α-synuclein as an emerging pathophysiological biomarker of Alzheimer’s disease

ABSTRACT

Introduction

α-syn aggregates represent the pathological hallmark of synucleinopathies as well as a frequent copathology (almost 1/3 of cases) in AD. Recent research indicates a potential role of α-syn species, measured in CSF with conventional analytical techniques, in the differential diagnosis between AD and synucleinopathies (such as DLB). Pioneering studies report the detection of α-syn in blood, however, conclusive investigations are controversial. Ultrasensitive seed amplification techniques, enabling the selective quantification of α-syn seeds, may represent an effective solution to identify the α-syn component in AD and facilitate a biomarker-guided stratification.

Areas covered

We performed a PubMed-based review of the latest findings on α-syn-related biomarkers for AD, focusing on bodily fluids. A dissertation on the role of ultrasensitive seed amplification assays, detecting α-syn seeds from different biological samples, was conducted.

Expert opinion

α-syn may contribute to progressive AD neurodegeneration through cross-seeding especially with tau protein. Ultrasensitive seed amplification techniques may support a biomarker-drug co-development pathway and may be a pathophysiological candidate biomarker for the evolving ATX(N) system to classify AD and the spectrum of primary NDDs. This would contribute to a precise approach to AD, aimed at implementing disease-modifying treatments.

KEYWORDS:

• Alzheimer’s disease
• alpha-synuclein
• fluid biomarkers
• neurodegenerative diseases
• RT-QuIC
• PMCA
• precision medicine

Article highlights

• Brain α-syn aggregates are a frequent copathology in AD

• α-syn species have been explored in the CSF of AD patients with conventional measurement techniques and may hold potential in discriminating AD from non-AD NDDs such as synucleinopathies and tauopathies

• Seed amplification techniques display high diagnostic accuracy in detecting α-syn pathology especially in CSF and plausible future applications of these techniques may concern the identification of the α-syn component in AD

• The integration of alternative pathophysiological biomarkers in the clinical definition of dementia should be encouraged, aiming at implementing disease-modifying therapies

Declaration of interest

H Hampel is an employee of Eisai Inc. He declares no competing financial interests related to the present article and his contribution to this article reflects entirely and only his own academic expertise on the matter. H Hampel serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019 he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. He is inventor of the following patents and has received no royalties:

•In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8,916,388

•In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8,298,784

•Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20,120,196,300

•In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20,100,062,463

•In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20,100,035,286

•In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20,090,263,822

•In Vitro Method for The Diagnosis of Neurodegenerative Dis- eases Patent Number: 7,547,553

•CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20,080,206,797

•In Vitro Method for The Diagnosis of Neurodegenerative Dis- eases Publication Number: 20,080,199,966

•Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20,080,131,921

•Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: Publication number: United States Patent 10,921,330

A Vergallo declares no competing financial interests related to the present article; his contribution to this article reflects only and exclusively his own academic expertise on the matter. This work was initiated during his previous position at Sorbonne University, Paris, France. A Vergallo was an employee of Eisai Inc. (November 2019–June 2021). A Vergallo does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier.

The authors have neither other relevant affiliation nor financial involvement with any organization or entity with a financial interest or in financial conflict with the subject discussed in the manuscript with the exception of those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

This paper was not funded.