Research Question
Can lifestyle factors (diet, exercise) interplay with genetic risks (APOE4, GBA) to disrupt protein homeostasis (neuroinflammation) and drive neurodegenerative diseases (NDDs) like Alzheimer’s and Parkinson’s via metabolic imbalances, accelerating biological aging?
Core Hypothesis
Genetic predisposition (polygenic risk scores) and protein dysregulation (GFAP, neurofilament light chain) mediate lifestyle-driven aging (epigenetic clocks, accelerometry) effects on NDD risk through systemic metabolite changes (ceramides, branched-chain amino acids).
Objective
Identify gene-protein-metabolite networks linking accelerated aging to NDDs.
Assess lifestyle modulation (diet/exercise) of genetic risks on aging pathways.
Validate protein biomarkers (e.g., complement proteins) bridging epigenetic aging, metabolites, and neurodegeneration phenotypes.
Rationale
NDD progression follows multi-omics interactions:
Genetic susceptibility: Polygenic risk scores (PRS) integrate variants (e.g., CLU, PICALM) for baseline risk.
Protein dysregulation: Plasma proteomics (Olink) detects neuronal damage (!NfL/GFAP) and inflammation (IL-6, TNF-!), linking aging to pathology.
Metabolic dysfunction: Altered metabolites (!plasmalogens, !acyl-carnitines) reflect mitochondrial/membrane defects.
Epigenetic clocks (e.g., DNAm GrimAge) connect lifestyle (e.g., smoking-associated methylation) to proteomic/metabolic shifts. The UK Biobank’s multi-omics data (genomic, proteomic, metabolic, accelerometry) enables causal analysis across 500,000+ individuals.
