A new study, published on 7 May in the Nature Medicine journal, has identified APOE4 homozygosity as a distinct, genetic form of Alzheimer’s disease. According to the re-search team, led by Juan Fortea and Victor Montal at the Biomedical Research Institute of Sant Pau (Spain), people with two APOE4 alleles almost always develop Alzheimer’s disease brain pathology – a sign that APOE4 homozygosity should be viewed as an inherited form of Alzheimer’s disease (AD). APOE4 has consistently been ranked as the strongest genet-ic risk factor for AD, with two copies boosting the odds of developing the disease up to 15-fold.
There are three types of APOE genes a person can carry (APOE2, APOE3 and AP-OE4) with each person inheriting two copies of APOE from their biological parents. Of these, APOE4 homozygosity – which means the possession of two copies of the APOE4 gene variant – confers the highest risk of developing AD. Until now, APOE4 has been viewed as a genetic risk factor: an element of our genetic makeup that strongly predisposes carriers to AD. Based on their new study, however, the Span-ish research team argue that APOE4 homozygosity should be viewed as a distinct, genetic form of AD, as 95% of people carrying two copies of APOE4 have amyloid plaques in the brain by age 65.
To understand how APOE4 genotype relates to AD, Juan Fortea and his team gathered brain pathology, biomarker, and clinical data from over 13 thousand participants in clinical studies, including the US-based ADNI, OASIS and NACC studies and the Spanish ALFA cohort. Of the 13,000 partici-pants involved in the research, 792 carried two copies of the APOE4 gene - the first time such a large number of individu-als with APOE4 homozygosity have been studied. When examining brain pathology data, amyloid-PET scans, and cerebrospinal fluid biomarkers (CSF) amyloid-beta42 and p-tau181, the research team observed that by the age of 65, nearly all APOE4 homozygotes had abnormal CSF levels of amyloid beta42. 75% showed signs of amyloid deposition in brain PET scans. By age 80, 88% of APOE4 homozygotes were positive for all biomarker tests: amyloid-PET, and CSF levels. Next, Fortea and his team looked at clinical symptoms, to see when and how people with two copies of APOE4 started showing symptoms of cognitive impairment and dementia.
On average, mild cognitive impairment started at age 71, with dementia developing around two years later. It is important to note that the age of symptom onset varied widely, ranging between 49 to 81 years. In addition, half the individuals with two copies of APOE4 lived until 85 without developing dementia, despite having signs of AD pathology (as measured by PET or fluid biomarker tests) in the brain. Nevertheless, the researchers conclude that APOE4 homozygosity represents a genetic form of AD based on a biological definition of the disease, suggesting the need for individualised prevention strategies, clinical trials and treatments for people carrying two copies of APOE4.
