A new study has suggested that a gene variant thought only to increase the risk of developing Alzheimer’s disease could actually be one genetic cause of the condition.

The gene is called APOE, and the specific variant in question is called APOE4. The gene, present on chromosome 19, codes for a protein called apolipoprotein E that pairs up with fats like cholesterol and transports them through the bloodstream.

Professor Jonathan Schott, Chief Medical Officer at Alzheimer’s Research UK (who was not directly involved in the new work), told the Science Media Centre (SMC) 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.” The seemingly neutral and most common form is APOE3.

There is a difference between genes in which a mutation directly causes Alzheimer’s disease and those that affect the risk of developing it. The genes APP, PSEN1, and PSEN2 have been placed in the first category, whereas APOE4 has been placed in the second – but this new research indicates that it could be in the first category instead, being a causal factor rather than a risk factor.

“About 1 in 50 people carry two copies of APOE4, and we have known for some time that these individuals have substantially increased risk,” Schott said. However, it’s not exactly clear why those who carry APOE4 appear to be at a higher risk of Alzheimer’s. One 2021 study in yeast and human cells pointed towards a potential role in how the gene affects lipid metabolism.

“In this [new] 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,” Schott continued.

Study author Dr Reisa Sperling told the Associated Press that “this data for me says wow, what an important group to be able to go after before they become symptomatic,” but stressed, “It’s important not to scare everyone who has a family history,” clarifying, “It’s not quite destiny.”

The authors of the study examined how having two copies of the gene affected Alzheimer’s pathology and biomarkers. The team used data from 3,297 brain donors – 273 of which had two copies of APOE4 – from the National Alzheimer’s Coordinating Center (NACC), and 10,039 individuals from five multi-center clinical cohorts, 519 of which had two copies of the gene variant.

The researchers found that, at the age of 55, those with two APOE4 copies had higher levels of biomarkers amyloid and tau compared to those with two APOE3 copies. By the age of 65, almost all subjects with two APOE4 copies had abnormal amyloid-β levels in their cerebrospinal fluid, and 75 percent had positive amyloid scans (although the hypothesis that amyloid-β is the major driver of Alzheimer’s has been called into question). However, during the dementia phase, there appeared to be no difference in amyloid-β or tau accumulation.

Those with two APOE4 copies also started experiencing Alzheimer’s symptoms at an average (mean) age of 65.6 years old, which the researchers say is “approximately 7–10 years earlier” than those with two APOE3 copies.

The researchers also propose that the number of copies of the gene variant has an effect, with subjects with one each of APOE3 and APOE4 showing “intermediate phenotypes” between those with two copies of the same variant.

“This study adds compelling data to suggest that people with two 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,” Professor Tara Spires-Jones, President of the British Neuroscience Association and Group Leader at the UK Dementia Research Institute at the University of Edinburgh, told the SMC. “The increased risk of Alzheimer’s disease with inheriting the APOE4 gene has been known for over 30 years.”

“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,” Dr Richard Oakley, Alzheimer’s Society’s Associate Director of Research and Innovation, told the SMC. “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.”

However, not everyone is convinced. 

“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,” Professor David Curtis, Honorary Professor in the UCL Genetics Institute, told the SMC. “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.”

The researchers propose “a reconceptualization” of how we see the genetics behind Alzheimer’s, which they say will come with “profound consequences.” These include "the need for individualized prevention strategies, clinical trials and treatments", as well as counseling and screening those with cognitive complaints for APOE4. However, Schott said that genetic testing for APOE4 is not currently advised outside of research.

“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,” said Spires-Jones.

The study is published in the journal Nature Medicine.