May 26, 2020

expert reaction to study on COVID-19 and a faulty gene linked to dementia

A study, published in the Journal of Gerontology: Medical Sciences, reports on COVID-19 and a faulty gene linked to dementia.

Prof John Gallacher, Director of Dementias Platform UK, University of Oxford, said:

“This paper provides strong evidence of a link between genetic risk for Alzheimer’s disease and genetic risk for COVID-19. This suggests one or more common mechanisms underlying both conditions. A common mechanism would indicate increased risk of COVID-19 in those with Alzheimer’s disease, but not that Alzheimer’s disease itself is a direct cause of COVID-19 susceptibility. However, Alzheimer’s disease may be an indirect cause. For example, increased frailty in those with Alzheimer’s disease would imply reduced resistance to infection and increased disease severity. Increased risk and increased frailty are reasons enough to consider those with dementia to be a high risk group for COVID-19.”

Prof Tara Spires-Jones, UK Dementia Research Institute Group Leader and Deputy Director, Centre for Discovery Brain Sciences, The University of Edinburgh, said:

“Using data from over 300,000 people in the UK BioBank, Prof Melzer and colleagues observe an association between the APOE4 gene and risk of testing positive for COVID-19.  

“This study is robustly conducted, and the observation is important and will lead to future research into how APOE4 may influence the risk of contracting COVID-19 or having severe symptoms requiring hospitalisation, where most tests are performed.  This is interesting because recent research into why APOE4 also increases the risk of Alzheimer’s disease indicate that APOE4 is involved in the immune system.  

“An important limitation of the current paper is that this type of observational study cannot prove that the APOE4 gene is the cause of the observed increased risk of COVID-19.  The scientists did a thorough job of trying to control for other things associated with APOE4 that could account for the risk, but it is still possible that there is an unknown related factor causing the increased risk.”

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“The concern I have about this study is that the results could potentially be explained by the possibility that more subjects with two copies of the high risk APOE e4 allele might have had dementia than those who had none.

“It seems clear that people with dementia have a higher risk of COVID-19, whether because they are more frail, more exposed to carers or for other reasons. If a proportion of subjects with two copies of the high risk APOE e4 allele had dementia then we would expect more of them to test positive for COVID-19. The study authors try to exclude this possibility by removing subjects who had dementia at the time of recruitment to UK Biobank or recorded on a hospital discharge diagnosis but, perhaps unsurprisingly, very few people meet these criteria. The number of subjects for which GP records could be examined is much smaller and the results obtained are less statistically significant. But since the latest GP records are from 2017 I would still be concerned that some subjects might have developed dementia in the interim and that this could explain the observed association with APOE e4.

“I’m afraid this study does not really convince me that the APOE e4 allele is really an independent risk factor for severe COVID-19 infection.  I would want to see this tested in a sample where dementia could be more confidently excluded, perhaps a younger cohort. I am sure additional data will soon emerge to illuminate this issue.”

Prof Clive Ballard, Medical School Pro-Vice-Chancellor, University of Exeter, said:

“The E4 gene is a major risk gene for Alzheimer’s disease – people with one copy are at 3-4 fold increased risk and people with two copies have at least a 10 fold increased risk.  The current findings may partly explain why people with dementia are more at risk of severe COVID, and we should be taking more care of this vulnerable group of individuals at this challenging time”

“The implications of the study are well beyond the significant implications for people with dementia.  25% of people in the population carry one E4 gene, and this is clearly an important risk factor for developing severe COVID.  ApoE4 plays a major role in lipid and cholesterol metabolism and also has some role in immune response.  This may give us important clues in helping to develop new approaches to reduce risk.”    

Dr Carol Routledge, Director of Research at Alzheimer’s Research UK, said:

“A previous study from this group of researchers found that dementia was the diagnosis associated with the greatest risk of severe COVID-19 in a group of participants over the age of 65. 

“One explanation for people with dementia being more vulnerable to COVID-19 could be high rates of infection in care homes, but this research highlights a potential biological link.

“The study found that people with a key genetic risk factor for Alzheimer’s disease appear to be more likely to test positive for COVID-19, even if they don’t have dementia.

“We don’t yet know how this Alzheimer’s risk gene might make people more susceptible to the virus. Despite the large study group, only 37 people with the risk gene tested positive for COVID-19, and we must be careful about the conclusions we draw from such small numbers.

“These findings will need to be followed up with further research to see if this link could present avenues for new treatments.

“This study analysed data from participants with European ancestry so the findings may not be relevant to other groups and it is important for other studies to look into COVID-19 risk for people with a different genetic background.

“The COVID-19 outbreak is having a particularly strong impact on many people with dementia and their families. It is essential that people with dementia have the support they need to minimise their risk of being exposed to the virus.”

Dr Fiona Carragher, Director of Research and Influencing at the Alzheimer’s Society said:

“People with dementia have been the worst hit by coronavirus. Dementia is the most common pre-existing condition, accounting for a quarter of deaths so far, and tragically there’s an additional huge unexplained rise in deaths recorded to dementia alone. Now this study suggests the APOE e4e4 genotype, known to increase the risk of developing dementia, may also increase the risk of severe Covid-19 for people – however it is early stage research. Other factors may contribute, so it is difficult to draw firm conclusions at this stage. But clearly much more in-depth research is urgently needed to fully understand why people with dementia seem to be at a higher risk and to what extent factors like ethnicity and genetics might play a role.”

“People with dementia and their families are desperately worried. Forgotten at the start of this crisis, while bearing the brunt of it, they are largely reliant on a threadbare social care system. The Government needs to take urgent action putting people with dementia at the heart of a clear plan to protect those at risk.”

‘APOE E4 genotype predicts severe COVID-19 in the UK Biobank community cohort’ by Chia-Ling Kuo et al was published in the Journal of Gerontology: Medical Sciences at 5am UK time on Tuesday 26 May.

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Curtis: I have no conflict of interest.

No others received.