Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 67, Issue 1, Pages 327-341Publisher
IOS PRESS
DOI: 10.3233/JAD-180970
Keywords
Alzheimer's disease; dementia; amyloid-beta; biomarker; blood; cognitive decline; inflammation; metallo-proteinases; MMP-3; MMP-9; plasma
Categories
Funding
- Canadian Institutes of Health Research
- Alzheimer Society of Canada
- Oxford NIHR Biomedical Research Centre, UK
- Murray Speight foundation
- McGill Integrated Program in Neuroscience
- CIHR Doctoral Award
- Fonds de recherche du Quebec-Nature et Technologies
- National Council for Science and Technology (CONACyT) of Mexico
- Rhodes Trust
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Biomarker discovery is a major need for earlier dementia diagnosis. We evaluated a plasma signature of amyloid, metallo-proteinases (MMPs), and inflammatory markers in a cohort of at-risk individuals and individuals clinically diagnosed with probable Alzheimer's disease (pAD). Using multiplex arrays, we measured A beta(40), A beta(42), MMP-1, MMP-3, MMP-9, IFN-gamma, TNF-alpha, IL-6, IL-8, and IL-10 in plasma from 107 individuals followed every 6 months for 3 years. Final diagnoses included: pAD (n = 28), mild cognitive impairment (MCI, n = 30), subjective memory impairment (SMI, n = 30), and asymptomatic (NCI, n = 19). Blood was drawn at final follow-up. We used linear and logistic regressions to examine biomarker associations with prior known decline on the Montreal Cognitive Assessment (MoCA) and the Cambridge Cognitive Examination (CAMCOG); as well disease progression by the time of blood-draw. We derived a biomarker composite from the individual markers, and tested its association with a clinical diagnosis of pAD. Lower A beta(40) and A beta(42) and higher IL-8, IL-10, and TNF-alpha were associated with greater cognitive decline per the MoCA and CAMCOG. MMP-3 was higher in SMI, MCI, and pAD than NCI. Whereas the other investigative molecules did not differ between groups, composite scores-created using MoCA/CAMCOG-based trends in A beta(40), A beta(42), MMP-1, MMP-3, IL-8, IL-10, and TNF-alpha-were associated with a final diagnosis of pAD (c-statistic 0.732 versus 0.602 for age-sex alone). Thus, plasma amyloid, MMP, and inflammatory biomarkers demonstrated differences in individuals with cognitive deterioration and/or progression to MCI/pAD. Our findings support studying these markers earlier in the continuum of probable AD as well as in specific dementias.
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