Spanish researchers have identified a new genetic form of Alzheimer’s disease

A team of Spanish researchers has identified a new, much more common genetic variant that causes Alzheimer’s disease: carrying two copies of an already known genetic variant.

Genetic forms of Alzheimer’s disease are those in which certain gene variants They cause disease over time, and until now it was thought that certain rare changes in three genes were the cause. A group of Spanish researchers led by Hospital Sant Pau in Barcelona now suggests a new, much more common genetic form associated with the onset of the disease: almost all people who are carriers two copies of the ApoE4 allele in the ApoE genewhich was previously considered only a risk factor, over time also leads to the development of the disease.

Coordinates the work Juan Forteafrom the memory ward of the above-mentioned hospital center and Networked Biomedical Research Center for Neurodegenerative Diseases (Ciberned)in Barcelona, ​​published in a scientific journal Natural medicineaimed at assessing the effect of APOE4 homozygotes, which are a separate and genetically determined form in Alzheimer’s disease (AD).

To do this, five large AD biomarker cohorts were analyzed, which included 3297 people for the pathological study and 10,039 people for the clinical study. The results showed that almost all alleles (genetic variants) APOE4 homozygotes presented AD pathology and had significantly higher levels Biomarkers of Alzheimer’s disease after 55 years compared to APOE3 homozygotes.

By age 65, nearly all had abnormal levels of a key disease marker, amyloid protein, in their cerebrospinal fluid, and 75% had positive scans for amyloid. The prevalence of these markers increased with age, suggesting the involvement of APOE4 in disease biology. The study concluded that APOE4 homozygotes represent genetic form of Alzheimer’s diseasesuggesting the need for prevention strategies, clinical trials and individualized treatment.

Jordi Pérez-Tur, CSIC Senior Researcher at the Institute of Biomedicine of Valencia (CSIC-CIBERNED)

on the Science Media Center (SMC) platform explains that “it is not news in itself that Allele E4 This is a factor associated with Alzheimer’s disease. “We have known for more than 30 years that having one or two E4 alleles in our genome increases the risk of developing Alzheimer’s disease later in life.”

“We already knew that having two alleles was “bad” in terms of developing Alzheimer’s disease“, he continues. “The number of copies of the E4 allele (1 or 2) was associated with age at onset of the disease, earlier with two copies than with one, and with the number of lesions characteristic of AD, senile plaque. Individuals with two alleles had a greater number of these lesions, called senile plaques“.

“But there have been cases where people with two copies of the bad allele did not develop Alzheimer’s disease despite living to a very old age, which seems to support the idea that the APOE E4 allele is a risk factor, i.e. a factor predisposing to the development of Alzheimer’s disease. suffer from illness.”

This work, through analysis of a large number of patients, demonstrates that “have two copies of the E4 allele can be seen as new genetic form of AD which adds to the already known forms caused by the already known genetic variants of familial Alzheimer’s disease: APP, PSEN1 and PSEN2.

“The work aims to change the existing paradigm, in which having two copies of the E4 allele increased the likelihood of having Alzheimer’s disease, to a new one, in which the presence of these two copies means the development of the disease for sure.”

However, Perez-Tur notes: “This conclusion should be taken with some caution, since there are still a certain number of people who do not follow this direct link: people who have two copies of the E4 allele but who neither develop the disease nor exhibit signs that it is developing (…). Being a carrier of a genetic variant that causes a disease does not always mean that said disease will manifest itself.. There are many genetic diseases in which certain carriers of the variant that causes the disease avoid it. In such cases, a phenomenon known as reduced penetrance cannot be ruled out.”

This work represents a clear advance in the study of the causes of AD, since it focuses on a cause that, although not ignored until now, has not received the attention it needs. Now, Perez-Tur recalls, “the paper does not take into account the degree of familial aggregation that this phenotype may have, that is, it does not answer the question to what extent this disease occurs in families.

On the other hand, “the human genome contains about 20,000 variants relative to what is considered the reference, and collectively there are about 3,000,000 positions in the genome (among the 3,000 million bases contained in the human genome) where genetic variants can exist ” , some of which may partially contribute to the observed effect.

Eloy Rodríguez, neurologist at the Marquês de Valdecilla-IDIVAL University Hospital and professor at the University of Cantabriaadds that in this work the authors assume idea of ​​autosomal semi-dominant inheritance and they were able to collect a large amount of data to prove this, since the percentage of e4 homozygotes in the general population is very low, and give it the appropriate statistical treatment as if it were hereditary Alzheimer’s disease), “which reflects originality, tenacity, quality scientific work and undeniable performance.”

“Until now, there has been no data on large population sizes and the data has not been analyzed with the necessary care to assess this aspect. The study provides compelling evidence for the need to change the conceptual framework.“We have moved from looking at e4 homozygotes as a risk factor to looking at them as a determinant of disease.”

Something of major consequence as “we are entering a time where they begin to arrive drugs with potential disease-modifying effects, mainly on the accumulation of amyloid in the brain, which is universal in e4 subjects and an early phenomenon (as early as the 40s). Perhaps in the near future these topics will be Candidates to be treated from a very early age, avoid beta-amyloid accumulation and delay or avoid disease. “In addition, there is preliminary data on drugs that can block the action of ApoE e4, making them an ideal population to test.”

Paul Matthews, Director of the Rosalind Franklin Institute and Group Leader of the UK Dementia Research Institute at Imperial College Londonadds that “the work provides new and robust data that demonstrates that inheritance of two copies of the APOE4 gene causes Alzheimer’s disease. Given that two out of every 100 northern Europeans carry two copies of the gene, the authors emphasize that this discovery makes Alzheimer’s disease APOE4 one of the most common Mendelian genetic disorders (generated by a single gene).

“Because APOE4 homozygotes are widely distributed in the population, have a predictable age of onset and rate of disease progression, and are shown to show changes in easily measured biomarkers as the disease progresses, they also represent an attractive population to study.” clinical trials of new treatment methods.

David Curtis, Emeritus Professor, UCL Institute of Genetics (University College London)believes that the article does not support the claim that having two copies of APOE4 represents some special genetic form of Alzheimer’s disease, since “APOE4 has been known for decades to be an important risk factor for the development of Alzheimer’s disease in humans.” two copies carry a high and substantially higher risk than those who carry one.”

“This study confirms the important link between APOE4 and Alzheimer’s disease; however, this is not at all surprising,” he says. Tara Spears-Jones, President of the British Association of Neurosciences and Group Leader of the UK Dementia Research Institute at the University of Edinburgh.

“The increased risk of developing Alzheimer’s disease when inheriting the APOE4 gene has been known for more than 30 years. This study adds compelling evidence that people with 2 copies of this gene They are almost guaranteed to develop Alzheimer’s disease if they live long enough, and the disease will develop sooner than people without the gene. “This and other studies highlight the importance of conducting more basic research to understand how genes change our brain’s susceptibility to Alzheimer’s disease as we age.”

Nat Honey (2024). https://doi.org/10.1038/s41591-024-02931-w

https://doi.org/10.1038/s41591-024-02931-w