Abstract
INTRODUCTION: Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions. METHODS: In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case-control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume. RESULTS: We identified four risk proteins that were significantly associated with increased odds (peptidase inhibitor 3 (PI3), trefoil factor 3 (TFF3), pregnancy associated plasma protein A (PAPPA), agouti-related peptide (AGRP)) and two protective proteins (myostatin (MSTN), integrin aVb5 (ITGAV/ITGB5)) with decreased odds of baseline cognitive impairment or dementia. Of these, four proteins (MSTN, PI3, TFF3, PAPPA) were associated cognitive decline in subjects that were cognitively normal at baseline. ITGAV/ITGB5 was associated with lower brain amyloid burden, MSTN and ITGAV/ITGB5 were associated with larger brain volume and slower brain atrophy, and PI3, PAPPA, and AGRP were associated with smaller brain volume and/or faster brain atrophy. DISCUSSION: These proteins may be useful as non-invasive biomarkers of dementia and cognitive impairment.