Carrying two copies of the APOE4 gene (being APOE4 homozygous) constitutes a unique genetic variant of late-onset Alzheimer’s disease (after age 65), which is the most common form of this disease, according to a study carried out by experts from the Research Area in Neurological Diseases, Neuroscience and Mental Health of the Sant Pau Research Institute of Barcelona, led by Dr. Juan Fortea, who also directs the Memory Unit of the Neurology Service of said hospital. Between 15% and 20% of people over 65 years of age affected by this disease share this genetic peculiarity.
In genetic forms of Alzheimer’s, being a carrier of specific variants of a gene causes the disease to develop inevitably over time. Until now, only certain rare alterations in three genes were considered as such, but the scientists who carried out the new research have proposed a new, much more frequent form.
The researchers have published their findings in the journal Nature Medicine, where they explain that their objective was to evaluate the impact of being a double carrier of the APOE4 gene on Alzheimer’s disease, observing clinical, pathological and biomarker changes to determine if double carriers APOE4 constitute a different and genetically determined form of the disease.
Data from the National Alzheimer’s Coordinating Center and five large disease biomarker cohorts were analyzed. The analysis included the donated brain of 3,297 individuals for the pathological study and 10,039 for the clinical study and made it possible to verify that almost all people who carry two copies of the ApoE4 variant in the ApoE gene, which was previously only considered a risk factor, end up also for developing the disease.
Earlier Alzheimer’s symptoms in APOE4 double carriers
Specifically, the results showed that almost all APOE4 double carriers presented typical Alzheimer’s disease pathology and had significantly higher levels of disease biomarkers from the age of 55 years compared to APOE3 double carriers. By age 65, almost all showed abnormal levels of amyloid in their cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating almost complete penetration of the biology of the disease. in double APOE4 carriers.
The age of symptom onset was earlier in APOE4 double carriers, at 65.1 years, with a narrower prediction interval than in APOE3 double carriers. The predictability of symptom onset and the sequence of biomarker changes in APOE4 dual carriers were similar to those observed in autosomal dominant Alzheimer’s disease and Down syndrome.
However, in the dementia stage, there were no differences in amyloid or tau PET scans between the different genetic types, despite changes in clinical and earlier biomarkers. The study concludes that APOE4 double carriers represent a genetic form of Alzheimer’s disease, suggesting the need for individualized prevention strategies, clinical trials and specific treatments.
“This work aims to change the existing paradigm in which having two copies of the E4 allele increased the probability of having AD to a new one in which having these two copies implies certain development of the disease”
In the opinion of Jordi Pérez-Tur, senior scientist of the CSIC at the Institut de Biomedicina de València (CSIC-CIBERNED), who has not participated in the study and claims to have no conflicts of interest, and according to his statements to SMC Spain, it is of an exhaustive study on “a large number of patients for whom a very important and systematized amount of biochemical, genetic and clinical information was available”, so its results are of “high interest per se, regardless of their interpretation (which is also).”
Regarding the news that it provides, Pérez-Tur indicates that the fact that the E4 allele is a factor related to Alzheimer’s disease (AD) is not new, since it has been known for more than 30 years that having one or two E4 alleles in the genome increases the risk of developing Alzheimer’s if one reaches an advanced age, and that “the number of copies of the E4 allele (1 or 2) was related to the age at which the disease appears, more early with two copies than with one, and also with the number of lesions characteristic of AD, senile plaques. Individuals with two alleles had a greater number of these lesions (called senile plaques). That is, we knew that having two alleles ‘was bad’ from the point of view of AD development. But there were cases of individuals with two copies of the bad allele who did not develop Alzheimer’s disease despite living to very old ages, which seemed to support the idea that the APOE E4 allele was a risk factor, that is, a factor that predisposed one to suffer from the disease, but that was not its cause.”
“This work, through the analysis of a large number of patients, demonstrates that having two copies of the E4 allele can be considered a new genetic form of AD, adding to the already known forms caused by genetic variants. That is, APP, PSEN1 and PSEN2 are added as genes responsible for forms of familial AD. That is, it aims to change the existing paradigm in which having two copies of the E4 allele increased the probability of having AD to a new one in which having these two copies implies certain development of the disease.” Eloy Rodríguez, neurologist at the Marqués de Valdecilla-IDIVAL University Hospital, shares the same idea: “The study provides solid evidence to change the conceptual framework: we go from thinking about e4 homozygotes as a risk factor to considering it a determining factor of the disease”.
Pérez-Tur adds that “this must be taken with some caution since there is still a certain number of individuals who do not follow this direct relationship: individuals who have two copies of the E4 allele but who neither develop the disease nor show signs of it.” is developing. That is, the existence of individuals homozygous for the E4 allele without AD seems to go against the conclusion reached in the previous paragraph. However, contrary to generally established perception, being a carrier of a genetic variant that causes a disease does not always imply that said disease will manifest itself. There are multiple genetic diseases in which certain carriers of the variant that causes the disease escape it. This, known as reduced penetrance, cannot be ruled out in such cases.”
“In conclusion, this work represents a clear advance in the study of the causes of AD since it focuses on a cause that, although it had not been ignored until now, had not received the attention that was possibly necessary. had in view of the development of new therapies and also, in view of the design of therapeutic trials that could be carried out given that what until now was considered as just another variable should be considered, in light of these results, as a criterion of definition of the groups and the strategies to apply.”
For his part, Paul Matthews, Director of the Rosalind Franklin Institute and group leader at the UK Dementia Research Institute at Imperial College, points out to Science Media Center UK that “Given that 2 in 100 northern Europeans are carriers of two copies of the gene, the authors highlight that this discovery makes APOE4 Alzheimer’s disease one of the most common Mendelian genetic disorders.” He adds, “One of the implications of this work is that APOE4 gene homozygosity testing should be evaluated for clinical use when late middle-aged people present to their doctors with symptoms of dementia. Since APOE4 homozygotes are common in the population, have predictable ages of onset and rates of disease progression, and, as demonstrated in the work, show changes in easy-to-measure biomarkers as their disease progresses, they also constitute an attractive population for clinical trials of new treatments for Alzheimer’s disease.
