Polymorphisms at the paraoxonase 1 L55M and Q192R loci affect the pathophysiology of Alzheimer's disease: emphasis on the cholinergic system and beta-amyloid levels.

BACKGROUND

Paraoxonase 1 (PON1) functions to protect the cholinergic system against nerve gases and the organophosphate family of pesticides. Recent studies have shown that polymorphisms at the PON1 L55M and Q192R loci might affect individual susceptibility to experience-derived and environmental events such as the exposure to inhibitors of cholinesterase (ChEIs).

OBJECTIVE

ChEI therapy being the treatment of choice for mild-to-moderate Alzheimer's disease (AD) patients, we determined whether genetic variations in the PON1 loci are associated with AD risk and whether they affect brain choline acetyltransferase (CHAT) activity, nicotinic receptor density, and beta-amyloid (Abeta) levels in different regions of AD and age-matched control subjects.

METHODS

This pilot genetic study used a small cohort of brains from autopsy-confirmed AD patients and age-matched controls from the Douglas Hospital Brain Bank, Quebec, Canada.

RESULTS

The frequency of the M55M genotype at the PON1 L55M locus was found to be significantly increased in AD patients relative to age-matched controls (p < 0.05). Significant associations were observed between the PON1 L55M and Q192R polymorphisms and frontal cortex Abeta levels as well as CHAT activity and nicotinic receptor density in the temporal cortex.

CONCLUSIONS

Our results suggest a prominent role for PON1 in the pathophysiology of common AD with a marked impact on the cholinergic system and Abeta levels in the brain.