It has long been known that genetic factors also determine susceptibility to Alzheimer’s. Now doctors have discovered that an already known gene variant not only increases the risk of dementia, but also directly triggers Alzheimer’s. This is always the case when those affected carry two copies of this gene apolipoprotein-4 (APOE4) in their genome. Homozygous carriers of this gene variant almost all develop abnormal amyloid accumulations in their brains as they age. APOE4 is therefore not just a risk gene, but in its double form also a direct genetic trigger for Alzheimer’s, as the team reports.
The risk of developing Alzheimer’s dementia is partly genetic. Some rare gene mutations are already known that lead to an early onset of the disease. However, much more frequently, certain gene variants and their combinations do not necessarily lead to Alzheimer’s, but can increase the risk of dementia. These include, in particular, variants of the apolipoprotein E (APOE) gene. This gene plays an important role in cholesterol breakdown, fat metabolism and inflammatory reactions. However, the APOE4 gene variant may also increase the risk of Alzheimer’s disease, as previous studies have shown.
A closer look at APOE4
A team led by Juan Fortea from the Biomedical Research Institute Sant Pau in Barcelona has now examined the effect of the APOE4 gene variant in more detail. While some people have only inherited one copy of this gene variant from their parents and carry the non-risk variant APOE3 on the second allele, APOE4 occurs twice in the genome of around two percent of all people worldwide. Carriers of this double copy of APOE4 are therefore homozygous for this gene variant. The doctors have now determined in a clinical study what this means for their risk of Alzheimer’s.
To do this, Fortea and his colleagues examined the brains of 3,297 deceased Alzheimer’s patients from the USA. These included 273 people who were homozygous for the APOE4 gene. The doctors also analyzed 10,039 living Alzheimer’s patients from Europe and the USA, including 519 people with double APOE4 gene variants.
The result: Almost all people with two APOE4 variants showed Alzheimer’s symptoms. Even at the age of 55, higher levels of typical Alzheimer’s biomarkers were found in their blood than in people who carried the APOE3 variant in their genome instead of APOE4. At the age of 65 and over, 95 percent of the homozygous test subjects had abnormally increased levels of amyloid proteins in the cerebrospinal fluid. This is considered a clear indication of Alzheimer’s disease. These affected people will almost certainly develop Alzheimer’s symptoms over the course of their lives. On average, these occurred seven to ten years earlier than in people with a different APOE variant or just one APOE4 gene.
Own genetic variant of Alzheimer’s dementia
Fortea and his colleagues conclude that APOE4 is not only an important risk gene for Alzheimer’s, but that this gene variant even triggers its own genetic form of Alzheimer’s when it occurs twice. APOE4 homozygosity therefore fulfills three main characteristics of a genetically determined Alzheimer’s disease: those affected are almost certain to become ill, the onset of symptoms is predictable and the development of biomarkers and other medically detectable changes also follows a fixed pattern. After the onset of dementia, no features that could be distinguished from other types of Alzheimer’s were found in the brains of those affected. However, the path to get there was clearly understandable.
“This new definition presents APOE4 as a causative factor rather than a risk factor for Alzheimer’s disease and highlights the need to understand how APOE4 can initiate and drive the pathogenesis of Alzheimer’s disease,” writes a team led by Qin Xu from the Gladstone Institute of Neurological Disease in San Francisco in an accompanying commentary to the study. “The results of this study should motivate drug developers to prioritize APOE4 as a therapeutic target.” Special prevention and treatment strategies for this patient group could now be derived from this. Before doing so, however, it is necessary to elucidate the exact mechanism by which the double copy of the APOE4 gene variant makes its carriers sick.
Source: Juan Fortea (Biomedical Research Institute Sant Pau) et al., Nature Medicine, doi: 10.1038/s41591-024-02931-w