Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study

INTRODUCTION

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease.

METHODS

A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA−, and those who converted to SAA+ from SAA−.

RESULTS

SAA+ individuals had faster cognitive decline than SAA−, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline.

DISCUSSION

These results highlight the interplay between amyloid and α-syn and their association with disease progression.

Highlights

• Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset.
• Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA− to SAA+, that is, ≈ 5% conversion.
• SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline.
• SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers.
• Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA.
• SAA kinetic parameters were associated with clinical features and progression.