Johannes Frank

• Lautrup, Sofie Hindkjær; Cao, Shuqin; Long, Xi; Liu, Bonnie Hei Man; Doncel, Beatriz Escobar & Ferrante, Aristide [Show all 16 contributors for this article] (2026). A combined artificial intelligence–wet lab approach identifies a pivotal role of the NAD+–mitophagy axis on aging and neurodegeneration. Alzheimer's & Dementia. ISSN 1552-5260. 22(8). doi: 10.1002/alz.71680. Full text in Research Archive Show summary

  Introduction: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+–mitophagy axis contributes to brain aging and neurodegeneration. Methods: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+–mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons. Results: The NAD+–mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology. Discussion: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+–mitophagy axis as a central player in brain aging and AD.

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