Journal article
Cognitive Resilience in Apolipoprotein ε4 Carrier Women Predicted by Neuron-Derived Extracellular Vesicles
Annals of clinical and translational neurology, Vol.12(10), pp.2097-2106
10/2025
DOI: 10.1002/acn3.70143
PMCID: PMC12516249
PMID: 40665589
Abstract
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.
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 (Aβ
, 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.
No group differences were found for Aβ
, 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.
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.
Details
- Title: Subtitle
- Cognitive Resilience in Apolipoprotein ε4 Carrier Women Predicted by Neuron-Derived Extracellular Vesicles
- Creators
- Apostolos Manolopoulos - National Institute on AgingMaja Mustapic - National Institute on AgingCarlos Nogueras-Ortiz - National Institute on AgingFrancheska Delgado-Peraza - National Institute on AgingKrishna A Pucha - National Institute on AgingPamela J Yao - National Institute on AgingJoseph Blommer - National Institute on AgingMichael P Vreones - National Institute on AgingWilliam York - National Institute on AgingDe' Larrian Knight - National Institute on AgingStephen R Rapp - Wake Forest UniversityAladdin H Shadyab - University of California San DiegoJoAnn E Manson - Brigham and Women's HospitalRamon Casanova - Wake Forest UniversityRobert B Wallace - University of IowaLuigi Ferrucci - National Institute on AgingSusan M Resnick - National Institute on AgingDimitrios Kapogiannis - National Institute on Aging
- Resource Type
- Journal article
- Publication Details
- Annals of clinical and translational neurology, Vol.12(10), pp.2097-2106
- DOI
- 10.1002/acn3.70143
- PMID
- 40665589
- PMCID
- PMC12516249
- NLM abbreviation
- Ann Clin Transl Neurol
- ISSN
- 2328-9503
- eISSN
- 2328-9503
- Publisher
- WILEY
- Grant note
- HHSN271201700002C / NIA NIH HHS RF1AG079149 / NIA NIH HHS GlaxoSmithKline Consumer Healthcare 75N92021D00002 / NHLBI NIH HHS Intramural Research Program of the National Institute on Aging, National Institutes of Health 75N92021D00005 / NHLBI NIH HHS 75N92021D00003 / NHLBI NIH HHS Wyeth Pharmaceuticals 75N92021D00001 / NHLBI NIH HHS RF1AG074345 / NIA NIH HHS
- Language
- English
- Electronic publication date
- 07/15/2025
- Date published
- 10/2025
- Academic Unit
- Epidemiology; Injury Prevention Research Center
- Record Identifier
- 9984848117302771
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