Serial Cerebrospinal Fluid Sampling Reveals Trajectories of Potential Synaptic Biomarkers in Early Stages of Alzheimer’s Disease

Article type: Research Article

Authors: Duits, Flora H.^{a; b; c; *} | Nilsson, Johanna^d | Zetterberg, Henrik^{d; e; f; g; h} | Blennow, Kaj^{d; e} | van der Flier, Wiesje M.^{a; b; i} | Teunissen, Charlotte E.^{b; c} | Brinkmalm, Ann^{d; e}

Affiliations: [a] Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands | [b] Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands | [c] Department of Laboratory Medicine, Neurochemistry Lab, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands | [d] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [e] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [f] Department of Neurodegenerative Disease and UK Dementia Research Institute, UCL Institute of Neurology, London, UK | [g] Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China | [h] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [i] Department of Epidemiology and Biostatistics, Amsterdam UMC, Amsterdam, The Netherlands

Correspondence: [*] Correspondence to: Flora H. Duits, Amsterdam UMC location VUmc, Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Tel: +31 6 21 97 67 58; E-mail: [email protected].

Abstract: Background:Synaptic dysfunction is closely associated with cognitive function in Alzheimer’s disease (AD), and is present already in an early stage of the disease. Objective:Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. Methods:We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n = 50 amyloid-β+ [A +], n = 50 A–) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4–2.7] years). We analyzed 17 synaptic proteins and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. Results:At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, β-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] –0.27[0.12] to –0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] –0.10[0.04] to –0.15[0.05]) and SCD/MCI-A+ (St.B[SE] –0.07[0.03] to –0.12[0.03]), but not in SCD/MCI-A- (pinteraction < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] –1.75[0.58]), but not in the other groups (pinteraction < 0.05). Conclusions:CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages.

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, mass spectrometry, synapses

DOI: 10.3233/JAD-240610

Journal: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S103-S114, 2024