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Peer-reviewedCC BY 4.0JCI Insight

Purine metabolism disruption links pathology and cognitive decline in Alzheimer’s disease

  • Xiaohang Qian1,2
  • Zhongxuan Wang1
  • Siyue Chen1
  • Yang Xue1
  • Yawen Yang3
  • Peijing Cui1
  • Miao Zhang4
  • Huidong Tang1
4 affiliations
  1. 1Department of Geriatrics, Medical Center on Aging, Ruijin Hospital
  2. 2Department of Neurology and Institute of Neurology, Ruijin Hospital, and
  3. 3Department of Rehabilitation Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  4. 4Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China.
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Abstract

Purine metabolism dysregulation has been implicated in Alzheimer’s disease (AD), but its temporal dynamics and mechanistic links to core pathologies remain unclear. This translational study integrated a longitudinal preclinical AD mouse model and clinical cohort investigations to define the role of purine metabolism in AD progression. In APPswe/PSEN1dE9 (APP/PS1) mice, serum-untargeted metabolomics identified purine metabolism as the most notably altered pathway, with metabolite levels (e.g., adenine, adenosine) shifting dynamically across disease stages alongside increasing amyloid-β (Aβ) burden. In the pathology-defined clinical cohort, targeted analysis revealed that serum uric acid and allantoin were specifically depleted in the Aβ+ cognitively impaired (CI) group and correlated strongly with higher brain Aβ load, increased neuroinflammation, and poorer cognitive scores. Formal mediation analysis elucidated a plausible mechanistic cascade: the association of uric acid/allantoin with cognitive impairment was primarily mediated by Aβ pathology. Two-year longitudinal data further suggest that changes in specific purine metabolites might predict the rate of cognitive decline. Allantoin supplementation reduced Aβ pathology through promoting microglial phagocytosis of Aβ in APP/PS1 mice. Our findings identified purine metabolism as a key hub connecting Aβ pathology, neuroinflammation, and clinical progression in AD.

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Cite

BibTeXRIS
BibTeX
@article{qian2026purine,
  title = {{Purine metabolism disruption links pathology and cognitive decline in Alzheimer’s disease}},
  author = {Xiaohang Qian and Zhongxuan Wang and Siyue Chen and Yang Xue and Yawen Yang and Peijing Cui and Miao Zhang and Huidong Tang},
  journal = {JCI Insight},
  year = {2026},
  month = oct,
  doi = {10.1172/jci.insight.205511},
  url = {https://doi.org/10.1172/jci.insight.205511},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Purine metabolism disruption links pathology and cognitive decline in Alzheimer’s disease
AU  - Xiaohang Qian
AU  - Zhongxuan Wang
AU  - Siyue Chen
AU  - Yang Xue
AU  - Yawen Yang
AU  - Peijing Cui
AU  - Miao Zhang
AU  - Huidong Tang
PY  - 2026
DA  - 2026/10/22
JO  - JCI Insight
DO  - 10.1172/jci.insight.205511
UR  - https://doi.org/10.1172/jci.insight.205511
AB  - Purine metabolism dysregulation has been implicated in Alzheimer’s disease (AD), but its temporal dynamics and mechanistic links to core pathologies remain unclear. This translational study integrated a longitudinal preclinical AD mouse model and clinical cohort investigations to define the role of purine metabolism in AD progression. In APPswe/PSEN1dE9 (APP/PS1) mice, serum-untargeted metabolomics identified purine metabolism as the most notably altered pathway, with metabolite levels (e.g., adenine, adenosine) shifting dynamically across disease stages alongside increasing amyloid-β (Aβ) burden. In the pathology-defined clinical cohort, targeted analysis revealed that serum uric acid and allantoin were specifically depleted in the Aβ+ cognitively impaired (CI) group and correlated strongly with higher brain Aβ load, increased neuroinflammation, and poorer cognitive scores. Formal mediation analysis elucidated a plausible mechanistic cascade: the association of uric acid/allantoin with cognitive impairment was primarily mediated by Aβ pathology. Two-year longitudinal data further suggest that changes in specific purine metabolites might predict the rate of cognitive decline. Allantoin supplementation reduced Aβ pathology through promoting microglial phagocytosis of Aβ in APP/PS1 mice. Our findings identified purine metabolism as a key hub connecting Aβ pathology, neuroinflammation, and clinical progression in AD.
SN  - 2379-3708
ER  -