APOE4 Homozygotes Represent a Unique Genotypic Subset of Alzheimer’s Disease

Introduction

Alzheimer’s disease (AD) is one of the neurodegenerative diseases that modern medicine has yet to conquer, usually with a complex genetic background. While mutations in three genes (APP, PSEN1, and PSEN2) lead to early-onset autosomal dominant Alzheimer’s disease (ADAD), variants in dozens of genes are associated with increased risk of the more common sporadic (late-onset) AD. Among these, APOE is the most prominent genetic risk factor. Compared to sporadic AD, AD with definitive genetic typology of APOE shows higher pathogenic penetrance, predictability of clinical symptom onset age, distinctly characteristic pathologies, clinical, and biomarker changes.

Building on existing research regarding the biological effects of APOE4 heterozygotes and homozygotes in AD, this study aims to explore whether APOE4 homozygotes constitute a unique form of genetically determined AD by analyzing clinical, pathological, and biomarker changes using data from the National Alzheimer’s Coordinating Center (NACC) and five large AD biomarker cohorts in the United States.

Research Team and Publication Date

This study was conducted by scientists Juan Fortea, Jordi Pegueroles, and others from institutions such as the Sant Pau Memory Unit, San Pau Biomedical Research Institute, University of Barcelona, and the Wisconsin Alzheimer’s Disease Research Center. The paper was published in the May 2024 issue of “Nature Medicine”.

Research Process

The study comprises two parts: pathological research and clinical research, aimed at verifying the comprehensive penetrance of AD biology in APOE4 homozygotes and its predictiveness compared to ADAD and Down syndrome-associated AD.

Pathological Research

Analyzing the pathological data of 3,297 brain donors from the NACC data set, the study used a widely accepted ADNC scoring system to quantify neuropathological burden. The distribution of this scoring system among APOE4 and APOE3 homozygotes was further analyzed. The study also examined AD biomarker levels in different age groups and conducted comparisons of gene dosage effects, symptom prediction, and benchmark models related to ADAD and Down syndrome-associated AD.

Clinical Research

The clinical research involved 10,039 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), A4 Study, ALFA Study, Wisconsin Register for Alzheimer Prevention (WRAP Project), and OASIS3 Project. It further investigated AD risk, clinical onset age, and changes in biomarkers among individuals with different APOE genotypes. Using these multi-center databases spanning the entire AD spectrum, the study formed a multimodal AD biomarker information library to uncover the clinical and pathological characteristics of APOE4 homozygote AD.

Research Results

Pathological Findings

APOE4 homozygotes demonstrated nearly complete AD biological penetrance with moderately to highly elevated ADNC scores regardless of age.

Clinical Research Findings

APOE4 homozygotes exhibited higher abnormal biomarker levels. For instance, by age 65, most APOE4 homozygotes showed significant amyloid protein level abnormalities. The penetrance of biomarkers increased with age, reaching 88% abnormality at age 80.

Predictive Clinical Manifestations

Based on biomarker changes and clinical manifestations, the study achieved high predictiveness for symptom onset age in APOE4 homozygotes. Similar to ADAD patients and Down syndrome-associated AD patients, this predictiveness aligns with the age and timeline observed in other genetically determined AD categories.

Discussion and Research Value

Conclusion

The study provides clear evidence that APOE4 homozygotes represent another form of genetically determined AD, comparable to ADAD and Down syndrome-associated AD. Leveraging extensive multi-center data, the team elucidated the significant physiological characteristics of APOE4 homozygotes.

Genetic Remodeling

As the genetic framework and characteristics of AD, including APOE4 homozygotes, have been redefined, it is recommended that newly established genetic and disease metrics distinguish between APOE4 heterozygotes and homozygotes rather than combining them in studies. For AD research, it is imperative to investigate its biological models across different ethnic groups.