APOE4: Potential cognitive benefits of the major Alzheimer’s risk gene


By Ed Pinches | Thursday 07 October 2021

A team of scientists at UCL have found that having the Alzheimer’s risk gene, APOE4 is linked with better performance on tests of a cognitive skill known as visual working memory.

The scientists studied a unique group of volunteers, who were all born in the same week in 1946. The findings are published on Thursday 7 October, in the scientific journal Nature Aging.

 Our DNA code is the blueprint for our biology. It holds the information needed to make specific proteins, which allow our bodies to function. Sometimes the DNA code can contain changes that increase our likelihood of getting a disease. To date, scientists have found versions of around thirty different genes that are associated with an altered risk of developing Alzheimer’s disease, the most common cause of dementia.

The most studied gene with the largest effect on our Alzheimer’s risk is called APOE. Everyone has two copies of the APOE gene each of which can take three forms (E2, E3, E4). People who inherit one copy of the APOE E4 version (roughly one in four people) are around three times more likely to develop Alzheimer’s disease, compared to people without this version of the gene. Those with two copies may be more than eight times more likely to develop Alzheimer’s.

Some evidence suggests that APOE4 might confer some advantages, explaining the survival of this gene in the population.

What did the scientists do?

The UCL team led by Dr Kirsty Lu, Prof Seb Crutch and Prof Jonathan Schott worked with a unique group of nearly 400 volunteers, recruited from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth Cohort. They were all born in the same week in 1946 and did not have dementia.

The team assessed the effects of the APOE4 risk gene, and b-amyloid – one of the hallmark Alzheimer’s proteins – as measured by a PET brain scan, on visual working memory.

Scientists used a computerised ‘What was where?’ task designed by colleagues at Oxford University to measure volunteers’ visual working memory. This task involved participants being shown one to three objects displayed on a screen in random locations, presented on a black background. Scientists asked participants to look at the objects and to try to remember their identities and locations.

What did they find?

In 398 study participants who do not have memory and thinking problems, having the APOE4 gene and the presence of b-amyloid in the brain had opposing effects on object identification, with APOE4 predicting better recall and amyloid build-up predicting poorer recall. APOE4 carriers were also able to recall locations more precisely.

The results, suggesting better visual working memory in those with APOE4, suggests that there are some benefits of this gene in the older age, and even when proteins associated with Alzheimer’s disease are building up.

What do the experts say?

Prof Jonathan Schott, from University College London, said that the results of this study – which suggest that APOE4 is associated with better visual memory – may provide clues as to why the gene variant is so common.

Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK

“Understanding why APOE4 might result in better memory, may also help us to understand why it also leads to increased risk for Alzheimer’s disease.”

Dr Kirsty Lu, first author of the study, echoed Prof Schott. She highlighted the finding that “APOE4’s benefits may in fact persist into old age, at the same time that the harms of Alzheimer’s disease are beginning to develop.”

Commenting on the outcomes of this study, Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, emphasised the fact that people with the APOE4 gene will not necessarily go on to develop Alzheimer’s, although it can increase our overall risk.

Looking to the future, she noted that “better understanding of the most impactful Alzheimer’s risk gene is crucial for building a more complete picture of the development of the disease.”

Want to read more?

The full paper title is Dissociable effects of APOE-ε4 and β-amyloid pathology on visual working memory by Lu et al., and is published in Nature Aging.

Read a blog on the Alzheimer’s risk gene riddle here: https://alzheimersresearchuk.org/blog/the-risk-gene-riddle/

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Ed Pinches