Vast Majority of Alzheimer’s Cases Attributable to One Gene

According to a new study, as many as 90% of Alzheimer’s cases can be attributed to “suboptimal” variants of the APOE gene. These results highlight the gene’s importance for Alzheimer’s prevention [1].

Three alleles of APOE

A growing amount of research links Alzheimer’s disease to the gene APOE, which codes for apolipoprotein E [2]. This protein helps move cholesterol and other fats around the body and brain, facilitating, among other things, membrane repair and post-injury cleanup.

APOE has three common alleles: ε2, ε3, and ε4 (often written APOE2/3/4). APOE3 is the most widespread and is usually considered the “normal” one – that is, neither protective nor risk-associated. Having APOE4 substantially increases the risk of eventually getting Alzheimer’s, especially in homozygous (ε4/ε4) individuals. Conversely, APOE2 confers significant protection, but it’s also the rarest of the three. A new study from University College London, published in the journal npj Dementia, purports to show how much of Alzheimer’s burden can be directly attributed to APOE genetics.

Genetics explain the majority of cases

The study analyzes data from approximately 470,000 participants across four large cohorts: UK Biobank (UKB), FinnGen, the A4 Study, and the Alzheimer’s Disease Genetics Consortium (ADGC). It included participants aged 60 and older, focusing on those with genetic data and confirmed diagnoses.

Outcomes were assessed through clinical diagnoses, neuropathology, and amyloid-β positivity, with population attributable fractions (PAFs) calculated to quantify the burden of Alzheimer’s and dementia linked to APOE genotypes. PAF is the proportion of cases that would not occur in a population if the causal effect of the exposure were removed, assuming everything else stayed the same.

The PAF for Alzheimer’s cases attributable to APOE3 and APOE4 ranged from 71.5% in FinnGen to 92.7% in ADGC, linking a vast majority of Alzheimer’s cases to these alleles. For all-cause dementia, PAFs were 44.4% in UKB and 45.6% in FinnGen. In the A4 Study, where the outcome was amyloid-β positivity on PET scans at baseline, 85.4% of cerebral amyloidosis cases were attributable to APOE3 and APOE4.

These striking results were mostly due to choosing the most protective ε2/ε2 variant as baseline, despite it also being the rarest (0.3% to 0.6% in the study’s cohorts). This constitutes a significant departure from most previous studies, which treated APOE3 as the baseline “neutral” allele and only considered the additional risk from APOE4.

Lead author Dr. Dylan Williams said: “We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease. The ε4 variant of APOE is well recognized as harmful by dementia researchers, but much disease would not occur without the additional impact of the common ε3 allele, which has been typically misperceived as neutral in terms of Alzheimer’s risk.”

Some experts push back

Not all Alzheimer’s researchers appreciated this approach. “The claim that ‘most cases’ are linked to a single gene is simply an artefact of the authors’ choice to use the rare, protective ε2/ ε2 genotype as their baseline, effectively labelling approximately 95% of the population (who have ε3 or ε4 alleles) as being ‘at genetic risk’,” said Anneke Lucassen, Professor of Genomic Medicine at the University of Oxford.

Some scientists also highlighted the fact that Alzheimer’s is a multifactorial disease, where “nothing is guaranteed” and where risk can be substantially reduced by lifestyle interventions such as diet, exercise, and sleep [3].

“While these findings offer a better understanding of the role of genetics, it is important to remember that having a high-risk form of the gene is not a certain diagnosis,” said Dr. Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society: “Alzheimer’s remains a complex condition influenced by a mix of people’s backgrounds, genetics, and lifestyle. As we continue to further our understanding of risks and causes, we must not lose sight of the risk factors that remain within our control.”

A paradigm shift

The authors’ choice to treat the most protective genetic variant as baseline is a sign of a paradigm shift worth dwelling on. Conventional medicine tends to equate “normal” with “good enough” – something that does not warrant investigation or intervention. This study, on the other hand, considers the entire range of effects of various APOE genotypes on Alzheimer’s risk, demonstrating an approach that can be described as “suboptimal is pathological” as opposed to “abnormal is pathological.”

This echoes the geroscience postulate that aging is a pathological process in its entirety. Armed with the latest tech, including rapidly advancing gene editing techniques, medicine should aim at the biggest possible prize rather than confine itself to treating deviations from the norm.

“There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly,” said Williams, “Moreover, genetic risk also points us towards parts of our physiology that we could target with more conventional drugs. Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease.”

That said, the study had several noteworthy limitations. The PAF estimates may be imprecise due to the rarity of ε2 homozygotes, which served as the reference group, potentially affecting confidence intervals. Additionally, most participants were of European ancestry, limiting the generalizability of findings to other ethnic groups.

Literature

[1] Williams, D. M., Heikkinen, S., Hiltunen, M., FinnGen, Davies, N. M., & Anderson, E. L. (2026). The proportion of Alzheimer’s disease attributable to apolipoprotein E. npj Dementia, 2(1), 1.

[2] Troutwine, B. R., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. M. (2022). Apolipoprotein E and Alzheimer’s disease. Acta Pharmaceutica Sinica B, 12(2), 496-510.

[3] Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., … & Mukadam, N. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The lancet, 404(10452), 572-628.