Breakthrough in APOE4-Related Alzheimer’s Disease

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Breakthrough in APOE4-Related Alzheimer’s Disease: A Potential Solution Unveiled

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Breakthrough in APOE4-Related Alzheimer’s Disease: A Potential Solution Unveiled

Last Wednesday, the research conducted by Michael E. Belloy’s team at Stanford University garnered significant attention due to its potential breakthrough in addressing the heightened risk of Alzheimer’s disease (AD) associated with the APOE4 gene.

Published in the renowned journal JAMA Neurology, the study revealed that the APOE4 gene, the most potent risk factor for sporadic Alzheimer’s disease, inflicts the greatest harm on individuals of East Asian descent.

Notably, the study also found that the protective APOE2 gene, most effective against sporadic AD, does not offer the same protection for East Asians.

This “discriminatory” behavior of the APOE gene has left many readers concerned.

In response to queries about the prevalence of APOE4 in different populations, data from a 2020 paper by Jia Jianping’s team at Peking Union Medical College Hospital was referenced. The frequency of APOE4 carriers was reported as 9% among Asians, 12% among Hispanics, 14% among Caucasians, and 19% among Africans.

Although APOE4 poses a significant risk to East Asians, the relatively lower prevalence of APOE4 among Asians is considered a positive aspect.

However, the real cause for optimism comes today with a groundbreaking research publication in the prestigious journal *Nature Neuroscience* led by the team headed by Huang Yadong at the Gladstone Institutes.

The researchers discovered that introducing a protective mutation, APOE3 R136S, identified in familial AD in 2019, into the APOE4 gene effectively neutralizes its toxicity. Specifically, the homozygous APOE4 R136S mutation completely prevents APOE4-driven Tau pathology, neurodegeneration, and neural inflammation.

The protective effect of homozygous APOE4 R136S is beginning to emerge

Given that APOE4 is the most potent risk gene for AD, carried by 55%-75% of AD patients, this research signifies a turning point in combating the “most harmful” gene APOE4, opening new doors for AD treatment.

To understand the impact of the R136S mutation on APOE4, the researchers conducted studies in Tau pathology mouse models (PS19) and human induced pluripotent stem cells (hiPSCs) with different copies of APOE4 R136S.

Effect of R136S on neuronal Tau levels

They constructed four mouse models: PS19-E4 (homozygous APOE4), PS19-E4-S/S (homozygous APOE4 R136S), PS19-E4-R/S (heterozygous), and PS19-E3 (homozygous APOE3).

The results showed that APOE4-S/S mice exhibited Tau levels similar to APOE3 mice, while APOE4-R/S mice did not show a significant reduction.

R136S inhibits Tau uptake

Furthermore, in hiPSCs from APOE4 homozygous AD patients, introducing the R136S mutation reduced Tau accumulation in neurons. The protective effect was most pronounced in homozygous APOE4 R136S.

Effects of R136S on the hippocampus and lateral ventricles

Overall, the research demonstrates that the R136S mutation protects against APOE4-driven neurodegeneration in Tau pathology mouse models. The discovery has profound implications for potential AD treatments, although further research is required to assess its impact on Aβ pathology and cognitive function in mouse models.

In conclusion, the study by Huang Yadong’s team marks a significant advancement in understanding and potentially treating APOE4-related Alzheimer’s disease.

Breakthrough in APOE4-Related Alzheimer’s Disease: A Potential Solution Unveiled

References:

[1] Belloy ME, Andrews SJ, Le Guen Y, et al. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023. doi:10.1001/jamaneurol.2023.3599

[2] Jia L, Xu H, Chen S, et al. The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer’s disease. Alzheimers Dement. 2020;16(12):1613-1623. doi:10.1002/alz.12153

[3] Nelson, M.R., Liu, P., Agrawal, A. et al. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023. doi:10.1038/s41593-023-01480-8

[4] Arboleda-Velasquez JF, Lopera F, O’Hare M, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25(11):1680-1683. doi:10.1038/s41591-019-0611-3

(source:internet, reference only)

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