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

Alzheimers Dement. 2024 Dec;20(12):8444-8460. doi: 10.1002/alz.14276. Epub 2024 Oct 20.

Abstract

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.

Keywords: Alzheimer's disease; Lewy body; cognitive decline; co‐pathology; seed amplification assay.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / cerebrospinal fluid
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides* / cerebrospinal fluid
  • Biomarkers* / cerebrospinal fluid
  • Cognitive Dysfunction* / cerebrospinal fluid
  • Cognitive Dysfunction* / genetics
  • Cross-Sectional Studies
  • Disease Progression*
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Neuroimaging
  • Peptide Fragments / cerebrospinal fluid
  • alpha-Synuclein* / cerebrospinal fluid
  • tau Proteins* / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • tau Proteins
  • alpha-Synuclein
  • Biomarkers
  • Peptide Fragments
  • amyloid beta-protein (1-42)