The Genetic Basis of Cognitive Impairment and Dementia in Parkinson's Disease

Abstract

Cognitive dysfunction is a common feature of Parkinson's disease (PD) with mild cognitive impairment affecting around a quarter of patients in the early stages of their disease, and approximately half developing dementia by 10 years from diagnosis. However, the pattern of cognitive impairments and their speed of evolution vary markedly between individuals. While some of this variability may relate to extrinsic factors and comorbidities, inherited genetic heterogeneity is also known to play an important role. A number of common genetic variants have been identified, which contribute to cognitive function in PD, including variants in catechol-O-methyltransferase, microtubule-associated protein tau, and apolipoprotein E. Furthermore, rarer mutations in glucocerebrosidase and α-synuclein and are strongly associated with dementia risk in PD. This review explores the functional impact of these variants on cognition in PD and discusses how such genotype-phenotype associations provide a window into the mechanistic basis of cognitive heterogeneity in this disorder. This has consequent implications for the development of much more targeted therapeutic strategies for cognitive symptoms in PD.

Keywords: APOE; COMT; GBA; MAPT; Parkinson’s disease; cognition; dementia; genetics.

Figure 1

Schematic representation of the two distinct cognitive syndromes of Parkinson’s disease. “Frontal executive” impairments in early disease appear to be a consequence of a hyperdopaminergic state in the prefrontal cortex, which is in turn modulated by COMT genotype and dopaminergic medication. These deficits can get better or worse over time but are not associated global cognitive decline and dementia risk. In contrast, early deficits on more posterior cortically based cognitive tasks do not have a dopaminergic basis, but reflect the early stages of a dementing process due to Lewy body deposition and Alzheimer’s type changes in posterior cortical areas. This irreversible pathological process is influenced by early on by GBA mutations, MAPT H1/H2 haplotypes, and at a later disease stage by variation in APOE.

Figure 2

The relationship between working memory (WM) performance and dopamine levels in the prefrontal cortex follows an inverted U-shaped curve. Behavioral and functional imaging data from PD patients indicates that an individual’s position on the curve is dependent on their stage of disease as well as their COMT val¹⁵⁸met genotype (which determines the activity of the COMT enzyme). Hence, the relationship between executive function and COMT genotype in PD is complex, and executive deficits may improve rather than worsen in certain genotypic groups as the disease progresses. Reproduced from Williams-Gray et al. (84).