APOE4 gene linked to early onset Alzheimer's, target for therapeutic intervention

In a recent study published in the journal Nature Medicine, researchers investigated the effect of APOE4 (short for Apolipoprotein E4) homozygosity on Alzheimer's disease (AD) using pathological, clinical, and biomarker analyses. They found that APOE4 homozygotes showed AD pathology and elevated AD biomarker levels from 55 years of age, representing a distinct variant of AD and an emerging therapeutic target.

Study: APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Image Credit: mapush ShutterstockStudy: APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Image Credit: mapush Shutterstock

Background

Alzheimer's disease (AD) involves both rare and common genetic variants contributing to its pathogenesis. Mutations in genes like APP, PSEN1, and PSEN2 cause early-onset autosomal dominant AD (ADAD), while numerous other genes increase the risk of sporadic AD. APOE is a significant genetic risk factor, with APOE4 homozygotes having a significantly higher lifetime risk of AD dementia compared to heterozygotes or noncarriers. However, the predictability of symptom onset in APOE4 homozygotes has not been thoroughly studied. The predictable sequence of pathological, biomarker, and clinical changes in genetically determined AD provides insights into AD's pathophysiology. While previous studies have assessed APOE's impact on biomarker changes, few have analyzed the gene dose effect across AD biomarker categories in APOE4 homozygotes. Understanding these genetic influences could inform individualized prevention strategies and treatment approaches for AD.

Therefore, the objective of the present study was to evaluate the pathological, clinical, and biomarker alterations in individuals with APOE4 homozygosity, investigating whether they could be categorized as a distinct type of genetically determined dementia, potentially representing one of the most prevalent Mendelian diseases.

About the study

In the present study, two separate human data sources were used: (1) a neuropathological investigation making use of data from brain donors in the National Alzheimer's Coordinating Center (NACC) (n = 3,297), and (2) an in vivo analysis from five clinical cohorts with various biomarkers (n = 10,039). NACC individuals with neuropathological evaluation, APOE haplotype data, clinical assessment, and age-of-onset information were included. Further, the five clinical cohorts involved data from the Alzheimer's Disease Neuroimaging Initiative, the A4 study, the ALFA study, the Wisconsin Register for Alzheimer's Prevention, and the OASIS3 Project. These cohorts covered diverse biomarkers, emphasizing preclinical AD. All the available data on clinical diagnosis and APOE haplotype were used from participants.

As a part of biochemical analysis, biofluid measurements were conducted on 1,665 participants from three sites. Elecsys technology was used for cerebrospinal fluid (CSF) Aβ1–42 and pTau181 and SIMOA (short for single molecule array) for plasma pTau and NfL. Aβ1–40 measurements were unavailable in three sites, and the Aβ1–42 or Aβ1–40 ratio was not included.

As a part of brain imaging, hippocampal volume was assessed via T1-weighted MRI (short for magnetic resonance imaging) in 5,108 participants. Additionally, amyloid PET (short for positron emission tomography) imaging was conducted using various tracers in 7,490 participants, and 1,267 participants were subjected to tau-PET imaging with flortaucipir.

Further, various statistical methods were employed in the study, including chi-square tests, Kruskal–Wallis tests, pairwise comparisons, Kaplan–Meier survival analysis, Cox regression model, and Welch's t-test.

Results and discussion

In postmortem data, APOE4 homozygotes consistently showed high or intermediate AD neuropathological change scores across all ages. In vivo biomarker analysis revealed that APOE4 homozygotes had significantly higher levels of abnormal biomarkers compared to APOE3 homozygotes, beginning at 55 years of age and with near-complete penetrance of abnormal biomarker levels by 65 years of age.

APOE4 homozygotes showed earlier onset of AD symptoms, mild cognitive impairment, dementia, and death compared to APOE3 homozygotes. The predictability of symptom onset in APOE4 homozygotes was comparable to that in PSEN1 and Down syndrome.

AD biomarkers in APOE4 homozygotes showed early deviations, with CSF Aβ1–42 and Centiloid scores changing before age 50. Increases in CSF and plasma pTau occurred in the early 50s, about 10–15 years before symptoms. Neurofilament light chain levels increased steeply, indicating neurodegeneration, while hippocampal atrophy started earlier, suggesting a distinct APOE4-associated biomarker trajectory. Integrated modeling highlighted the similarities in biomarker changes between APOE4 homozygotes, ADAD, and Down syndrome, with notable distinctions in hippocampal atrophy. Biomarker changes in the AD dementia stage showed no significant differences across APOE haplotypes, suggesting consistent pathology irrespective of genotype and age. Furthermore, distinct gene dose effects were found in APOE3 and APOE4 heterozygotes on neuropathology, cognitive alterations, death age, and biomarker profiles.

Despite its large-scale analysis of APOE4 homozygotes, the study is limited by biases introduced through convenience sampling, as well as variability between datasets, lack of Aβ1–40 levels, cross-sectional design, and predominantly White participant demographics. In the future, prioritizing diverse population inclusion in research will be crucial for understanding the full impact of APOE4 on AD risk.

Conclusion

In conclusion, the study offers strong evidence suggesting that APOE4 homozygotes constitute a distinct genetic manifestation of AD. This finding holds significant implications for public health, genetic counseling practices for carriers, and the direction of future research initiatives.

Journal reference:
Dr. Sushama R. Chaphalkar

Written by

Dr. Sushama R. Chaphalkar

Dr. Sushama R. Chaphalkar is a senior researcher and academician based in Pune, India. She holds a PhD in Microbiology and comes with vast experience in research and education in Biotechnology. In her illustrious career spanning three decades and a half, she held prominent leadership positions in academia and industry. As the Founder-Director of a renowned Biotechnology institute, she worked extensively on high-end research projects of industrial significance, fostering a stronger bond between industry and academia.  

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