Involvement of paraoxonase 1 genetic variants in Alzheimer’s disease neuropathology

Abstract

Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men (P < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P < 0.05) and later age of onset (1.5 years, P < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels (P < 0.001), senile plaque accumulation (P < 0.001) and choline acetyltransferase activity (P < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.

Original article Paraoxonase 1 (PON1) gene -108C>T and p.Q192R polymorphisms and arylesterase activity of the enzyme in patients with dementia

“…It was shown that low enzyme activity was associated with the increased oxidative stress, increased risk of cardiovascular disease, stroke and type 2 diabetes [2,17,23], known dementia risk factors [8]. Recently in autopsy-confirmed AD study of Leduc et al [21], PON1 p. L55M and p.Q192R genetic variants were significantly associated with β-amyloid levels, senile plaque accumulation and choline acetyltransferase activity in different brain areas. These observations could suggest an involvement of the PON1 in AD pathogenesis and response to treatment.…”

“…The carriers of R allele were found to be better responders [27]. This influence of the polymorphism could result from the interaction between PON1 and cholinesterase [4,21].…”

Lack of association between paraoxonase-1 Q192R polymorphism and rheumatoid arthritis in southeast Iran

“…The association of PON1 gene polymorphism and risk of certain diseases has been documented (Sidoti et al, 2007;Leduc and Poirier, 2008;Agrawal et al, 2009;Leduc et al, 2009). In addition, PON1 gene polymorphisms (Q192R, L55M) alter both the level and activity of the enzyme (Humbert et al, 1993;Garin et al, 1997;Mackness et al, 1998;Aviram et al, 2000).…”

The Past and Present of Paraoxonase Enzyme: Its Role in the Cardiovascular System and Some Diseases

“…Patients who developed dementia were found to have a higher frequency of the 55M allele (91)(92). Although Helpecque et al reported that the -107T allele meant high risk of dementia (93), it was concluded in another study that this observation was a contradiction (94).…”