In this large population-based case-control study among non-Hispanic Caucasians, ApoE ε4 was associated with a lower odds of having PD, although ε4-carriers, as expected, tended to have a higher prevalence of dementia among PD cases. ApoE ε2, on the other hand, was not associated with PD occurrence. Neither ε4 nor ε2 seems to affect age of PD onset in our study population. Our primary findings were consistent with the supplemental meta-analyses.
The exact physiological and pathological roles of ApoE in the central nervous systems are not entirely clear, but ApoE protein is produced in abundance in the brain by glia, macrophages, and neurons (Elliott, et al., 2007
, Pitas, et al., 1987
). It is well-known that ApoE ε4 is a major genetic risk factor for late onset sporadic AD (Farrer, et al., 1997
), and has also been associated with poor clinical outcome in patients with acute head trauma and stroke (Nicoll, et al., 1996
, Slooter, et al., 1997
). On the other hand, the ApoE ε2 allele was associated with lower risk for AD (Farrer, et al., 1997
) and is over-represented among centenarians (Rea, et al., 2001
, Schachter, et al., 1994
The hypothesis that ApoE ε4 also increases PD risk has been investigated in over thirty epidemiological studies (www.PDgene.org
) with inconsistent results. Most studies reported a null association, although few reported either a significantly lower (1997, Blazquez, et al., 2006
) or a significantly higher risk for PD among ε4 carriers (Ghebremedhin, et al., 2006
, Papapetropoulos, et al., 2007
). Most of these studies were included in two recently published meta-analyses: first by Huang et al. (Huang, et al., 2004
), and then updated by Williams-Gray et al. (Williams-Gray, et al., 2009
) In both reports, ApoE ε4 was not associated with a higher risk of PD. In contrast, ApoE ε2, the allele that protects against AD, was associated with slightly higher odds of PD. While these meta-analyses are informative, conclusions must be drawn cautiously. First, previous studies were often hospital-based with heterogeneous study populations, had small sample sizes, and did not consider potential confounders. In addition, publication bias could not be easily excluded for publications on ApoE ε4 given its well-known adverse effect on AD and cardiovascular diseases (Stampfer, 2006
). Nevertheless, results from previous studies appear to exclude a detrimental role of ApoE ε4 in PD.
One potential link between ApoE and PD may come from the role of ApoE in lipoprotein metabolism (Menzel, et al., 1983
). The ApoE ε4 allele was associated with higher plasma cholesterol (Weisgraber and Mahley, 1996
), and ApoE ε2 allele was associated with lower plasma cholesterol. Several recent prospective studies suggested that higher plasma cholesterol was associated with a lower occurrence of PD (de Lau, et al., 2006
, Huang, et al., 2008
, Mascitelli, et al., 2009
), although the evidence is not entirely consistent (Hu, et al., 2008
). It may very well be useful for future studies to include serum cholesterol in the investigation of ApoE in PD pathogenesis.
We briefly asked for the presence of dementia as part of PD diagnostic confirmation and therefore was not ideal to assess the relationship between ApoE and dementia/AD among PD patients. We nevertheless evaluated ApoE genotypes in relation to dementia among PD cases to make sure that our data are compatible with previous knowledge. Although not associated with higher PD risk, ApoE ε4 tended to be associated with about 60% higher risk of dementia among PD patients, which was consistent with the previous two meta-analyses: OR=1.6 [95% CI (1.0–2.5)] (Huang, et al., 2006
) and 1.74 [95% CI (1.36–2.23), p= 0.0001] (Williams-Gray, et al., 2009
The current study was based on a large number of participants. We controlled for several known PD risk factors in data analysis, and conducted multiple sensitivity analyses to examine the robustness of study results. Nonetheless, our report has several limitations. First, although the diagnoses were confirmed either by each patient’s treating physician or by medical record review, a few PD cases might have been misdiagnosed due to the lack of standardized clinical examinations. Second, our study included prevalent cases with various disease durations. It is conceivable that individuals with dementia might have been less likely to participate than individuals without dementia. This, however, might have affected both cases and controls. Further, because dementia is more prevalent among elderly participants and PD patients with long disease duration, we conducted stratified analysis by year of birth () and year of PD diagnosis. Both subgroup analyses showed similar results across subgroups and therefore we expect limited impact of this bias on our analysis. In addition, ApoE genotypes tended to be associated with dementia among PD patients in the expected direction.
In summary, in this large population-based study, the presence of ApoE ε4 was associated with a lower occurrence of PD. Although this is somewhat unexpected when viewed in isolation, it is consistent with what would be predicted based on recent reports of the association between higher cholesterol and lower risk of PD.