Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease
Year: 2020
Type: article
Study design: Observational Study
Abstract: It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
Source: Brain
Institutions: Lund University, Karolinska Institutet, Amsterdam Neuroscience, Amsterdam UMC Location Vrije Universiteit Amsterdam, Sahlgrenska University Hospital, University of Gothenburg, Skåne University Hospital, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,570
Funders: Alzheimer's Drug Discovery Foundation, Parkinson Research Foundation, Gun och Bertil Stohnes Stiftelse, EU Joint Programme – Neurodegenerative Disease Research, Australian Government, European Commission, Lunds Universitet, Hjärnfonden, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Alzheimerfonden, Marcus och Amalia Wallenbergs minnesfond, UK Dementia Research Institute, Demensfonden, Parkinsonfonden, Avid Radiopharmaceuticals, H2020 European Research Council
Awards: G1075922514, G1253720191, G1373393710, G1442296065, G1551449788, G1642014339, G2108271864, G2385484910, G2521197280, The Alzheimer biomarker toolbox – use in pathogenic studies, diagnostics and theragnostics, G2841269746, G3120681622, G313301595, G3609843232, G4075158157, G4181470480, G4232409942, G4404751248, G4962764320, G5062390926, G510517891, G5111822078, G5180844870, G56684467, Alterations in the Brain Connectome as an Early Indicator of Alzheimer’s disease, G6069138294, G6168044258, Pathways to Alzheimer's disease, G712881263, G7143958211, G7198253607, G7404442218, G791739130, G7956815115, What determines amyloid beta aggregation and toxicity in Alzheimer’s disease?, G8709394893, G8711430475, G958583170, G96521508
OpenAlex ID: W3111108465