Objective: To determine whether plasma biomarkers of Alzheimer’s disease (AD) pathology can predict phenoconversion from idiopathic/isolated REM sleep behavior disorder (iRBD) to dementia with Lewy bodies (DLB).

Background: Blood-based biomarkers for AD pathology have been intensively investigated as markers for AD-related neurodegeneration. Comorbid AD pathology is common in DLB. Plasma AD biomarkers might be useful to detect prodromal DLB in iRBD, an incipient synucleinopathy.

Method: Participants with polysomnography-confirmed iRBD were recruited at the Hôpital du Sacré-Coeur de Montréal, Canada between 2004 and 2022, each providing plasma sampling for assessment of Aβ40, Aβ42 and pTau181 levels. All participants were prospectively followed to determine phenoconversion to a defined neurodegenerative disorder (‘phenoconvertors’) based upon meeting diagnostic criteria for DLB, Parkinson’s disease (PD) or Multiple System Atrophy (MSA). People who did not meet any criteria at censoring date were considered ‘non-phenoconvertors’. Association analysis between plasma AD biomarkers at baseline and eventual development of dementia with Lewy bodies was performed as well as regression for plasma markers and baseline cognitive function.

Results: 142 people with iRBD (109 male (77%), 67.7±8.0 years) were analyzed. On prospective follow-up (2.9±2.1 years after sampling), 30 individuals phenoconverted to a defined neurodegenerative syndrome (17 DLB, 12 PD, 1 MSA). In phenoconverters, plasma Aβ42/40 ratio was lower compared to non-phenoconvertors (0.103±0.010 vs. 0.114±0.012, p<0.001), and higher pTau181 levels (0.997±0.355 vs. 0.786±0.268pg/ml, p=0.004). These differences were selectively seen in prodromal DLB compared to non-phenoconverters, showing plasma Aβ42/40 ratio 0.101±0.011 (p=0.002) and pTau181 levels of 1.138±0.334pg/ml (p<0.001). Plasma pTau181 correlated with cognitive manifestations across various domains.

Conclusion: These results are the first to demonstrate that plasma Aβ42/Aβ40 ratio and pTau181 can identify prodromal dementia with Lewy bodies. Moreover, they suggest AD pathology is a critical determinant of whether an iRBD patient develops primary dementia or parkinsonism. Trials of amyloid-reduction therapy in iRBD patients with positive AD plasma markers may be warranted.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/plasma-biomarkers-of-alzheimers-pathology-identify-prodromal-dementia-with-lewy-bodies/