A Shared Genetic Link Between Alzheimer Disease and Severe COVID-19

Alzheimer disease (AD) and severe COVID-19 share a genetic risk factor, as study results published in the journal Brain indicate that a genetic variant previously associated with severe COVID-19 outcomes is also associated with an increased risk for AD.

Previous studies have shown an association between oligoadenylate synthetase 1 (OAS1), an anti-viral gene expressed in microglia, with increased risk for AD.

Using genotyping from 1,313 patients (mean age at death, 76.7 years; 60.9% women) with sporadic AD and 1,234 control individuals (mean age at death, 72.6 years; 53% women), the researchers assessed 4 variants of the OAS1 gene which dampens its expression: rs1131454 and rs4766676 (associated with AD) and rs10735079 and rs6489867 (associated with critical illness with COVID-19).

The analysis indicated that genetic variants within OAS1 associated with AD show linkage disequilibrium with variants associated with critical illness in COVID-19.

Investigation of the transcriptome expressed by microglia and macrophages indicated genetic co-expression networks consisting of genes in interferon response pathways. The data suggest that OAS1 is expressed alongside interferon-responsive genes in both microglia and alveolar macrophages, and may play a role in the interferon-response in both myeloid subtypes. This response is upregulated during severe COVID-19, ageing, and amyloid β-pathology.

Knockdown of OAS1 expression using small interfering RNA resulted in exaggerated production of pro-inflammatory cytokines with interferon-gamma stimulations, suggesting that the up-regulation of interferon-responsive genes with age might mitigate age-related damage by limiting pro-inflammatory signaling. Interferon signaling dysfunction with a blunted response against pathogens secondary to genetic variants is associated with increased risk for developing AD and severe COVID-19.

“[O]ur data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centered on OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression, ” concluded the researchers.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Magusali N, Graham AC, Piers TM, et al. A genetic link between risk for Alzheimer’s disease and severe COVID-19 outcomes via the OAS1 gene. Brain. Published online October 7, 2021. doi: 10.1093/brain/awab337