Reduced Serum PON1 Lactonase Activity Is Associated with Mild Cognitive Impairment and Mixed Dementia.

High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) contributes substantially to the antioxidant and anti-inflammatory functions of HDL. Impairment of these protective properties has been associated with Alzheimer's disease (AD) and other forms of dementia, particularly those involving neurovascular dysregulation. In the present study, we investigated for the first time the potential involvement of the putative physiological lactonase activity of PON1 in serum samples from a large cohort of older adults (n = 691), including cognitively healthy controls and patients with mild cognitive impairment (MCI), AD, vascular dementia (VAD), mixed AD/VAD (MIXED dementia), and other forms of dementia. A difference was observed between controls and MCI patients (-34%, p < 0.001). The next largest differences were observed in the VAD and MIXED dementia groups, both showing a decrease of approximately 25% compared with controls (p < 0.05 and p < 0.001, respectively), and in AD patients (-14%, p < 0.05). After adjustment for confounding factors, only MCI and MIXED dementia remained significantly different from controls. These findings suggest that reduced serum PON1 lactonase activity is already detectable at the MCI stage and is particularly evident in conditions combining neurodegenerative and vascular pathology. Longitudinal studies are required to determine whether lower PON1 lactonase activity precedes, accompanies, or follows cognitive decline.