This study evaluated expression of 102 NAD⁺/mitophagy-related genes across 12 human brain regions and blood using 77 public transcriptomic datasets (1,966 neurodegenerative disease patients vs. 1,523 controls) spanning AD, PD, HD, and ALS. Key AI-prioritized targets were then validated in *C. elegans*, a HEK293 Tau-Venus cell model, and APOE4/4 iPSC-derived cortical neurons.
The NAD⁺–mitophagy axis was more severely dysregulated in neurodegeneration than in normal brain aging, with CNS samples showing broader gene dysregulation than blood. Five AD-protective genes were prioritized: **ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1**. Knockdown of MFN1 or LAMP2 worsened Tau aggregation in the cell model; neuronal knockdown of eat-3 (OPA1) or fzo-1 (MFN1) impaired cholinergic synaptic function in *C. elegans*. Pharmacological activation of mitochondrial fusion (SML0629/OPA1 pathway) in APOE4/4 cortical neurons reduced p-Tau217 levels.
- Experimental validation used lower-organism (*C. elegans*) and non-neuronal cell models; effects in higher organisms remain untested. - iPSC cortical neuron experiments were limited to short treatment windows (24 h) and single biological repeats for some endpoints, reducing statistical power. - The study is observational/transcriptomic for human data; causality in human brain aging and neurodegeneration cannot be established.
The NAD⁺–mitophagy axis—particularly OPA1, MFN1, LAMP2, and ATP6V0E1—represents a promising but preclinical therapeutic target in AD; no clinical interventions are ready based on this data alone. Clinicians should watch for trials targeting mitochondrial fusion or NAD⁺ pathways as this mechanistic evidence matures.
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