May 6, 2024

expert reaction to study of the APOE-4 genetic variant and Alzheimer’s disease

A study published in Nature Medicine looks at the genetic variants and Alzheimer’s disease.

Prof Jonathan Schott, Chief Medical Officer at Alzheimer’s Research UK, said:

“Alzheimer’s disease is a complex disorder which becomes more common as people get older. In very rare cases, a fault (mutation) in one of three genes is sufficient to cause Alzheimer’s disease. This form of the disease runs in families – and so is called familial Alzheimer’s disease – and usually causes young-onset dementia.

“We also know that inheriting certain genes can increase an individual’s risk of developing Alzheimer’s. The best known of these is a gene called APOE. There are three different versions of this gene, APOE2, APOE3, and APOE4. Each of us carries two copies of APOE, one inherited from each parent – and this means there are different combinations people can carry. APOE2 decreases and APOE4 increases risk for Alzheimer’s disease.

“About 1 in 50 people carry two copies of APOE4, and we have known for some time that these individuals have substantially increased risk. In this large well-conducted study, researchers showed that people who inherited two copies of APOE4 almost all developed Alzheimer changes in the brain by their mid 60’s. These individuals were more likely to develop dementia and tended to do so at a younger age than those with different APOE combinations.

“At the present time we do not advise that people have genetic testing for APOE except when taking part in research, but this may change in the future.  At Alzheimer’s Research UK, we are funding several research projects to try and understand why having the APOE4 gene increases the risk of Alzheimer’s, and equally why some people with APOE4 do not develop dementia.  We hope this work will lead to the development of new treatments for people both with and without APOE4, and so bring us closer to a cure.”

Dr Richard Oakley, Alzheimer’s Society’s Associate Director of Research and Innovation, said:

“There are 900,000 people living with dementia in the UK. Understanding the causes of the disease in greater detail is vital and can unlock new ways of diagnosing, treating and caring for people affected by Alzheimer’s disease in the future. Further understanding the role of different gene mutations is one way in which researchers can understand what might be causing people to develop the disease.  

“This study has shown us that this particular gene might play an important role in Alzheimer’s disease development, suggesting its presence is not only a risk factor, but could also indicate a new form of Alzheimer’s disease. The insights from the study suggest that in the future it could be important to take into account a person’s genetics when planning how to reduce their risk of developing Alzheimer’s disease, or when considering their treatment if they already have the disease.

“Dementia is the UK’s biggest killer and this new insight into the role of genes shows there is still a lot to learn about this devastating disease and reinforces how crucial research will be in one day beating dementia. Alzheimer’s Society funds research into dementia treatments, diagnosis, cure, innovation.”

Prof Paul Matthews, Director of The Rosalind Franklin Institute and Group Leader, UK Dementia Research Institute Centre at Imperial College, said:

“This report provides new, strong data showing that inheritance of two copies of the APOE4 gene is a cause of Alzheimer’s disease. The results force a change in thinking of APOE4 simply as a risk factor for Alzheimer’s.  As 2 of 100 Northern Europeans carry two copies of the gene, the authors highlight that this discovery makes APOE4 Alzheimer’s Disease one of the most common of all Mendelian genetic disorders. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically when late middle-aged people present to their doctors with symptoms of dementia.  Because APOE4 homozygotes are common in the population, have predictable ages of onset and rates of progression of disease and, as demonstrated in the paper, show easy to measure biomarker changes as their disease evolves, they also constitute an attractive population for clinical trials of new treatments for Alzheimer’s disease.”

Prof Tara Spires-Jones, President of the British Neuroscience Association and Group Leader at the UK Dementia Research Institute at the University of Edinburgh, said:

“This study by Dr Fortea and colleagues in Barcelona looked at data from over 10,000 individuals and observed that almost everyone in the study who inherited two copies of the APOE4 gene had Alzheimer’s disease as they aged. This is a strong study confirming an important link between APOE4 and Alzheimer’s; however it is not at all a surprise. The increased risk of Alzheimer’s disease with inheriting the APOE4 gene has been known for over 30 years.  This study adds compelling data to suggest that people with 2 copies of this gene are almost guaranteed to develop Alzheimer’s if they live long enough and that they will develop Alzheimer’s earlier than people without this gene.  Moving forward, this study and others highlight the importance of more fundamental research into understanding how genes change the susceptibility of our brains to Alzheimer’s disease as we age.”

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

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some “distinct genetic form” of Alzheimer’s disease. It has been known for decades that APOE4 is a strong risk factor for Alzheimer’s disease, that people carrying two copies are at high risk and that people carrying two copies are at substantially higher risk than those carrying one. No matter how many alleles of APOE4 one carries the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed, would have broad applicability.”

‘APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease’ by Juan Fortea et al. was published in Nature Medicine at 16:00 UK time on Monday 6^th May.

DOI: https://doi.org/10.1038/s41591-024-02931-w

Declared interests

Prof Paul Matthews: Consultancies with Sudo Biosciences, Nimbus, Redburn

Member of Trial Safety Monitoring Board for GSK

Research Funding from Merck, BMS and Biogen

Prof Tara Spires-Jones: I have no direct conflicts with this study but have co-authored papers with one of the authors in the past.

Prof David Curtis: No conflicts 

For all other experts, no reply to out request for DOIs was received.