Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease

TLDR

Parkinson's disease is a neurodegenerative disorder that presents primarily as a movement disorder but is also associated with variable cognitive impairment, including dementia. The study aimed to investigate the genetic basis of susceptibility to Parkinson's disease and its cognitive heterogeneity. Researchers examined 659 PD patients (109 followed for 3.5 years) and 2,176 controls, focusing on candidate genes involved in protein aggregation—MAPT, GSK3B, and SNCA. Results showed that the MAPT inversion polymorphism is strongly linked to cognitive decline and PD dementia, and that a synergistic interaction between this inversion and SNCA rs356219 nearly doubles disease risk, indicating shared tau/α‑synuclein pathways in PD pathogenesis. Ann Neurol 2007.

Abstract

Abstract Objective Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease. Methods In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of parkinsonism: microtubule‐associated protein tau ( MAPT ), glycogen synthase kinase‐3β ( GSK3B ), and α‐synuclein ( SNCA ). Results We observed that cognitive decline and the development of PD dementia are strongly associated ( p = 10 −4 ) with the inversion polymorphism containing MAPT . We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3′ region of SNCA . In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease ( p = 3 × 10 −6 ). Interpretation Our data support the hypothesis that tau and α‐synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and α‐synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD. Ann Neurol 2007