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Late-Onset Alzheimer's Disease Features Thwarted by Protective Variant

NEW YORK – New research suggests that a genetic variant that protects against early-onset Alzheimer's disease stemming from a PSEN1 gene mutation also has a dose-dependent effect on disease features associated with late-onset Alzheimer's risk in mouse models or cell lines carrying risky alterations in the apolipoprotein 4 gene APOE4.

As they reported in Nature Neuroscience on Monday, investigators at the University of California, San Francisco, the Gladstone Institutes, and elsewhere used CRISPR-Cas9-based gene editing and other approaches to establish mouse models carrying one or two copies of a late-onset Alzheimer's disease-related version of APOE4 alongside one or two copies of a protective R136S variant in APOE3, also known as the Christchurch variant.

"Recently, a rare APOE variant, APOE3-R136S (APOE3-Christchurch), was found to protect against early-onset [Alzheimer's disease] in a PSEN1-E280A carrier," corresponding author Yadong Huang, a UCSF and Gladstone Institute of Neurological Disease researcher and director of the Gladstone Center for Translational Advancement, explained in an email. "In this study, we sought to determine if the R136S mutation also protects against APOE4-driven pathologies in late-onset [Alzheimer's disease]."

With the help of approaches such as immunostaining and single-cell RNA sequencing on hippocampus samples, the team demonstrated that the protective variant can also thwart features linked to late-onset Alzheimer's disease in the presence of risky APOE4 variants — from neurodegeneration and neuroinflammation to Tau pathology.

In a mouse model, for example, the authors noted that the two copies of the protective R136S variant "fully protects against APOE4-driven Tau pathology, neurodegeneration, and neuroinflammation" — results that were backed up by their subsequent experiments in human induced pluripotent stem cells (hiPSCs) generated from an Alzheimer's patient with two copies of an Alzheimer's-associated APOE4 variant.

"Our extensive and multidisciplinary analyses revealed for the first time that the APOE-R136S mutation strongly protects against APOE4-driven [Alzheimer's disease] pathologies, including Tau pathology, neurodegeneration, and neuroinflammation," Huang said, noting that the study "provides compelling evidence to support, for the first time, the conclusion that the APOE-R136S mutation also strongly protects against APOE4-driven [Alzheimer's disease] pathologies."

The Tau pathology, neurodegeneration, and neuroinflammation features typically associated with the APOE4 variant all dissipated in model organisms or cells carrying two copies of the protective R136S variant. On the other hand, the investigators found that Tau pathology remained in mouse models or hiPSCs with one copy of the protective R136S variant, despite reduced neurodegeneration and neuroinflammation.

"Overall, this study illustrates the AD-protective effects of the R136S mutation against APOE4-promoted pathologies in a gene dose-dependent manner, both in vivo in a tauopathy mouse model and in vitro in hiPSC-derived neurons," the authors explained.

By taking a closer look at the molecular and cellular mechanisms behind the APOE4-R136S variant's protective effects, Huang explained, the team also gained new clues about possible targets for future treatment development in Alzheimer's disease.

With single-nucleus transcriptome profiling, for example, the researchers saw an uptick in neuronal, astrocytic, or microglial cell subpopulations that protect against disease when the R136S mutation was present, the researchers reported, along with a dip in disease-linked subpopulations of oligodendrocyte, astrocyte, or microglia in the mouse hippocampus.

Together, the authors suggested, the findings "indicate that the R136S mutation not only modifies APOE4-driven [Alzheimer's disease] pathologies in general, but it does so by differentially affecting the disease-associated transcriptomes in specific types of cells."

"These findings warrant further studies," they argued, "and further analysis and validation of these cell type-specific effects may provide clues to the underlying mechanisms of the [Alzheimer's disease]-protective APOE-R136S mutation."