Impaired mitochondrial dynamics and reduced mitophagy represent a shared energy crisis converging on synaptic vulnerability. NAD+ supplementation has tolerable safety profile and pilot data (NADPARK Phase 1) shows brain NAD increase in PD. However, PINK1/Parkin mutations cause PD-specific familial disease, not AD/ALS/FTD, and mitochondrial dysfunction is a final common pathway in normal aging—lacking disease specificity. Best positioned as an adjunctive metabolic intervention in biomarker-enriched subgroups.
Auto-built from this analysis's top knowledge-graph edges.
graph TD
GBA1_mutations["GBA1 mutations"] -->|increases risk| PD["PD"]
TREM2_R47H_variant["TREM2 R47H variant"] -->|increases risk| Ad["Ad"]
alpha_synuclein_fibrils["alpha-synuclein fibrils"] -->|activates| NLRP3_Inflammasome["NLRP3 Inflammasome"]
TFEB_overexpression["TFEB overexpression"] -.->|inhibits| tau_A__pathology["tau/Aβ pathology"]
TARDBP_MUTATIONS["TARDBP MUTATIONS"] -->|causes| ALS_FTD["ALS/FTD"]
TDP_43_INCLUSIONS["TDP-43 INCLUSIONS"] -->|associated with| ALS_FTD_1["ALS/FTD"]
NfL_reduction["NfL reduction"] -->|biomarker for| als["als"]
TARDBP["TARDBP"] -->|cross disease mech| ALS["ALS"]
TARDBP_2["TARDBP"] -->|cross disease mech| FTD["FTD"]
TARDBP_3["TARDBP"] -->|cross disease mech| AD_LATE["AD/LATE"]
h_cross_synth_tdp43_rna_p["h-cross-synth-tdp43-rna-proteostasis"] -->|proposes shared me| TARDBP_4["TARDBP"]
SNCA["SNCA"] -->|cross disease mech| PD_5["PD"]
style GBA1_mutations fill:#ce93d8,stroke:#333,color:#000
style PD fill:#ef5350,stroke:#333,color:#000
style TREM2_R47H_variant fill:#ce93d8,stroke:#333,color:#000
style Ad fill:#ef5350,stroke:#333,color:#000
style alpha_synuclein_fibrils fill:#4fc3f7,stroke:#333,color:#000
style NLRP3_Inflammasome fill:#ce93d8,stroke:#333,color:#000
style TFEB_overexpression fill:#4fc3f7,stroke:#333,color:#000
style tau_A__pathology fill:#4fc3f7,stroke:#333,color:#000
style TARDBP_MUTATIONS fill:#ce93d8,stroke:#333,color:#000
style ALS_FTD fill:#ef5350,stroke:#333,color:#000
style TDP_43_INCLUSIONS fill:#4fc3f7,stroke:#333,color:#000
style ALS_FTD_1 fill:#ef5350,stroke:#333,color:#000
style NfL_reduction fill:#ce93d8,stroke:#333,color:#000
style als fill:#ef5350,stroke:#333,color:#000
style TARDBP fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000
style TARDBP_2 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style TARDBP_3 fill:#4fc3f7,stroke:#333,color:#000
style AD_LATE fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_tdp43_rna_p fill:#4fc3f7,stroke:#333,color:#000
style TARDBP_4 fill:#4fc3f7,stroke:#333,color:#000
style SNCA fill:#4fc3f7,stroke:#333,color:#000
style PD_5 fill:#ef5350,stroke:#333,color:#000No linked papers recorded for this hypothesis yet.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for PINK1, PARK2, MFN2, SIRT3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF patients with prodromal Parkinson's disease and biomarker evidence of impaired mitochondrial quality control (serumGDF15 >300pg/mL or fibroblast mitophagy flux <40% of age-matched controls) receive | Synaptic density preservation (SV2A PET % change from baseline) in active arm: mean ≥-5% (vs. expected -12% in placebo); CSF NAD+ elevation: mean ≥+40% | — no observation — | pending | 0.45 |
| IF participants with PINK1 or PARK2 mutations (familial PD cohort) are compared to sporadic PD, AD, ALS, and FTD patients matched for disease duration and severity, THEN mitochondrial quality control | MitoScreener score in PINK1/PARK2: median 0.3 (normalized); sporadic PD: 0.6; AD: 0.7; ALS: 0.8; FTD: 0.7 (higher=better function) | — no observation — | pending | 0.55 |