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. 2024 Apr;20(4):2444-2452.
doi: 10.1002/alz.13658. Epub 2024 Feb 7.

Investigating alpha-synuclein co-pathology in Alzheimer's disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay

Giovanni Bellomo  1 , Andrea Toja  1 , Federico Paolini Paoletti  1 , Yihua Ma  2 , Carly M Farris  2 , Lorenzo Gaetani  1 , Nicola Salvadori  1 , Davide Chiasserini  3 , Anna Lidia Wojdaƚa  1 , Luis Concha-Marambio  2 , Lucilla Parnetti  1
Affiliations

Investigating alpha-synuclein co-pathology in Alzheimer's disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay

Giovanni Bellomo et al. Alzheimers Dement. 2024 Apr.

Abstract

Introduction: Lewy body disease, a frequently observed co-pathology in Alzheimer's disease (AD), can be identified antemortem in cerebrospinal fluid (CSF) by α-synuclein seed amplification assay (αS-SAA). The prevalence and clinical impact of CSF αS-SAA positivity in AD are still unknown.

Methods: αS-SAA was performed on CSF samples from 240 AD patients (preclinical, prodromal, and dementia stages), 85 controls, 84 patients with Parkinson's disease (PD), and 21 patients with PD with dementia or dementia with Lewy bodies. In AD patients, associations between αS-SAA positivity and cognitive changes were also evaluated.

Results: In agreement with available neuropathological studies, αS-SAA positivity was observed in 30% of AD patients (vs 9% in controls), and was associated with cognitive decline, visuospatial impairment, and behavioral disturbances.

Discussion: αS-SAA positivity in AD patients reflects the prevalence observed in neuropathological series and is associated with a worse clinical outcome. These data confirm the validity of CSF αS-SAA positivity as biomarker of synucleinopathy.

Keywords: Alzheimer's disease; biomarkers; cerebrospinal fluid; neuropsychological evaluation; seed amplification assay; synucleinopathy.

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Conflict of interest statement

The authors declare the following competing financial interests: Prof. Parnetti served as an Advisory Board Member for Fujirebio, IBL, Roche, and Merck. Dr. Concha, Ms. Farris, and Mr. Ma are inventors of several patents related to SAA technology (PMCA) and are associated with Amprion Inc., a biotech company focused on the commercial utilization of SAA for diagnosis. All other authors declare no financial and non‐financial competing interests. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Overview of αS‐SAA maximum fluorescence (Fmax) in all clinical groups considered. Violin/scatter plots displaying log2 of Fmax values averaged on three replicates. αS‐SAA, α‐synuclein seed amplification assay; AD‐dem, Alzheimer's disease at dementia phase; CTRL‐CN, controls, cognitively normal; CTRL‐MCI, controls, with mild cognitive impairment, stable after 2‐years, with normal CSF profile and other neurodegenerative disorders excluded; DLB, dementia with Lewy bodies; MCI‐AD, mild cognitive impairment due to AD; PD‐CN, cognitively normal Parkinson's disease; PDD, Parkinson's disease with dementia; PD‐MCI, mild cognitive impairment associated to Parkinson's disease; pre‐AD, preclinical Alzheimer's disease.
FIGURE 2
FIGURE 2
CSF αS‐SAA outcome in the clinical groups and subgroups considered. (A) Bar plot representing the percentages of CSF αS‐SAA positive, inconclusive, and negative subjects for CTRL, AD, and PD/DLB groups. (B) Bar plot representing the percentages of CSF αS‐SAA positive, inconclusive, and negative subjects for CTRL‐CN, CTRL‐MCI, pre‐AD, MCI‐AD, and AD‐dem subgroups. (C) Bar plot representing the percentages of CSF αS‐SAA positive, inconclusive, and negative subjects among typical/amnestic AD, lv‐PAA, and PCA‐AD clinical variants. The absolute number of positive, negative and inconclusive outcomes is reported on the top of each bar. αS‐SAA, α‐synuclein seed amplification assay; AD, Alzheimer's disease; AD‐dem, Alzheimer's disease at dementia phase; CSF, cerebrospinal fluid; CTRL, controls; CTRL‐CN, controls, cognitively normal; CTRL‐MCI, controls, with mild cognitive impairment, stable after 2‐years, with normal CSF profile and other neurodegenerative disorders excluded; lv‐PPA, logopenic variant of primary progressive aphasia AD presentation; MCI‐AD, mild cognitive impairment due to AD; PD, Parkinson's disease; PCA‐AD, posterior cortical atrophy AD clinical presentation; pre‐AD, preclinical Alzheimer's disease.
FIGURE 3
FIGURE 3
CSF αS‐SAA outcome and cognitive worsening in AD patients. (A) Box plots representing the rate of change of MMSE score over time (∆MMSE/∆t) in CSF αS‐SAA positive, negative, and inconclusive AD patients. Boxes represent the interquartile range, the horizontal lines within boxes represent the medians, and whiskers reflect the first/third quartile ± 1.5 times the interquartile range. The adj. p‐value reported is calculated by linear regression for pairwise comparisons adjusted for age and sex differences between groups. (B,C) Linear regression between ΔMMSE/ΔT and AUFC (B) and TTT (C) with 95% confidence intervals of the linear regression and Spearman's correlation coefficients (ρ) displayed. αS‐SAA, α‐synuclein seed amplification assay; AD, Alzheimer's disease; AUFC, area under the fluorescence curve; CSF, cerebrospinal fluid; MMSE, Mini‐Mental State Examination; TTT, time‐to‐threshold.
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