We found that DRS-2 scores declined nearly 3 points per year faster among APOE
ε4 carriers with PD (). It seems likely that this disparity should be clinically significant, as, if ongoing, it might be expected to result in a 10-15 point differential over 5 years. The difference between baseline DRS-2 score in our cohort and a commonly used cutoff for dementia (<124)(33
)was approximately 10 points. Indeed, APOE
ε4 carrier status was associated with a 2.8-fold increased risk of a ≥10 point decline in DRS-2 score during follow-up (). These results indicate that the more rapid decline in mean DRS-2 scores among APOE
ε4 carriers was not driven by large changes in only a few individuals. Also, carrier status was associated with increased risk for earlier onset of clinically significant cognitive decline. More rapid cognitive decline among APOE
ε4 carriers was observed across multiple cognitive domains, arguing for a diffuse, rather than focal, degenerative process.
Notably, however, APOE
ε4 was not associated with changes on the DRS-2 attention subscale (). We did observe an association between COMT
genotype and performance on a measure of attention, as has been described by others, and is thought to reflect modulation of a fronto-striatal network.(12
) However, COMT
genotype did not influence overall rates of DRS-2 score decline consistent with the hypothesis that these deficits represent a distinct cognitive phenotype that does not herald dementia.(21
) In contrast, MAPT
H1/H1 genotype was associated with worse performance only on the memory subscale of the DRS-2, perhaps suggesting a temporal lobe-predominant effect, as seen in AD. The idea that individual genetic factors could influence distinct cognitive domains is intriguing and warrants further investigation.
Our findings add to a growing body of evidence on the association of APOE
with cognitive decline in PD. The ε2 allele has been associated with increased incidence of PD(34
) and a potentially protective effect in dementia,(13
) but we did not observe an association between the ε2 allele and cognitive decline. In cross-sectional analyses, the APOE
ε4 allele has been associated with higher risk of dementia in several studies,(17
)whereas others have failed to find an effect.(15
A meta analysis summarizing some of these studies and examining 458 pooled PD cases (163 with dementia and 295 without) supported an association between APOE
ε4 and cognitive decline(30
) A more recent study updating this analysis (1145 PD cases, 501 PDD cases) found an overrepresentation of ε4 carriers amongst PDD cases (OR 1.74, 95% CI 1.36-2.23) but raised concerns that small samples, heterogeneity of odds ratios and publication bias may have confounded the finding(22
). Together, these reports support an association between APOE
and PDD but suggest that the effect size may be small. Further, they highlight many of the difficulties in trying to study longitudinal change with cross-sectional studies. In one community-based longitudinal study of 107 newly-diagnosed PD patients from Cambridge, UK followed for an average of 5 years, APOE
genotype was not associated with the rate of cognitive decline in PD.(22
That some studies should fail to find any effect of APOE
genotype on cognitive status is surprising given the influence of this gene on cognitive decline in Alzheimer's disease and in the general population.(37
) One possibility is that PD patients are somehow "protected" from the effects of APOE
variation, though it is unclear through what mechanism this might occur. Another explanation is that these studies failed to detect an effect due to lack of power or other factors. For example, in the longitudinal cohort described above,(22
) detection of an association between cognitive decline and APOE
genotype may have been obscured by smaller sample size and the use of the Folstein Mini-Mental State Examination (MMSE), a relatively insensitive measure of cognitive function in PD,(39
) as the primary outcome measure.
We did not find a significant association between MAPT
haplotype and rates of cognitive decline. The MAPT
H1variant has been associated with a higher risk of PD and cognitive decline, and a specific sub-haplotype (H1p) has recently been implicated. (20
) However, several other studies failed to demonstrate a relationship between MAPT variants and dementia in PD.(16
) In the same longitudinal cohort from Cambridge, UK described above,(22
) there was a faster rate of decline in MMSE scores among indivudials with the MAPT
) All subjects developing dementia during the initial three year follow-up (11/109) carried the H1/H1 genotype,(20
) and the increased risk persisted after 5 years.(21
One key distinction between the present study and that of the Cambridge cohort is that we enrolled subjects primarily in the middle of the course of PD, while the other cohort was enrolled near the time of diagnosis. One explanation for the discrepancy in our findings is that different genetic mechanisms may subserve early versus late-onset cognitive decline in PD. These prior studies demonstrated an association between MAPT haplotype and cognitive decline within the first 5 years of diagnosis. Conversely, we found an association between APOE genotype and cognitive decline that occurs later in the course of PD.
Our findings cannot definitively establish whether the association we observed between APOE
and cognitive decline is specific to PD or simply the previously described effect of APOE
genotype on cognitive function that may be seen in otherwise healthy older individuals.(38
) However, several lines of evidence support overlap in the pathology of PDD and AD. Alzheimer pathology is often observed in post-mortem PDD brains and abnormalities in aβ and Tau protein are possible biomarkers of cognitive change in PD.(10
) Disruption of APOE
ameliorates aβ accumulation and neurodegeneration in a mouse model of PD,(43
) thus this overlap may reflect interaction of ApoE with distinct neural substrates to produce the specific pattern of changes seen in PDD rather than superimposed, unrelated accumulation of AD pathology. In this study, we did not find that APOE
ε4 carriers had disproportionate memory impairments compared to other domains as would be expected if the effect of APOE
genotype was simply due to co-existing AD pathology. Combined with our report of depressed aβ but not elevated CSF tau in PD patients,(10
) this finding suggests that the accelerated cognitive decline observed in APOE
carriers is not simply due to an increased risk of coexisting AD, but rather a disease-specific effect of APOE
gene status on cognition in PD.
The prospective design and size of the longitudinal cohort are strengths of the present study. However, these results should be interpreted in the context of several limitations. Education level in this cohort was high (mean 16 years), but observed DRS-2 scores were consistent with those in previously reported PD cohorts and education was not a significant covariate in any of our mixed-effects models or survival analysis. The majority of patients were followed for a relatively short period of time, and the number of subjects with more than 2 years of follow-up was modest compared with the size of the entire cohort. However, use of mixed-effects models accounts for variability in length of follow-up. The cohort was not incident and disease duration at enrollment varied widely, complicating an unbiased assessment of the time to onset of cognitive decline; however, adjustment for disease duration and other clinical characteristics in mixed effects models did not affect the associations observed. It should be noted that while mixed effects models account, in part, for variations in length of followup and disease duration, associations between genetic factors and longitudinal change or effects at a particular disease stage could have been underestimated.
Aging is a risk factor for countless human diseases, but appears to play a particularly important role in cognitive decline seen in neurodegenerative disorders and the general population. The previously described strong association between MAPT
and cognitive decline in the Cambridge cohort was highly age-dependent(20
) , although we did not observe significant effects for gene*age interaction terms in our mixed effects models (not shown). Thus, the importance of aging in PD-associated cognitive decline may depend on particular genetic factors. Ultimately, cognitive changes over time in any given PD patient may reflect multiple, potentially overlapping, pathologic processes superimposed onto "normal" aging or specific gene-age interactions Although the present study was not powered to do so, investigating potential gene-gene interactions and their effect on cognitive status in PD may be of particular interest. As the effect size for any one factor may be relatively modest, future studies of larger prospective cohorts examining multiple candidate loci, perhaps in combination with other biologic markers, may be necessary to fully elucidate the predictive value and etiologic roles of these genes in neurodegenerative dementias including PDD.