Annals of clinical and translational neurology · 2025
Cognitive Resilience in Apolipoprotein ε4 Carrier Women Predicted by Neuron-Derived Extracellular Vesicles.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Manolopoulos Apostolos, Mustapic Maja, Nogueras-Ortiz Carlos, Delgado-Peraza Francheska, Pucha Krishna A, Yao Pamela J, Blommer Joseph, Vreones Michael P, York William, Knight De' Larrian, Rapp Stephen R, Shadyab Aladdin H, Manson JoAnn E, Casanova Ramon, Wallace Robert B, Ferrucci Luigi, Resnick Susan M, Kapogiannis Dimitrios
Аннотация
OBJECTIVE: The Apolipoprotein (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD); however, many ε4 carriers remain cognitively intact into old age. Leveraging plasma neuron-derived extracellular vesicles (NDEVs), we sought to identify biomarkers of cognitive resilience and their interplay with APOE genotype.
METHODS: In this case-control study nested within the Women's Health Initiative (WHI), we analyzed 1130 plasma samples from 676 women in the WHI Memory Study (WHIMS)/Long Life Study (LLS), with APOE ε4 or ε3/ε3 genotypes. At baseline, all participants were cognitively intact and at LLS visit, 13-17 years later, were classified as still cognitively intact (resilient) or having become impaired at age > 80 or ≤ 80 years. We isolated NDEVs using immunoaffinity capture for the neuronal marker L1CAM and quantified AD pathogenic proteins (Aβ42, total Tau, p181-Tau), insulin signaling (pSer312-IRS-1), TNFR1/NFκB pathway mediators and targets, and mitochondrial Complex V. Linear mixed models assessed group differences, adjusting for NDEV yield, age, and education, with FDR correction.
RESULTS: No group differences were found for Aβ42, Tau proteins, or pS312-IRS-1. Resilient ε4 carriers had higher baseline levels of phosphorylated TNFR1, NFκB, c-Myc, and FADD than ε4 carriers who eventually developed impairment at > 80 or ≤ 80 years. Additionally, resilient ε4 carriers had higher baseline Complex V levels than ε4 carriers impaired at age > 80.
INTERPRETATION: Augmented neuronal TNFR1/NFκB signaling and Complex V levels may promote cognitive resilience in ε4 carrier women. Boosting these mechanisms may have preventive and therapeutic potential against cognitive decline in this high-risk population.
METHODS: In this case-control study nested within the Women's Health Initiative (WHI), we analyzed 1130 plasma samples from 676 women in the WHI Memory Study (WHIMS)/Long Life Study (LLS), with APOE ε4 or ε3/ε3 genotypes. At baseline, all participants were cognitively intact and at LLS visit, 13-17 years later, were classified as still cognitively intact (resilient) or having become impaired at age > 80 or ≤ 80 years. We isolated NDEVs using immunoaffinity capture for the neuronal marker L1CAM and quantified AD pathogenic proteins (Aβ42, total Tau, p181-Tau), insulin signaling (pSer312-IRS-1), TNFR1/NFκB pathway mediators and targets, and mitochondrial Complex V. Linear mixed models assessed group differences, adjusting for NDEV yield, age, and education, with FDR correction.
RESULTS: No group differences were found for Aβ42, Tau proteins, or pS312-IRS-1. Resilient ε4 carriers had higher baseline levels of phosphorylated TNFR1, NFκB, c-Myc, and FADD than ε4 carriers who eventually developed impairment at > 80 or ≤ 80 years. Additionally, resilient ε4 carriers had higher baseline Complex V levels than ε4 carriers impaired at age > 80.
INTERPRETATION: Augmented neuronal TNFR1/NFκB signaling and Complex V levels may promote cognitive resilience in ε4 carrier women. Boosting these mechanisms may have preventive and therapeutic potential against cognitive decline in this high-risk population.