Researchers headed by a team at the dementia neurobiology group, Sant Pau Research Institute, have found that over 95% of individuals over 65 years of age who have two copies of the APOE4 gene—APOE4 homozygotes—show biological characteristics of Alzheimer’s disease (AD) pathology in the brain or biomarkers of the disorder in cerebrospinal fluid and PET scans. Led by Juan Fortea, MD, PhD, director of the research area on neurological diseases, neuroscience, and mental health at the Sant Pau Research Institute and the memory unit of the neurology service at the same hospital, the researchers analyzed data from a Spanish cohort and an American cohort of over 10,000 patients and samples from over 2,000 brains.

The findings also indicated that individuals who are homozygous for APOE4 develop Alzheimer’s disease earlier than those with other variants of the APOE gene. The results, the team concluded, suggest that having two copies of APOE4 could represent a new genetic form of Alzheimer’s disease, and potentially one of the most frequently occurring Mendelian diseases worldwide.

Fortea said, “These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene. This gene has been known for over 30 years and it was known to be associated with a higher risk of developing Alzheimer’s disease. But now we know that virtually all individuals with this duplicated gene develop Alzheimer’s biology. This is important because they represent between 2% and 3% of the population.”

Fortea and colleagues reported on their study in Nature, in a paper titled, “APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease,” in which the authors stated, “In conclusion, our study provides compelling evidence to propose that APOE4 homozygotes represent a distinct, genetically determined form of AD, which has important implications for public health, genetic counseling of carriers, and future research directions.”

AD is a genetically complex disorder with both rare and common genetic variants involved in its pathogenesis, the team explained. It is known that mutations in three genes, APP, PSEN1, and PSEN2, are involved in the development of autosomal dominant Alzheimer’s disease (ADAD), an early-onset form of the disorder that is considered genetic and can appear from the age of 40 years. In contrast, they noted, “… variants in dozens of other genes have been associated with an increased risk of developing the more common sporadic (late-onset) form of the disease.” Among these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. “APOE4 homozygotes have a lifetime risk for AD dementia that can reach 60% at age 85, markedly increased compared to heterozygotes or noncarriers,” the investigators continued.

For their study, the team aimed to assess the clinical, pathological, and biomarker changes in people homozygous for APOE4 “… to test the hypothesis that they can be considered as another form of genetically determined dementia, in fact constituting one of the most frequent Mendelian diseases,” they wrote.

To do this the investigators evaluated clinical, pathological, and biomarker changes in APOE4 homozygotes to determine their risk of developing Alzheimer’s disease. They used data from 3,297 brain donors, including samples from 273 APOE4 homozygotes from the U.S. National Alzheimer’s Coordinating Center (NACC) and collected clinical and biomarker data from over 10,000 individuals, including 519 APOE4 homozygotes, from five large multicenter cohorts from Europe and the United States, among them the Pasqual Maragall Foundation, of subjects with Alzheimer’s disease biomarkers.

Their results indicated that virtually all APOE4 homozygotes showed Alzheimer’s pathology and had higher levels of disease-associated biomarkers at age 55 years, compared with individuals carrying the APOE3 gene. At age 65, over 95% of APOE4 homozygotes showed abnormal levels of amyloid in cerebrospinal fluid (CSF)—a key early pathological feature in Alzheimer’s disease—and 75% had positive amyloid scans. “Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined AD, namely near-full penetrance, symptom onset predictability, and a predictable sequence of biomarker and clinical changes,” the team stated.

Based on their results, the authors suggest that the APOE4 gene is not only a risk factor for Alzheimer’s disease, as previously thought, but could also represent a distinct genetic form of the disorder.

“This reconceptualization of the disease is similar to what we proposed from Sant Pau with Down syndrome, which a few years ago was also not considered a genetically determined form of Alzheimer’s,” added Fortea. The authors further stated, “The reconceptualization of genetically determined AD, inclusive of conditions like APOE4 homozygosity and Down syndrome, necessitates reevaluating established beliefs … given that the incidence of APOE4 homozygotes is approximately 2% (with racial and geographical variations), they would in fact constitute one of the most frequent Mendelian diseases. This will have consequences in counseling and the recommendations to screen for APOE in the population and in the study of patients with cognitive complaints.”

The authors noted that their findings could be useful for the future development of individualized prevention strategies, clinical trials, and targeted treatment approaches for this specific patient population. Co-author Alberto Lleó, MD, PhD, at the dementia neurobiology group at the Sant Pau Research Institute and director of the neurology service at the same hospital, commented, “The data clearly show that having two copies of the APOE4 gene not only increases the risk, but also anticipates the onset of Alzheimer’s, reinforcing the need for specific preventive strategies.” Corresponding author Víctor Montal, PhD, who actively participated in this study during his time at Sant Pau and now studies the molecular structure of the APOE gene at the Barcelona Supercomputing Center, added that “the findings emphasize the importance of monitoring APOE4 homozygotes from an early age for preventive interventions.”

Acknowledging the limitations of their study, the team noted that all participants were from the United States or Europe and were predominately white. However, they noted, there are geographical differences in APOE4 frequency and ethnic risk mitigation, “… with APOE4 conferring a lesser risk in black than in white populations.” Future studies, they noted, “… must prioritize the inclusion of diverse populations to elucidate the full scope of effect of APOE4 on AD risk, ensuring that genetic insights translate into benefits for all ethnicities.”

In an associated News & Views, Qin Xu, PhD, Zherui Liang, and Yadong Huang, MD, PhD, from the Gladstone Institutes, said that redefining APOE4 homozygosity as a genetic form of Alzheimer’s disease will have a substantial effect on Alzheimer’s disease diagnosis, research, and therapeutic development. “This new definition establishes APOE4 as a causal factor instead of a risk factor for Alzheimer’s disease, emphasizing the need to understand how APOE4 may initiate and drive Alzheimer’s disease pathogenesis.”

Redefining APOE4 homozygosity as a genetic form of AD underscores the urgent need for targeted drug development focused directly on APOE4, they noted. “The findings of this study should motivate drug developers to prioritize APOE4 as a therapeutic target.” The newly reported research, the News & Views authors commented, also “lays a solid genetic foundation for exploring CRISPR-based gene therapies and cell replacement therapies based on human induced pluripotent stem cells that are specifically tailored for patients with APOE4-homozygous Alzheimer’s disease.”

They further pointed out that while to date, APOE4 homozygotes have not been treated as a separate treatment group in clinical trials, the new findings suggest that APOE4 status should be an important parameter in trial design, patient recruitment, and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. “Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

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