2024-05-13 09:47:09
Anyone with two copies of APOE4 is likely to develop Alzheimer’s. This is shown by the results of a study by Dr. Victor Montal from the Biomedical Research Institute at Sant Pau Hospital in Barcelona and his colleagues, who are currently Nature Medicine It seems [1]. The study also suggests that APOE4 is not just a risk gene, but a genetic variant of Alzheimer’s.
Alzheimer’s disease can be inherited through certain mutations in genes. So far, mutations in 3 genes – APP, PSEN1 and PSEN2 – are known to cause early-stage Alzheimer’s, and many other genes have been linked to an increased risk of the most common, late-onset form of Alzheimer’s dementia.
To date, apolipoprotein E has been the strongest risk gene for this late form when it is present in the e4 (APOE4) isoform. Previously it was known that up to 15% of all individuals carry 2 copies of this APOE variant. increases who are at risk of the disease. About 2% of the population is homozygous for APOE4.
By 65, nearly all APOE4 homozygotes have abnormal amyloid levels
In their large-scale study, Montal and his colleagues now show that almost all carriers of the gene mutation develop Alzheimer’s dementia during their lifetime. They examined data from 3,297 people who donated their brains to the National Alzheimer’s Coordinating Center in the US and data from 10,039 people who participated in Alzheimer’s clinical trials. Among them were more than 500 people who were homozygous for ApoE4.
The results showed that almost all APOE4 homozygotes had Alzheimer’s disease pathology and had significantly higher levels of Alzheimer’s biomarkers compared to APOE3 homozygotes from the age of 55 years.
By age 65, nearly all APOE4 homozygotes had abnormal levels of amyloid in the cerebrospinal fluid, and 75% had amyloid deposits in the brain. The frequency of these markers increased with age, suggesting that Alzheimer’s disease was almost complete in APOE4 homozygotes.
The authors of the study suggest that the predictability of the onset of symptoms and the sequence of changes in biomarkers in APOE4 homozygotes correspond to the already known Alzheimer’s genetic variants. They conclude that APOE4 homozygotes therefore represent a genetically determined form of Alzheimer’s disease.
Compelling work that provides a significant gain of knowledge
“The work provides a significant increase in knowledge in the field of Alzheimer’s dementia for a genetic constellation that is quite common with an incidence of about 2%,” said Professor Dr Elisabeth Stögmannhead of the outpatient clinic for memory disorders and dementia and senior physician at the Medical University of Vienna, said the Science Media Center (SMC) the results of the study.
The work provides a significant increase in knowledge in the field of Alzheimer’s dementia for a genetic constellation that is quite common with an incidence of about 2%.
As well as that Professor Dr. Alfredo Ramírez, head of the Molecular Neuropsychiatry department at the Cologne University Hospital, speaking of “resolute work”. Ramirez recalls that over the years it has become increasingly clear that APOE is not just a risk factor, but a causative gene for Alzheimer’s. “For this reason, it is not surprising that the evidence in this publication supports the classification of APOE as a monogenic form of Alzheimer’s disease rather than as a risk/susceptibility factor for Alzheimer’s disease,” explains Ramirez.
dr. Nicolai Franzmeier, who researches Alzheimer’s disease at the LMU Munich, confirms that gene dosage effects are known: that 2 copies of the risk version of Alzheimer’s disease carry a greater risk than one copy. “However, the results of the current study are surprising in that penetrance is almost complete and predictable in APOE4 homozygotes, and those affected show Alzheimer-typical brain changes in the brain,” says Franzmeier.
Early detection? Still a long way to go…
According to Ramirez, there is still “a long way to go” before the results can be used for early detection. However, he sees important consequences for genetic counseling, since the interpretation of APOE4 depends on whether the e4 allele was found in the homozygous or heterozygous state. “However, it is still difficult to tell when the right time to test is. We are born with genetic variants, but when and how they translate into pathology is still a matter of speculation. “Genetics says something about probability, but not about fate,” Ramirez explains.
Genetics says something about probability, but not fate.
Therefore, genetic testing for APOE is needed, but additional biomarkers are needed to investigate the translation of genetic effects into pathology. Ramirez sees the need for more research: “We still need to determine the timing of the events associated with amyloid pathology in homozygous APOE4. This will help determine the best time in life to undergo genetic testing for prevention and early treatment.”
Experts recommend against testing for APOE
The study has little impact on diagnostics – at least not in Germany at the moment,” says Franzmeier. “The new anti-amyloid antibody therapies, which are already approved in the USA and are still undergoing approved testing in our country, have significant side effects on APOE4 carriers, such as brain swelling and minor bleeding. Therefore, before starting therapy, it should be examined whether the patient is an APOE4 carrier or not. This makes it easier to assess the profile of side effects in order to suspend treatment if necessary,” explains Franzmeier.
The study has little impact on diagnostics – at least not in Germany at the moment.
In S3 guidelines In cases of “dementia”, “the determination of apolipoprotein E genotype as a genetic risk factor is not recommended due to the lack of diagnostic selectivity and predictive value in the context of diagnostics”.
Stögmann also advises against pre-symptomatic testing for APOE for diagnosis: “Heterozygous APOE4 carrier status is not significant enough to confirm an etiological diagnosis of dementia, and knowledge of a genetic risk factor can be stressed.”
Franzmaier adds: “I wouldn’t recommend testing for APOE4 right now, because there are no therapeutic consequences. So you would have to live with the result first and, above all, with the knowledge, but sometimes you feel helpless because medicine in Germany cannot do much from May 2024.” In the future, APOE4 genotyping may soon become relevant. detection and therapy “provided we succeed in developing a sensible treatment approach,” concludes Franzmeier.
Currently, I would not recommend testing for APOE4 as there are no therapeutic consequences.
Can a new genetic variant protect APOE4 carriers from Alzheimer’s?
New genetic variant in APOE4 carriers linked to 70% reduced risk of Alzheimer’s disease, new findings show research results. To find possible defensive versions, in order Dr AS Caghan Kizil from the Department of Neurology at Columbia University in New York and his team examined the genomes of more than 3,500 APOE4 carriers over the age of 70 with and without Alzheimer’s from different ethnic groups.
They identified 2 variants on the FN1 gene, rs116558455 and rs140926439, which are present in healthy APOE4 carriers and appear to protect APOE4 carriers from Alzheimer’s disease. The researchers estimate that 1% to 3% of APOE4 carriers in the United States – about 200,000 to 620,000 people – may have the protective mutation.
#risk #gene #Alzheimers #disease