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Existing research has suggested that certain genes increase the risk of cognitive decline and development of neurodegenerative diseases, in particular Alzheimer's. Of all the genes studied to date, APOE ε4 has been most strongly identified as a significant risk factor for developing Alzheimer's disease. The Klotho gene, studied for its role in ageing and neurodegeneration, is also believed to significantly influence cognitive function.
However, the evidence for the role played by both of these genes is conflicting. It is still widely debated whether carrying the APOE or Klotho genes indicates a greater risk of cognitive decline, or whether they can in fact protect against it.
A recent study from a team at the Nuffield Department of Clinical Neurosciences and Department of Experimental Psychology, University of Oxford, aimed to resolve much of this uncertainty by revealing the specific roles played by these two genes in brain health and function, and looking at how this varies according to age and sex.
This study examined the largest cohort studied to date, drawing on data from UK Biobank, a large-scale biomedical database and research resource. Researchers looked at cognitive performance and brain volumes and how this was affected if the subject was a carrier of certain variants of the APOE and Klotho genes. They then analysed how the effect of these genes varied depending on the age and sex of individuals.
These findings not only help resolve long-standing debates about the role of APOE and Klotho, but also open the door to tailored approaches to predict and manage cognitive decline
Their research reveals that the effects of carrying different variants of the APOE gene on cognition is highly affected by age and sex. The results showed that carrying two copies of the APOE ε4 gene significantly accelerates cognitive decline with ageing. However, they also discovered that female carriers of this gene actually showed better cognitive function in their forties, which was not the case in males.
In contrast, the Klotho gene was not found to affect cognition or brain structure, regardless of the subjects age or sex, and whether or not they were carriers of the APOE ε4 gene.
These findings offer new insights into genetic risks of cognitive decline and potential treatments, including the development of sex-specific therapies.
Lead author Kengo Shibata says ‘this study reveals that genetic effects on cognitive health are age and sex specific. These findings not only help resolve long-standing debates about the role of APOE and Klotho, but also open the door to tailored approaches to predict and manage cognitive decline.’
Senior author Professor Masud Husain commented ‘the findings might also explain why the APOE ε4 gene continues to be present in the human population: women who have the gene are smarter at younger ages than those who don’t.’
Read the full paper in Proceedings of the National Academy of Sciences.