Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals

Neurobiol Aging. 2023 Nov:131:11-23. doi: 10.1016/j.neurobiolaging.2023.05.012. Epub 2023 May 29.


Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer's disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.

Keywords: Cerebrospinal fluid; Cognitively unimpaired older adults; Magnetic resonance imaging; Matrix metalloproteinases; Tissue inhibitor of metalloproteinases.

MeSH terms

  • Alzheimer Disease* / pathology
  • Atrophy / pathology
  • Biomarkers / cerebrospinal fluid
  • Brain / diagnostic imaging
  • Brain / pathology
  • Humans
  • Matrix Metalloproteinase 2* / cerebrospinal fluid
  • Matrix Metalloproteinase 3


  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 3
  • Biomarkers