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The APOE4 variant may be more than just a genetic risk factor for Alzheimer's disease, new data from several cohorts suggested.

Clinical, pathological, and biomarker changes indicated that APOE4 homozygotes may have a distinct, genetically determined form of Alzheimer's, according to Juan Fortea, MD, PhD, of the Hospital of Sant Pau in Barcelona, Spain, and co-authors.

In an analysis spanning several cohorts, almost all APOE4 homozygotes had Alzheimer's pathology and significantly higher levels of Alzheimer's biomarkers from age 55 compared with APOE3 homozygotes. By age 65, nearly all had abnormal cerebrospinal fluid (CSF) levels, and 75% had positive amyloid scans, Fortea and colleagues reported in . The prevalence of these markers increased with age, reaching almost full penetrance over time.

"What we found was that individuals who had two copies of the APOE4 gene developed signs of Alzheimer's disease; over 95% had Alzheimer's disease pathology, either in the brain or in the biomarkers that we analyzed," Fortea said during a press conference.

Patterns echoed what researchers have found with other mutations in genes like PSEN1, PSEN2, or APP, which are known to cause early-onset autosomal dominant Alzheimer's or Down syndrome-associated Alzheimer's disease.

Reframing APOE4 homozygosity is particularly important in light of anti-amyloid therapies, noted co-author Reisa Sperling, MD, of Brigham and Women's Hospital in Boston. "It's been challenging to understand why APOE4 carriers have a higher rate of what we call amyloid-related imaging abnormalities, or ARIA" in clinical trials of anti-amyloid drugs, she said.

"We have to think about how we can treat APOE4/4 carriers," Sperling continued. "These individuals are desperate. They've seen [Alzheimer's disease] in both of their parents often and really need therapies. We can see that amyloid is a major driver in this population in particular, and I hope we ... find ways to treat them safely, and especially work on prevention trials."

Fortea and colleagues studied pathological data from 3,297 brain donors, including samples from 273 APOE4 homozygotes from the and biomarkers and clinical data from 10,039 people, including 519 APOE4 homozygotes, from five large multicenter cohorts in Europe and the U.S. Most participants in these studies were white.

Symptom onset started at age 65 years in APOE4 homozygotes, compared with 74 years in APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant Alzheimer's disease and Down syndrome, the researchers said. However, in the dementia stage of Alzheimer's, there were no differences on PET in amyloid or tau compared with other forms of the disease, despite earlier clinical and biomarker changes.

Redefining APOE4 homozygosity as a genetic form of Alzheimer's will have a substantial effect on diagnosis, research, and drug development, observed Yadong Huang, MD, PhD, of the University of California San Francisco, and co-authors in an .

The global average proportion of APOE4 homozygotes is around 2% and the genetic form of APOE4-homozygous Alzheimer's disease would represent one of the most frequently occurring Mendelian diseases, they noted.

A new definition would emphasize the need to understand how APOE4 might drive Alzheimer's disease pathogenesis and underscore the need for targeted drug development, they added. "Although the Alzheimer's disease field has recently expanded beyond amyloid-beta-centric therapies to encompass multiple targets, such as tau and neuroinflammation, there has been limited emphasis on APOE4-related drug development," Huang and co-authors pointed out.

The study also lays a genetic foundation for exploring CRISPR-based gene therapies and cell replacement therapies for patients with APOE4-homozygous Alzheimer's disease, they noted, and sets the stage for APOE4 homozygotes to be treated as a separate group in clinical trials of other agents.

The findings call for individualized prevention strategies, clinical trials, and treatment approaches to be developed, Fortea and co-authors said. They also identified the need for more research studies across ethnic groups, as APOE4 prevalence may vary based on ethnic backgrounds. "Future studies should focus on population-based studies with diverse origins," they wrote.

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