Dementia associated with PD has 2 major underlying pathologic subtypes: neocortical Lewy bodies and Lewy neurite deposition (Braak Lewy body stage V/Vl) or neocortical synucleinopathy associated with substantial pathologic accumulation of Aβ (Braak amyloid stage B–C). Only a single person (1 of 32 [3%]) had a combination of neocortical synucleinopathy, abnormal Aβ deposition, and significant neocortical tau (Braak tangle stage V/VI) deposition. The combination of synuclein plus Aβ but not widespread neocortical tau disease comprises the largest subgroup (19 [59%]), compared with 12 (38%) with synucleinopathy only. The relatively low frequency of neocortical tau deposition suggests that tauopathy associated with AD is not a major contributor to dementia associated with PD. In the context of PD, Aβ deposition alone does not necessarily indicate AD or an early stage of AD. This finding also has important implications for interpretation of positive PiB positron emission tomographic scan results in those with PD, A positive PiB scan result likely reflects pathologic Aβ only, rather than a combination of Aβ and tauopathy that occurs in those with dementia due to AD.13
To determine whether distinct combinations of pathologic protein deposits define clinically distinct subtypes of PD with dementia, we analyzed subgroups based on whether neocortical α-synuclein accumulation was accompanied by substantial accumulation of Aβ. Our analysis of the 2 subgroups provides novel insight into whether the presence of Aβ accumulation is associated with distinct clinical features in dementia with PD. We found that many of the demographic and clinical features are similar among the subgroups but that the synuclein plus Aβ group has significantly shorter survival than the synuclein only group. There was also a trend toward earlier dementia onset in the synuclein plus Aβ group. The shorter survival identified by Kaplan-Meier and Cox regression analysis for those with the combination of synuclein and Aβ deposition suggests that this classification is clinically meaningful and that further prospective studies are needed to characterize the distinct clinical characteristics of the 2 subgroups.
Our findings are consistent with previous observations that Aβ accumulation occurs commonly in people with dementia and PD. 1,3,5,9,10,17,32,33
However, because widespread neocortical tau deposition (Braak stage V–VI) rarely accompanied Aβ deposition in our cohort, we conclude that Aβ accumulation may represent pathologic processes in PD that are distinct from those occurring in AD. Thus, definition of subgroups based on individual pathologic protein deposits, as done in this study, may provide a less ambiguous classification scheme than the application of terms such as AD-like pathology.
Clearly, our interpretation overlaps with previous classifications and relies on NIA-Reagan criteria for pathologic diagnosis of coexisting AD in someone with PD. Higher CERAD Aβ plaque scores have been associated with shorter time to onset of dementia in PD.3
Furthermore, PD patients with low CSF Aβ levels, a measure highly correlated with Aβ plaque deposition, experience a faster rate of cognitive decline in 2 years.33
These observations are consistent with the decreased, survival and trend toward shorter time to onset of dementia observed for the synuclein plus Aβ group in our analysis. This finding also supports others who report that Aβ accumulation shortens survival regardless of the timing of the onset of dementia with respect to motor symptoms in PD.34
Thus, the results from our study and previous studies support a primary association between Aβ plaque deposition and increased disease progression in people with PD and dementia. More important, our results suggest that the association with Aβ is independent of tau and therefore does not include the full pathologic spectrum (neurofibrillary tangles and neuritic plaques) associated with a diagnosis of “definite” AD according to NIA-Reagan criteria. However, our analysis does not exclude the possibility that tau accumulation limited to entorhinal cortex and medial temporal lobe (Braak stage I–IV) also could contribute to progression in either the synuclein only or synuclein plus Aβ groups, which will require additional studies with larger numbers of patients.
The mechanisms responsible for Aβ accumulation in PD and the associations between Aβ accumulation and other pathogenic processes in PD remain unclear. Impaired protein homeostasis may be one mechanism by which the accumulation of Aβ is linked to pathologic α-synuclein accumulation. Primary pathways that promote intraneuronal accumulation of α-synuclein may be distinct from those that promote extracellular accumulation of Aβ, but progressive accumulation of one protein could further impair protein homeostasis pathways in ways that, predispose individuals to the accumulation of the other misfolded protein,35
which is supported by a previously observed correlation between cortical Lewy body disease and Aβ plaque scores.32
Imaging agents to monitor α-synuclein accumulation, when available and combined with Aβ imaging and Aβ CSF measurements, could clarify the temporal relationship between neocortical α-synuclein accumulation and Aβ accumulation.36
Other mechanisms, potentially influenced by age or APOE
ε4 genotype, may impair neuronal and nonneuronal function in PD and promote Aβ accumulation. It remains unknown whether fibrillar Aβ accumulation directly impairs cognitive function and survival or whether Aβ accumulation positively correlates with other factors that affect the rate of disease progression. Larger, prospective studies using PiB-amyloid imaging, CSF Aβ measurements, and postmortem tissue analysis are needed to clarify the association between Aβ accumulation and clinical features of PD. Further support for the role of Aβ accumulation in promoting disease progression for PD would provide rationale for testing the therapeutic effects of one or more evolving approaches for reducing Aβ accumulation that, so far, have focused on AD.