α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Alzheimers Dement. 2024 Jun;20(6):4351-4365. doi: 10.1002/alz.13818. Epub 2024 Apr 26.

Abstract

Introduction: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.

Methods: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.

Results: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo.

Discussion: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity.

Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Keywords: Dominantly Inherited Alzheimer Network; Lewy body pathology; alpha‐synuclein seed amplification assay; real‐time quaking‐induced conversion.

MeSH terms

  • Aged
  • Alzheimer Disease* / cerebrospinal fluid
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism
  • Brain / pathology
  • Disease Progression
  • Female
  • Humans
  • Lewy Bodies* / pathology
  • Male
  • Middle Aged
  • Mutation
  • alpha-Synuclein* / cerebrospinal fluid
  • alpha-Synuclein* / genetics

Substances

  • alpha-Synuclein
  • Amyloid beta-Peptides