Nearly all individuals in a multicenter study carrying two copies of APOE4a variant of the gene APOE associated with the disease Alzheimer, developed signs of the disease, reports a study published in Nature Medicine. These people carrying two copies of APOE4, called APOE4 homozygotes, also showed earlier signs of clinical changes compared to those with other APOE variants. The findings suggest that homozygosity for APOE4 may represent a distinct genetic form of Alzheimer’s disease.
Mutations of APP, PSEN1 and PSEN2
Mutations in three genes, APP, DOG1 e PSEN2, are known to cause the early autosomal dominant form of Alzheimer’s disease (ADAD), while variants in several other genes have been associated with an increased risk of developing the more common (late-onset) form of the disease. APOE is one of the genes considered the strongest genetic risk factor for late-onset Alzheimer’s disease. APOE4 homozygotes are known to have an increased lifetime risk of developing Alzheimer’s disease dementia – a much higher risk than those who have only one copy of the gene or non-carriers.
News on Alzheimer’s treatment
Juan Fortea, Victor Montal and colleagues evaluated clinical, pathological, and biomarker changes in homozygotes APOE4 to determine their risk of developing the disease Alzheimer. They used pathology data from 3,297 brain donors, including analyzes of 273 APOE4 homozygotes from the National Alzheimer’s Coordinating Center in the United States, and biomarker and clinical data from more than 10,000 people, including 519 APOE4 homozygotes from five large multicenter cohorts (from Europe and the United States) of subjects with Alzheimer’s disease biomarkers.
They found that nearly all APOE4 homozygotes showed Alzheimer’s pathology and had higher levels of disease-associated biomarkers at age 55 compared to those of people with the APOE3 gene. By age 65, nearly all APOE4 homozygotes (at least 95%) showed abnormal levels of amyloid in the cerebrospinal fluid, a key early pathological feature in Alzheimer’s disease, and 75% had positive amyloid scans. The authors note that the prevalence of these markers appeared to increase with age, indicative of near-complete penetrance of Alzheimer’s disease biology in APOE4 homozygotes. The authors also showed that APOE4 homozygotes experienced clinical symptoms of Alzheimer’s disease around age 65, which is 7-10 years before the development of symptoms for other APOE variants.
Fort and coauthors suggest that the predictability of symptom onset and biomarker changes was similar to ADAD. They also note that during the dementia phase, there appeared to be no difference in the accumulation of amyloid or tau compared to those in other forms of the disease, despite the early appearance of biomarkers and clinical symptoms among APOE4 homozygotes.
A new genetic form of Alzheimer’s
The authors suggest that the genetic variant APOE4 it is not only a risk factor for Alzheimer’s disease, like other APOE variants, but may also represent a distinct genetic form of Alzheimer’s disease. They indicate that this may require the development of individualized prevention strategies, clinical trials and therapeutic approaches. They conclude that further research, including in larger populations, is needed.
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