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Genetic risk factors for PD-D

The identification of rare causal mutations for PD and PD-D has been extremely successful over the last 10 years, yet the search for genetic variants that alter risk for disease has been more difficult. The primary work in this area has been done in PD cohorts that include patients both with and without dementia; this is primarily because such cohorts are easier to collect and more readily available. In the instances where PD-D has been separated out as a distinct entity, the sample size tends to be quite small. As geneticists now clearly appreciate, cohorts of several thousand cases are required to discover novel genetic loci that exert a small effect in complex diseases, and thus success for PD-D in this area will require a concerted effort to collect larger sample sizes.

APOE

The APOE e4 allele is probably the best-known genetic risk factor in adult-onset human disease. This variant confers substantial risk for AD: heterozygous carriers are approximately three times more likely and homozygous carriers eight times more likely to develop AD. Apolipoprotein E (ApoE) is a glycoprotein involved in the transport of lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. ApoE is synthesized and secreted by many tissues, primarily liver, brain, skin, and tissue macrophages, throughout the body, sites where it plays critically important roles [76]. The gene coding for ApoE resides on the long arm of chromosome 19 in a cluster with apolipoprotein C1 (APOC1) and apolipoprotein C2 (APOC2). It is a polymorphic gene with three major alleles, which translate into three isoforms of the protein, ApoE-e3, ApoE-e2, and ApoE-e4. These isoforms differ from each other by amino acid substitutions at positions 112 and 158 [77].

Although genetic variability at APOE is neither necessary nor sufficient for the development of AD, its risk has been shown to be dose dependent and correlated with the age at onset of the disease [78]. Given the robust association between ApoE and AD it has been hypothesized that a similar relationship exists with PD-D and DLB. Several studies have evaluated the role of ApoE in PD-D, with contradictory results [79-82]. As previously noted, however, these studies are individually of quite limited sample size. A meta-analysis of the studies published between 1966 and 2004 concluded that the APOE e4 allele appears to be associated with a higher prevalence of dementia in PD (with an increased odds ratio of 1.6) [83]. APOE e4 has been clearly associated with DLB, lending further support for the idea that PD-D, DLB, and AD are, at least in part, members of an aetiological spectrum of disorders.

 
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