Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease

Michael X Henderson,Virginia M Y Lee,John Q Trojanowski,Medha Sengupta

doi:10.1186/s40478-019-0836-x

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). While the clinical presentation of LRRK2 mutation carriers is similar to that of idiopathic PD (iPD) patients, the neuropathology of LRRK2 PD is less clearly defined. Lewy bodies (LBs) composed of α-synuclein are a major feature of iPD, but are not present in all LRRK2 PD cases. There is some evidence that tau may act as a neuropathological substrate in LB-negative LRRK2 PD, but this has not been examined systematically. In the current study, we examined α-synuclein, tau, and amyloid β (Aβ) pathologies in 12 LRRK2 mutation carriers. We find that α-synuclein pathology is present in 63.6% of LRRK2 mutation carriers, but tau pathology can be found in 100% of carriers and is abundant in 91% of carriers. We further use an antibody which selectively binds Alzheimer’s disease (AD)-type tau and use quantitative analysis of tau pathology to demonstrate that AD tau is the prominent type of tau present in LRRK2 mutation carriers. Abundant Aβ pathology can also be found in LRRK2 mutation carriers and is consistent with comorbid AD pathology. Finally, we assessed the association of neuropathology with clinical features in LRRK2 mutation carriers and idiopathic individuals and find that LRRK2 PD shares clinical and pathological features of idiopathic PD. The prevalence of AD-type tau pathology in LRRK2 PD is an important consideration for understanding PD pathogenesis and refining clinical trial inclusion and progression criterion.

Highlights

Parkinson’s disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB) represent a spectrum of neurodegenerative diseases [1–5] collectively known as α-synucleinopathies due to the aggregation of αsynuclein into intracellular Lewy bodies (LBs)
While the schizophrenia case was included in histological analyses, it was not included in subsequent determination of pathology prevalence since the patient did not suffer from neurodegenerative disease
We found that 8.3% (9/109) of all idiopathic PD (iPD) cases or 3.7% (9/242) of the iPD-PDD cases in our database met these criteria and were classified as “atypical PD,” similar to the leucine-rich repeat kinase 2 (LRRK2) mutation carriers lacking LBs

Summary

Introduction

Parkinson’s disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB) represent a spectrum of neurodegenerative diseases [1–5] collectively known as α-synucleinopathies due to the aggregation of αsynuclein into intracellular Lewy bodies (LBs). Up to 80% of patients develop dementia (PDD) during their disease course [7], and this progression is associated with the presence of LBs in cortical areas [8]. Progression to dementia is associated with increasing tau co-pathology in a pattern that is similar to that seen in Alzheimer’s disease (AD) [4, 9], but with a greater temporal neocortical distribution [10]. Together, these studies have suggested that α-. Synuclein and tau pathologies are associated with each other in PD-PDD and may directly influence each other or be driven by a common factor to augment the progression of neurodegeneration. Identifying factors that could influence the progression of disease could provide a valuable target for modifying disease trajectory

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