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APOE4 Homozygosity Constitutes Genetic Form of Alzheimer's Disease, Study Suggests


NEW YORK – New research by a team in Spain suggests that homozygosity for the APOE4 allele should be considered a genetic form of Alzheimer's disease (AD) rather than merely a genetic risk factor for the condition.

In a study published in Nature Medicine on Monday, Juan Fortea and Victor Montal of the Biomedical Research Institute Sant Pau in Barcelona, Spain, and their colleagues wrote that their work "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."

Alzheimer's is generally divided into two types: genetic forms — either early-onset autosomal dominant Alzheimer's disease (ADAD) caused by mutations in the APP, PSEN1, or PSEN2 genes or Down syndrome-associated Alzheimer's disease (DSAD) — and late-onset or sporadic forms that have a number of genetic risk factors.

Up until now, the APOE4 allele of the APOE gene — which is homozygous in 2 percent to 5 percent of the population and heterozygous in about 20 percent — had been regarded as a strong genetic risk factor for sporadic AD. Homozygous APOE4 confers a 60 percent lifetime risk of developing AD-related dementia by age 85, similar to the lifetime risk of many Mendelian disease genes.

"[W]e aimed to assess the clinical, pathological, and biomarker changes in APOE4 homozygotes 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," the authors wrote.

For their study, the researchers analyzed pathology data from 3,300 brain donors in the National Alzheimer's Coordinating Center cohort as well as clinical Alzheimer's biomarker data for 10,000 people from five large multicenter cohorts. Together, these cohorts included nearly 800 APOE4 homozygotes and more than 4,000 APOE3/4 heterozygotes.

Virtually all APOE4 homozygotes showed some form of AD pathology, including abnormal amyloid levels in their cerebrospinal fluid by age 65, suggesting that AD biology — which does not necessarily include clinical symptoms — was nearly fully penetrant in these individuals.

In addition, age of symptom onset was as predictable in the APOE4 homozygotes as in individuals with ADAD or DSAD.

Finally, biomarkers in APOE4 homozygotes changed in a predictable pattern that the researchers said was "remarkably similar" to the sequence of biomarkers observed in ADAD or DSAD.

The study also looked at differences between APOE4 homozygotes and APOE3/4 heterozygotes and found a "distinct gene dose effect" of APOE4 on several measurements, with heterozygotes consistently showing intermediate phenotypes between APOE3 and APOE4 homozygotes.

The results have "critical implications in the Alzheimer's disease field," Yadong Huang, a researcher at the Gladstone Institute of Neurological Disease and the University of California, San Francisco, and colleagues wrote in a commentary in Nature Medicine, adding that the study "undoubtedly opens exciting new avenues in APOE4-related Alzheimer's disease research, therapeutic development, and clinical trial design."

The fact that approximately 2 percent of the population has two copies of APOE4, combined with the new recognition of homozygous APOE4 as a Mendelian disease, "could not only enhance public awareness of Alzheimer's disease, but could also prompt pivotal changes in diagnosis, management of, and care strategies for Alzheimer's disease," Huang and colleagues suggested, such as screening recommendations and counseling.

In addition, the study's findings "should motivate drug developers to prioritize APOE4 as a therapeutic target," they wrote, including for CRISPR-based gene therapies and cell replacement therapies.

According to the study authors, APOE4 homozygotes and heterozygotes should also no longer be lumped together in studies and clinical trials because of their different genetic risk profiles.

One of the limitations of the work is that it mainly included participants of European ancestry, and future research needs to expand to diverse populations to fully understand the effect of APOE4 on AD risk, the researchers acknowledged.