Distinct tau and alpha-synuclein molecular signatures in Alzheimer's disease with and without Lewy bodies and Parkinson's disease with dementia.

Alpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer's disease (AD) cases at autopsy and might impact the age-of-onset and disease progression in AD. Here, we aimed to determine whether tau and aSyn profiles differ between AD cases with Lewy bodies (AD-LB), pure AD and Parkinson's disease with dementia (PDD) cases using epitope-, post-translational modification- (PTM) and isoform-specific tau and aSyn antibody panels spanning from the N- to C-terminus. We included the middle temporal gyrus (MTG) and amygdala (AMY) of clinically diagnosed and pathologically confirmed cases and performed dot blotting, western blotting and immunohistochemistry combined with quantitative and morphological analyses. All investigated phospho-tau (pTau) species, except pT181, were upregulated in AD-LB and AD cases compared to PDD and control cases, but no significant differences were observed between AD-LB and AD subjects. In addition, tau antibodies targeting the proline-rich regions and C-terminus showed preferential binding to AD-LB and AD brain homogenates. Antibodies targeting C-terminal aSyn epitopes and pS129 aSyn showed stronger binding to AD-LB and PDD cases compared to AD and control cases. Two pTau species (pS198 and pS396) were specifically detected in the soluble protein fractions of AD-LB and AD subjects, indicative of early involvement of these PTMs in the multimerization process of tau. Other phospho-variants for both tau (pT212/S214, pT231 and pS422) and aSyn (pS129) were only detected in the insoluble protein fraction of AD-LB/AD and AD-LB/PDD cases, respectively. aSyn load was higher in the AMY of AD-LB cases compared to PDD cases, suggesting aggravated aSyn pathology under the presence of AD pathology, while tau load was similar between AD-LB and AD cases. Co-localization of pTau and aSyn could be observed within astrocytes of AD-LB cases within the MTG. These findings highlight a unique pathological signature for AD-LB cases compared to pure AD and PDD cases.

[Risk factors for Parkinson's disease: possibilities for prevention and intervention]. / Risicofactoren voor de ziekte van Parkinson.

Considering age to be the primary risk factor for developing Parkinson's disease and the observation that the Dutch population is rapidly aging, the parkinson prevalence is expected to increase over the coming years, as there is still no cure available for the disease. This has been confirmed by epidemiological data, which show a steady increase of the disease prevalence in the Netherlands for the period 2010-2021. Genetic risk factors only partially explain the disease pathogenesis. Environmental factors, such as exposure to pesticides and trichloroethylene are associated with a higher risk for developing Parkinson's disease. Lifestyle factors such as exercise, caffeine intake and the Mediterranean diet are associated with a lower risk for developing the disease and possibly delay the disease progression. Policy makers and healthcare providers should employ stricter regulations for pesticide use and should stimulate a healthy lifestyle to slow down the increasing prevalence.