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Published on: March 7, 2019
Sex-specific associations of matrix metalloproteinases in Alzheimer's disease
Mari Aksnes1, Trine H Edwin2, Ingvild Saltvedt3,4
1Department of Geriatric Medicine, University of Oslo, 0315, Oslo, Norway. mari.aksnes@medisin.uio.no.
Introduction:
Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-β (Aβ) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD.
Methods:
In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aβ and tau pathology as well as disease progression. Further, we studied sex-specific interactions.
Results:
MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aβ biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women.
Conclusion:
Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.
Insights
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) show promise as Alzheimer's disease (AD) biomarkers. Specific MMPs/TIMPs correlate with tau and amyloid pathology, and MMP-10 may predict cognitive decline in women.
Area of Science:
- Neuroscience
- Biochemistry
- Biomarker Discovery
Background:
- Alzheimer's disease (AD) diagnosis relies on amyloid-β (Aβ) and tau pathology biomarkers.
- There is a need for additional biomarkers reflecting other pathological pathways in AD.
- Matrix metalloproteinases (MMPs) are emerging as potential biomarkers for sex-specific AD mechanisms.
Purpose of the Study:
- To investigate the role of nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in AD.
- To examine associations between MMPs/TIMPs, Aβ and tau pathology, and disease progression.
- To explore sex-specific interactions in these relationships.
Main Methods:
- Cross-sectional study analyzing cerebrospinal fluid from 256 AD patients (mild cognitive impairment or dementia) and 100 controls.
- Quantification of nine MMPs and four TIMPs.
- Statistical analysis of group differences, associations with Aβ/tau markers, disease progression, and sex-specific effects.
Main Results:
- Significant differences in MMP-10 and TIMP-2 levels were observed between AD patients and controls.
- MMP and TIMP levels strongly correlated with tau biomarkers; MMP-3 and TIMP-4 showed sex-specific associations with Aβ biomarkers.
- A trend indicated higher baseline MMP-10 predicted greater cognitive and functional decline over time, exclusively in women.
Conclusions:
- MMPs and TIMPs are valuable markers for understanding sex differences and progression in AD.
- MMP-3 and TIMP-4 exhibit sex-specific effects on amyloid pathology.
- Further research on MMP-10's sex-specific prognostic potential for cognitive and functional decline in AD is warranted.
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