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NIH grant 1K99AG104060-01: Plasma Biomarker-Based Cognitive Reserve and Its Dietary Determinants in Cognitive Aging and ADRD Progression
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Xiao Gu. Award: $123936.
Start: 2026-09-11T00:00:00.
1 Project Summary
2 Alzheimer’s disease and related dementias (ADRD) are leading causes of disability and death in aging
3 populations, yet substantial heterogeneity in clinical trajectories remains poorly explained. A key contributor to
4 this variation is cognitive reserve (CR), the brain’s capacity to sustain cognitive function despite age-related
5 pathology. Convergent evidence from neuroimaging, EEG/MEG, and emerging omics links CR to network
6 efficiency, compensatory recruitment, and neuroplasticity-related pathways, underscoring a biological substrate
7 for it. While CR is increasingly recognized as a dynamic and modifiable construct, its measurement remains a
8 major challenge for large-scale research, as most current methods rely on indirect behavioral proxies or
9 resource-intensive neuroimaging approaches. This project addresses these gaps by developing a biologically
10 grounded, plasma‑based measure of CR (plasma‑CR) using high‑throughput proteomics (e.g., NULISAseq)
11 capable of multiplexing ~120 ATX(N) and related CNS biomarkers to enable longitudinal, population‑scale
12 quantification across the AD continuum. In parallel, the Mediterranean diet (MedDiet) will be evaluated as a
13 modifiable determinant of CR and as a factor that may interact with CR to shape cognitive aging trajectories,
14 motivated by trial and cohort evidence that nutrient profiles rich in polyphenols and carotenoids support
15 neuroplasticity, reduce oxidative stress and neuroinflammation, and preserve cerebrovascular integrity.
16 Statistical innovations, including regression calibration to correct dietary measurement error and Bayesian
17 latent‑variable modeling to address error in CR, will strengthen causal interpretation of diet-CR associations.
18 The anticipated deliverables include a validated, scalable plasma-based CR measure, robust evidence on how
19 diet shapes and interacts with CR in influencing ADRD, and the identification of modifiable biological pathways
20 for prevention, directly supporting NIA’s mission to advance the understanding of aging processes, extend
21 health span, and reduce the burden of ADRD. During the K99 phase, Aim 1 will derive and validate plasma‑CR
22 from ATX(N) profiles in ADNI (n= 543), benchmarking its ability to predict cognitive decline and MCI‑to‑ADRD
23 conversion against imaging‑based CR; Aim 2 will test whether the MedDiet slows CR decline and whether
24 baseline CR modifies diet-cognition associations in PREDIMED‑Plus and DIRECT‑Plus trials (n=914) using
25 repeated plasma ATX(N) measures and error‑correction methods. In the R00 phase (Aim 3), a new Nurses’
26 Health Study II ancillary substudy (n=800) will generate high-throughput plasma ATX(N) proteomic data and
27 harmonize repeated cognitive assessments to model long-term plasma-CR dynamics and evaluate dietary
28 polyphenols and carotenoids as mechanistic mediators. Together, these advances will deliver a scalable
29 plasma-CR metric and diet-responsive targets that enable population-level risk assessment and precision-
30 nutrition strategies to delay cognitive decline and reduce dementia burden.document fetched 2026-09-20 02:42