, a new study suggests.
More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.
Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease.
“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.
Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
High AD Penetrance
Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease.
Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers.
Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.
Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.
Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death.
Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans.
Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%.
Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).
When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.