Apolipoprotein E (APOE)

The co-manifestation of AD and PD in families has led to the hypothesis of shared susceptibility genes, such as the apolipoprotein E (APOE) gene [82]. The APOE gene is located on chromosome 19q13.2 and has three major alleles designated e2, e3, and e4. The e4 variant is associated with an increased risk and possibly lower age at onset of AD [83]. In PD, evidence for an association between the e4 variant and dementia risk is less clear. Longitudinal studies show inconstant findings on the impact of e4 carrier status on the rate of cognitive decline [84-86]. However, a large meta-analysis conducted in 2009 found a modest overrepresentation of e4 carriers in PD-D versus PD without dementia [85]. In keeping with this, studies in autopsy-confirmed cases suggest that the e4 allele increases the risk of dementia across the spectrum of Lewy body diseases, including PD-D [87, 88].

Microtubule-associated protein tau (MAPT)

The MAPT gene encodes tau and is located on chromosome 17q21.1. It has two major haplotypes, H1 and H2. The H1/H1 genotype has been associated with increased risk for several neurodegenerative disorders, including PD [89]. Furthermore, two studies found the H1/H1 genotype to be strongly associated with increased risk for PD-D [90, 91], and a synergistic interaction between the H1/H1 genotype and a specific SNCA polymorphism on PD-D risk was reported in one of these studies [90]. However, no association between H1/H1 genotype and PD-D was found in a large clinico-pathological study [88].

Glucocerebrosidase (GBA)

The GBA gene is located on chromosome 1q21 and encodes the lysosomal enzyme beta-glucocerebrosidase. Homozygous mutations in GBA cause the lysosomal storage disorder Gaucher’s disease. During recent years, heterozygous GBA mutations have emerged as the most common genetic risk factor for PD [92, 93], affecting 4-7% of patients with the disease. Moreover, GBA-linked PD has also been associated with increased risk and earlier onset of dementia compared with PD patients without GBA mutations [93, 94]. A recent autopsy study reported glucocerebrosidase deficits to be associated with increased levels of aSyn even in sporadic PD without GBA mutations [95]. This supports the notion that in the general PD population dysfunctional lysosomal pathways may contribute to increased deposition and cortical spreading of aSyn, which has been linked to PD-D [13].

Cathecol-O-methyltransferase (COMT)

The COMT gene is located on chromosome 22q11.21 and encodes an enzyme that is involved in the catabolism of monoamines, including dopamine. In PD, the COMT Val158Met functional polymorphism has been proposed to be associated with frontal-executive deficits but not with incidence of dementia [10]. Similar findings have been described by another group [86], while a third study observed no direct effect of COMT Val158Met genotype on attention or executive function in PD [96].

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