Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology

  • Nat Aging. 2026 May;6(5):1079-1102. doi: 10.1038/s43587-026-01108-z.
Jun-Ping Pan  #  1  2  3 ,  Ping-Jie Wang  #  1  4 ,  Jianying Zhang  #  3  5 ,  Anne-Brita Knapskog  #  6 ,  Leiv Otto Watne  #  6  7  8 ,  He-Ling Wang  3 ,  Maria Jose Lagartos-Donate  3 ,  Sofie Lautrup  3 ,  Li-Peng Mao  1  9 ,  Qian Wang  4  10 ,  Zhi-Peng Ling  1 ,  Shi-Qi Zhang  3 ,  Tomás Schmauck-Medina  3 ,  Ruixue Ai  3 ,  Trine Holt Edwin  6 ,  Tianjiao Zhang  11 ,  Ingvild Saltvedt  12  13 ,  Rannveig Sakshaug Eldholm  12  13 ,  Annabel Smith  14 ,  Kateřina Veverová  15 ,  Domenica Caponio  3 ,  Asgeir Kobro-Flatmoen  16 ,  Huanhuan Pang  17 ,  Zijian Wang  1 ,  Haoyun Wang  1 ,  Li-Juan Gao  1 ,  Nathalie Bodd Halaas  6  18 ,  Garry Wong  11 ,  Martin Vyhnalek  15 ,  Oscar Junhong Luo  9 ,  William A McEwan  14 ,  Jon Storm-Mathisen  19  20 ,  Li Gan  21 ,  Zeping Hu  17 ,  Henrik Zetterberg  22  23  24  25  26  27 ,  Menno P Witter  16 ,  Dag Aarsland  28  29 ,  Geir Selbæk  6  30  31 ,  Guobing Chen  32  33  34 ,  Evandro Fei Fang  35  36  37  38  39
Affiliations
  • 1. Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China.
  • 2. Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Basic Medicine, School of Medicine, Jinan University, Guangzhou, China.
  • 3. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
  • 4. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 5. Xiangya School of Stomatology, Central South University, Changsha, China.
  • 6. Department of Geriatric Medicine, Oslo University Hospital (Ullevaal), Oslo, Norway.
  • 7. Institute of Clinical Medicine Campus Ahus, University of Oslo, Lørenskog, Norway.
  • 8. Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway.
  • 9. Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China.
  • 10. Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 11. Centre for Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau, China.
  • 12. Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
  • 13. Department of Geriatrics, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway.
  • 14. UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
  • 15. Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
  • 16. Kavli Institute for Systems Neuroscience, K.G. Jebsen Centre for Alzheimer's Disease, Centre for Algorithms in the Cortex, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
  • 17. School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.
  • 18. Institute of Clinical Medicine, Campus Ullevål, University of Oslo, Oslo, Norway.
  • 19. Synaptic Neurochemistry and Amino Acid Transporters Labs, Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences (IMB) and Healthy Brain Aging Centre (SERTA), University of Oslo, Oslo, Norway.
  • 20. The Norwegian Centre on Healthy Ageing (NO-Age) and The Norwegian National Anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway.
  • 21. Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
  • 22. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
  • 23. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  • 24. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
  • 25. UK Dementia Research Institute at UCL, London, UK.
  • 26. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 27. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
  • 28. Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
  • 29. Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway.
  • 30. Norwegian National Centre for Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway.
  • 31. Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 32. Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China. [email protected].
  • 33. Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Basic Medicine, School of Medicine, Jinan University, Guangzhou, China. [email protected].
  • 34. Zhuhai Institute of Jinan University, Jinan University, Zhuhai, China. [email protected].
  • 35. Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China. [email protected].
  • 36. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway. [email protected].
  • 37. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 38. Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 39. The Norwegian Centre on Healthy Ageing (NO-Age) and The Norwegian National Anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway. [email protected].
  • # Contributed equally.
PMID: 42135576 DOI: 10.1038/s43587-026-01108-z
Abstract

ULK1 (Atg1) initiates macroautophagy and Mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of Amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases Autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher Autophagy and Mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to Autophagy and Mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

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