Precision Neurodegeneration: Integrating Molecular Mechanisms, Biomarkers, and Targeted Therapeutics

Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's and related tauopathies are converging pathologies driven by protein misfolding, maladaptive microglial responses, epigenetic dysregulation and metabolic failure. Here we synthesize recent mechanistic advances that are already reshaping precision diagnostics and therapeutics. Cryo-EM has resolved distinct tau and α-synuclein strains, which correlate with discrete clinical phenotypes, enabling the development of conformation-selective PET tracers and the use of plasma p-tau217/NfL ratios to classify patients within the A/T/N framework with >90% accuracy relative to CSF or amyloid-PET. Single-cell transcriptomics have delineated disease-associated microglia (DAM) and NLRP3 inflammasome activation as therapeutic nodes; small-molecule TREM2 agonists and CSF1R modulators are entering phase II trials, while TSPO-PET and plasma GFAP provide pharmacodynamic read-outs. Epigenetic enhancer-promoter rewiring and DNA methylation clocks are emerging as reversible drivers of synaptic failure. CRISPR-dCas9-based epigenetic editors or brain-penetrant HDAC/HDAC6 inhibitors restore memory in transgenic mice, with first-in-human safety studies currently being planned. Metabolic interventions-including ketone esters, time-restricted feeding, and medium-chain triglycerides- restore mitochondrial quality control via PINK1-Parkin-mediated mitophagy, and synergize with immunotherapy to reduce amyloid and tau pathology in parallel. Integration of blood-based A/T/N algorithms with patient-specific genetics now enables adaptive platform trials that assign individuals to anti-amyloid, anti-tau, microglial, or metabolic arms based on real-time biomarker profiles. We conclude that mechanistically informed, multi-modal precision medicine is no longer aspirational for NDDs but is being operationalized in ongoing clinical pipelines.