Last Updated: 2026-03-29 PT | Kind: gap-analysis | Section: gaps
This page synthesizes cross-disease research priorities for neurodegenerative diseases, identifying areas where coordinated investment would have the highest impact across Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and rarer proteinopathies. The goal is to highlight research areas with high potential for translation across multiple diseases, avoiding duplication with disease-specific priority lists found in AD Knowledge Gaps Ranked, Parkinson's Knowledge Gaps, and ALS Knowledge Gaps.
| Priority | Research Area | Diseases | Why It Matters | Tractability |
|---|---|---|---|---|
| 1 | Protein aggregation mechanisms and strain diversity | AD, PD, ALS, FTD, HD, Prion | Common to nearly all neurodegenerative diseases; strains determine clinical phenotype and treatment response | High |
| 2 | Blood-based biomarker development for early detection | AD, PD, ALS, FTD | Enables prevention trials and early intervention; current biomarkers require invasive procedures | High |
| 3 | Selective neuronal vulnerability determinants | AD, PD, ALS, FTD | Explains why specific populations degenerate first; informs target discovery | Moderate |
| 4 | Neuroimmune modulation as therapeutic strategy | AD, PD, ALS | Microglia and astrocytes are key disease modifiers; TREM2, CD33, complement pathways implicated across diseases | High |
| 5 | Brain-body interaction pathways (gut-brain, immune-brain) | AD, PD, ALS | Emerging evidence that peripheral pathology influences CNS neurodegeneration | Moderate |
| Priority | Research Area | Diseases | Why It Matters |
|---|---|---|---|
| 6 | Mechanisms of prion-like propagation across diseases | PD, ALS, FTD, AD | Templated protein misfolding may explain progressive spread; common therapeutic targets possible |
| 7 | Lysosomal and autophagy pathway dysfunction | PD, AD, ALS | GBA, GAA, C9orf72 mutations implicate clearance pathways; TFEB activation as therapeutic strategy |
| 8 | Mitochondrial dysfunction and energy failure | PD, ALS, AD | Energy deficit is a convergent feature; metabolic support as neuroprotective strategy |
| 9 | Genetic modifiers of penetrance and phenotype | PD, ALS, FTD, HD | Same mutation causes different diseases (e.g., MAPT, C9orf72); understanding modifiers enables precision medicine |
| 10 | Glymphatic and perivascular clearance mechanisms | AD, PD | Sleep-dependent clearance of toxic proteins; glymphatic enhancement as therapeutic approach |
| Priority | Research Area | Diseases | Why It Matters |
|---|---|---|---|
| 11 | TDP-43 pathology in non-ALS diseases | ALS, FTD, AD, PD | TDP-43 inclusions found in many diseases beyond ALS; unified mechanism possible |
| 12 | Epigenetic regulation of neurodegeneration | AD, PD, ALS, HD | DNA methylation, histone modifications alter gene expression in disease; druggable targets |
| 13 | Metabolic syndrome and neurodegeneration intersection | AD, PD | Insulin resistance, diabetes modify disease risk and progression; GLP-1 agonists demonstrate metabolic neuroprotection |
| 14 | Cellular senescence in neurodegeneration | AD, PD, ALS | Senescent glia contribute to neuroinflammation; senolytics as therapeutic strategy |
| 15 | RNA metabolism and splicing alterations | ALS, FTD, AD | C9orf72 DPR proteins, TDP-43 mislocalization disrupt RNA processing |
Multiple neurodegenerative diseases share the feature of misfolded proteins forming toxic aggregates[1]:
Despite different initiating proteins, downstream pathways converge:
| Stage | Biomarker Type | Priority Needs |
|---|---|---|
| Discovery | Multi-omics (proteomics, metabolomics, lipidomics) | Large cohort collections, standardized protocols |
| Verification | CSF, plasma, serum assays | Assay validation, cross-platform standardization |
| Clinical validation | Longitudinal studies in prodromal populations | Regulatory-grade biomarker qualification |
| Deployment | Point-of-care or decentralized testing | Assay simplification, cost reduction |
| Gene | Disease Associations | Mechanistic Link |
|---|---|---|
| TREM2 | AD, PD, ALS | Microglial phagocytosis and inflammation |
| PTK2B | AD, PD | Synaptic dysfunction and calcium signaling |
| PLD3 | AD, PD | Amyloid processing and alpha-synuclein |
| SNCA | PD, AD, DLB | Protein aggregation and synaptic function |
| MAPT | AD, PSP, CBD, FTD | Microtubule stability and tau pathology |
Ryman SG, et al. Cross-disease commonality in neurodegenerative proteinopathies. Acta Neuropathologica. 2024. ↩︎