Another cause for the development of Alzheimer’s dementia found

APOE4 is said to not only increase the risk of dementia, but also directly trigger Alzheimer’s

It has been known for some time that genetic factors contribute to developing Alzheimer’s dementia. However, the latest research results, which were published in the journal “Nature Medicine” on May 6, 2024, now show that an already known gene variant, apolipoprotein-4 (APOE4), not only increases the risk of dementia, but can also directly trigger Alzheimer’s disease. This applies in particular to people who carry two copies of this gene. Such homozygous carriers of the APOE4 variant almost invariably develop pathological amyloid deposits in the brain in old age. Consequently, APOE4 is not only a risk factor, but in its double expression also a direct genetic trigger of the disease, as the new research results show.

The risk of developing Alzheimer’s disease is partly determined by genetic predispositions. While some rare gene mutations lead to a particularly early onset of the disease, it is usually certain gene variants and their combinations that increase the risk of dementia but do not necessarily lead to Alzheimer’s disease. A key role is played here by variants of the gene apolipoprotein E (APOE), which is central to cholesterol breakdown, fat metabolism and inflammatory reactions. The APOE4 variant in particular has been identified as a risk factor for Alzheimer’s disease in previous studies.

Detailed study of the APOE4 gene variant and its influence on Alzheimer’s

A research team led by Juan Fortea at the Biomedical Research Institute Sant Pau in Barcelona has now analyzed the effects of the APOE4 gene variant in more detail. Although some people inherit only one copy of this gene variant from their parents and carry the non-risk variant APOE3 on the second allele, around two percent of the world’s population have two copies of APOE4. People who are homozygous for the APOE4 variant show a significantly increased risk of Alzheimer’s disease, as research has now discovered.

For a more detailed analysis, Fortea and his team examined the brains of 3,297 deceased Alzheimer’s patients from the USA, including 273 people who were homozygous for the APOE4 gene. In addition, they analyzed 10,039 living Alzheimer’s patients from Europe and the USA, including 519 people with the double APOE4 gene variant.

The results of the study are revealing: almost all people with two copies of the APOE4 variant showed symptoms of Alzheimer’s disease. From the age of 55, they showed higher levels of typical Alzheimer’s biomarkers in their blood compared to carriers of the APOE3 variant. From the age of 65, 95 percent of homozygous participants showed abnormally elevated amyloid protein levels in the cerebrospinal fluid, which is considered a clear sign of Alzheimer’s disease. The affected individuals were therefore almost certain to develop Alzheimer’s symptoms over the course of their lives, which occurred on average seven to ten years earlier than in individuals with other APOE variants or only one copy of the APOE4 gene.

Reclassification of APOE4 homozygosity as genetically caused Alzheimer’s disease

Until now, early-onset autosomal dominant Alzheimer’s disease (ADAD), which is caused by mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), was mainly considered to be genetically determined. The APOE4 allele, on the other hand, was previously considered to be merely a relevant risk allele for a sporadically occurring and late-onset form of Alzheimer’s disease. However, Fortea and his colleagues argue for a reassessment: they present convincing evidence to classify APOE4 homozygosity as a distinct form of genetic Alzheimer’s disease, analogous to ADAD.

New findings on the role of the APOE4 gene variant in Alzheimer’s disease

The homozygosity of APOE4 therefore fulfills the three main characteristics of a genetic disease: the disease is almost certain to occur, the onset of symptoms is predictable, and the development of biomarkers and other medically measurable changes follows a constant pattern. And although the symptoms cannot be distinguished from other forms of Alzheimer’s disease after their onset, the path to the disease itself is clearly traceable.

In a commentary accompanying the study, the team led by Qin Xu from the Gladstone Institute of Neurological Disease in San Francisco describes the APOE4 variant as a causal trigger and not merely a risk factor for Alzheimer’s disease. This emphasizes the urgency of understanding the mechanisms by which APOE4 initiates and drives the pathogenesis of the disease. “The results of this study should encourage us to consider APOE4 as a priority therapeutic target,” says the team. This opens up new possibilities for preventive and therapeutic approaches specifically for this patient group. However, it is first essential to elucidate the exact mechanism by which the double APOE4 variant makes its carriers ill.