Summary: A novel study sheds new light on the link between the APOE4 gene and Alzheimer’s disease. The study reveals that over 95% of individuals over 65 who have two copies of the APOE4 gene exhibit biological markers of Alzheimer’s in the brain or through cerebrospinal fluid and PET scans.
These findings indicate that APOE4 homozygotes not only have a higher risk but also develop Alzheimer’s earlier than those with other gene variants, suggesting that APOE4 might be considered a distinct genetic form of the disease. This breakthrough could lead to more targeted prevention strategies and treatments for this demographic.
Key Facts:
- High Incidence of Alzheimer’s Pathology: Over 95% of APOE4 homozygotes over the age of 65 exhibit biomarkers indicative of Alzheimer’s, suggesting a near-certain development of the disease in these individuals.
- Early Onset: APOE4 homozygotes develop Alzheimer’s earlier than those with other gene variants, with significant pathology detected as early as age 55.
- Potential for Targeted Treatments: These findings advocate for individualized prevention strategies and clinical trials specifically tailored for APOE4 carriers, recognizing the gene’s unique impact on Alzheimer’s disease progression.
Source: Sant Pau Research Institute
Researchers from the Research Area on Neurological Diseases, Neuroscience, and Mental Health at the Sant Pau Research Institute, led by Dr. Juan Fortea, Director of the Memory Unit of the Neurology Service at the same hospital, have found that over 95% of individuals over 65 years old who have two copies of the APOE4 gene -APOE4 homozygotes- show biological characteristics of Alzheimer’s pathology in the brain or biomarkers of this disease in cerebrospinal fluid and PET scans.
The study, published today in Nature Medicine, also concludes that those individuals homozygous for APOE4 also develop the disease earlier than those with other variants of the APOE gene.
These findings suggest that having two copies of the APOE4 gene could represent a new genetic form of Alzheimer’s disease, as explained by Dr. Fortea.
“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,” explains this researcher.
New paradigm
It is known that mutations in three genes, APP, PSEN1, and PSEN2, are involved in the development of autosomal dominant early-onset Alzheimer’s disease -which is clearly considered genetic and can appear from the age of 40- while variants of other genes have been associated with an increased risk of developing sporadic or late-onset forms.
Additionally, it was already known that APOE was one of the genes considered the strongest genetic risk factor for late-onset Alzheimer’s disease.
In this work, researchers 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 National Alzheimer’s Coordinating Center (United States) and clinical and biomarker data from over 10,000 individuals, including 519 APOE4 homozygotes from five large multicenter cohorts (from Europe and the United States) of subjects with Alzheimer’s disease biomarkers.
The results suggest that virtually all APOE4 homozygotes showed Alzheimer’s pathology and had higher levels of disease-associated biomarkers at age 55 compared to individuals with the APOE3 gene. At age 65, over 95% of APOE4 homozygotes showed abnormal levels of amyloid in cerebrospinal fluid – a key early pathological feature in Alzheimer’s disease – and 75% had positive amyloid scans.
Based on these results, the authors suggest that the genetic variant of 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 Alzheimer’s disease.
“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,” adds Dr. Fortea.
The authors note that these findings could be useful for the development of individualized prevention strategies, clinical trials, and targeted treatment approaches for this specific population.
In this regard, Dr. Alberto Lleó, a researcher in the Dementia Neurobiology Group at the Sant Pau Research Institute and Director of the Neurology Service at the same hospital, points out that “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.”
On his behalf, researcher Dr. Víctor Montal, 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, adds that “the findings emphasize the importance of monitoring APOE4 homozygotes from an early age for preventive interventions.”
About this genetics and Alzheimer’s disease research news
Author: Karla Islas
Source: Sant Pau Research Institute
Contact: Karla Islas – Sant Pau Research Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease” by Juan Fortea et al. Nature Medicine
Abstract
APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease
This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed.
The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study.
Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes.
By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes.
The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome.
However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes.
The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.
