TY - JOUR
T1 - Associations between misfolded alpha-synuclein aggregates and Alzheimer's disease pathology in vivo
AU - Pichet Binette, Alexa
AU - Mammana, Angela
AU - Wisse, Laura
AU - Rossi, Marcello
AU - Strandberg, Olof
AU - Smith, Ruben
AU - Mattsson-Carlgren, Niklas
AU - Janelidze, Shorena
AU - Palmqvist, Sebastian
AU - Ticca, Alice
AU - Stomrud, Erik
AU - Parchi, Piero
AU - Hansson, Oskar
AU - ADNI
PY - 2024/11
Y1 - 2024/11
N2 - INTRODUCTION: We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER-2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross-sectional cerebrospinal fluid (CSF) α-synuclein measurement from seed-amplification assay as well as cross-sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS: Across cohorts, the main biomarker associated with α-synuclein positivity at baseline was higher levels of Aβ pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α-synuclein –positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α-synuclein –negative participants in BioFINDER-2 but not in ADNI. DISCUSSION: We showed associations between concurrent misfolded α-synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Highlights:: Amyloid beta (Aβ), but not tau, was associated with alpha-synuclein (α-synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α-synuclein–positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts.
AB - INTRODUCTION: We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER-2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross-sectional cerebrospinal fluid (CSF) α-synuclein measurement from seed-amplification assay as well as cross-sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS: Across cohorts, the main biomarker associated with α-synuclein positivity at baseline was higher levels of Aβ pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α-synuclein –positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α-synuclein –negative participants in BioFINDER-2 but not in ADNI. DISCUSSION: We showed associations between concurrent misfolded α-synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Highlights:: Amyloid beta (Aβ), but not tau, was associated with alpha-synuclein (α-synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α-synuclein–positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts.
KW - amyloid beta
KW - co-pathology
KW - Lewy body
KW - neurodegenerative diseases
KW - seed-amplification assay
KW - tau
U2 - 10.1002/alz.14225
DO - 10.1002/alz.14225
M3 - Article
C2 - 39258841
AN - SCOPUS:85203674904
SN - 1552-5260
VL - 20
SP - 7624
EP - 7634
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 11
ER -