literature Review

Two genetic variants modify risk of Alzheimer’s disease



Two variants of MS4A are associated with the risk of Alzheimer’s disease, according to research published online August 14 in Science Translational Medicine. The variants affect cerebrospinal fluid (CSF) concentrations of a soluble form of the TREM2 protein (sTREM2), which may be involved in Alzheimer’s disease pathology. “Increasing TREM2 or activating the TREM2 signaling pathway could offer a new therapeutic approach for treating Alzheimer’s disease,” wrote the researchers.

Yuetiva Deming, PhD, a postdoctoral research associate at the University of Wisconsin School of Medicine and Public Health in Madison

Dr. Yuetiva Deming

Previous investigations have indicated that CSF levels of sTREM2 are increased in patients with Alzheimer’s disease. Changes in these levels appear to follow amyloid accumulation at approximately 5 years before the onset of clinical symptoms in autosomal dominant forms of the disease.

Yuetiva Deming, PhD, of the University of Wisconsin–Madison and colleagues conducted a genome-wide association study to identify genetic modifiers of CSF sTREM2. They analyzed CSF sTREM2 levels in 813 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Of this population, 172 participants had Alzheimer’s disease, 169 were cognitively normal, 183 had early mild cognitive impairment (MCI), 221 had late MCI, and 68 had significant memory concerns.

The rs1582763 single-nucleotide polymorphism (SNP) on chromosome 11 within the MS4A gene region was significantly associated with increased CSF levels of sTREM2. Conditional analyses of the MS4A locus indicated that rs6591561, a missense variant within MS4A4A, was associated with reduced CSF sTREM2. Analyzing 580 additional CSF sTREM2 samples, along with associated genetic data, from six other studies replicated these findings in an independent dataset.

Furthermore, Dr. Deming and colleagues found that rs1582763 was associated with reduced risk for Alzheimer’s disease and older age at Alzheimer’s disease onset. In addition, rs6591561 was associated with increased risk of Alzheimer’s disease and earlier onset of Alzheimer’s disease.

Subsequent analyses showed that rs1582763 modified the expression of the MS4A4A and MS4A6A genes in various tissues. This finding suggests that one or both of these genes are important for influencing the production of sTREM2, wrote Dr. Deming and colleagues. Using human macrophages as a proxy for microglia, the investigators observed that the MS4A4A and TREM2 proteins colocalized on lipid rafts at the plasma membrane. In addition, sTREM2 concentrations increased with MS4A4A overexpression, and silencing of MS4A4A reduced sTREM2 production.

These findings “provide a putative biological connection between the MS4A family, TREM2, and Alzheimer’s disease risk,” wrote the researchers. The data also suggest that MS4A4A is a potential therapeutic target in Alzheimer’s disease. Understanding the role of sTREM2 in Alzheimer’s disease will require additional research, but it may be involved in pathogenesis, wrote Dr. Deming and colleagues.

One of the study’s limitations is that the investigators included only common variants and thus could not determine the effect of genes that only harbor low-frequency or rare functional variants. Another limitation is that the data cannot support conclusions about whether other genes in the MS4A locus also modulate sTREM2, wrote Dr. Deming and colleagues.

Grants from the National Institutes of Health supported this study. The investigators disclosed consulting and other relationships with various pharmaceutical companies.

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