Beyond social distancing and the need for care: Do Alzheimer’s Disease and COVID19 share genetic risk too? 

This piece was written by Dr Fiona Kerr (Edinburgh Napier University).

The COVID19 pandemic has impacted young and old both due to poor outcomes from the disease itself and through negative impacts on well-being due to lockdown and poor access to healthcare systems. One group that quickly emerged as being particularly vulnerable are people living with dementia, with almost 25% of those who died from COVID19 in 2020 also having Alzheimer’s Disease (AD) or other forms of dementia (COVID19 and Dementia Mortality, Alzheimer’s Society). Much of this disproportionate impact has been attributed to challenges for people with dementia to adhere to the social distancing and hand hygiene mitigations put in place to prevent infection, and their over-representation in care homes, which were particularly hard hit by COVID19 (Science Media Centre). In October this year, a new study in the journal Brain, by Magusali N et al., 2021, identified that a genetic variant may confer risk for both AD and severe COVID19. This suggests that there may also be molecular reasons to explain why people with dementia are particularly vulnerable to this infectious disease. 

What did the study show?   

Genetic variants are changes in our genes (DNA building blocks) that naturally explain some of the differences between individuals in a population. Previous genome-wide analyses have revealed that several genes involved in inflammatory responses are associated with increased risk of AD, and inflammation is a key pathological feature in the brains of patients with this condition. The Magusali et al. study builds on previous findings from the same group, led by Dervis Salih at the UK Dementia Research Institute, that a variant of a particular immune gene, OAS1, is associated with increased risk of AD. The current investigation aimed to confirm these observations in a new cohort of people and to establish whether these changes are linked to other variations in this same gene that have been shown to associate with severe COVID19. Using complex genetic analyses, the authors measured variations in the OAS1 gene in DNA samples from 1313 AD patients and 1234 healthy controls, of a similar age, obtained from six institutes in the Alzheimer’s Research UK Network. This confirmed significant association between a particular OAS1 variant (rs1131454) and AD diagnosis. Using publicly available data from the 1000 Genomes Project, the authors also showed that these were inherited together (genetically linked) with two other OAS1 variants associated with severe COVID19. Studying the potential function of OAS1 in immune cells from both AD and severe COVID19 patients, the authors showed that changes in levels of the OAS1 gene aligned with changes in interferon response genes. The interferon response activates a signal within immune cells that allows us to fight infection, but if stimulated too much it may lead to an inflammatory cytokine storm that damages tissue as observed in severe COVID19.

How well was the article reported in the media?

Due to the timeliness of this study in the midst of the COVID19 pandemic, it was critically appraised in expert commentaries (Science Media Centre) and widely reported in the media. Online sources Medicalnewstoday and Neuroscience News, as well as The Telegraph, accurately reported the main findings of the study and explained the role of OAS1 in controlling inflammatory responses in a clear and understandable way. Due to their scientific focus, Medical News Today and Neuroscience News provided more details on the experimental design of the study, including the number of individuals included and the cell types analysed. Some reporting on the degree of increased risk of AD could be slightly misleading, with all studies reporting an 11-22% increase for carriers of OAS1 variants. It’s important to clarify, as indicated in both The Telegraph and Neuroscience News, that these values relate to an individual carrier’s risk of developing disease and that the overall increased risk of AD in the population is 3-6%. All reports adopted titles that reflected the observations that genetic variants in OAS1 may increase susceptibility to both AD and severe COVID19, without suggesting that one disease causes the other. Overall, the media provided a balanced account of the findings of this investigation, supported by quotes from the authors highlighting the need for future work to translate the results into diagnostic tests to predict an individual’s risk of developing AD or severe COVID19, and to determine whether OAS1 may play a role in other neurological symptoms observed following COVID19 infection. Importantly, inclusion of comments from the charity sector (Alzheimer’s Research UK) and independent researchers, in Medical News Today and The Telegraph, provided expert validation for the study, but also additional perspective that there are probably several reasons as to why those living with dementia are susceptible to severe COVID19 and that shared genetic risk may be one possibility.

Conclusions and things to consider

This is a robust study that validates genetic associations between OAS1 variants and risk of AD, and that these variants are linked to those which also increase risk of severe COVID19.  At the moment, we don’t know whether inflammatory processes involved in severe COVID19 will lead to dementia, or whether OAS1 plays a role in causing these connections. We also don’t know whether changes in OAS1 function may explain some of the other neurological symptoms that are often observed in COVID19 patients. Magusali and colleagues provide compelling evidence that OAS1 is needed to dampen the effect of interferons, such as those produced in severe COVID19, in causing tissue-damaging inflammatory responses that are also observed in neurological conditions. But more experiments would be needed, using cells in a dish and animal models, to test whether this leads to loss of nerve cell function or production of other pathologies that characterise Alzheimer’s disease and other dementias. If so, these findings could open-up exciting new possibilities for diagnosis and discovery of disease-altering treatments for both COVID19 and dementia.