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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. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measuring synaptic proteins in CSF. In this study, both known and new synaptic proteins were investigated and compared as potential biomarkers of synaptic dysfunction, particularly in the context of Alzheimer's disease (AD). Seventeen synaptic proteins were quantified in CSF using two different targeted mass spectrometry assays in the prospective Swedish BioFINDER-2 study. The study included 958 individuals, characterized as having mild cognitive impairment (MCI, n = 205), AD dementia (n = 149) and a spectrum of other neurodegenerative diseases (n = 171), in addition to cognitively unimpaired individuals (CU, n = 443). Synaptic protein levels were compared between diagnostic groups and their associations with cognitive decline and key neuroimaging measures (amyloid-β-PET, tau-PET and cortical thickness) were assessed. Among the 17 synaptic proteins examined, 14 were specifically elevated in the AD continuum. SNAP-25, 14-3-3 zeta/delta, β-synuclein, and neurogranin exhibited the highest discriminatory accuracy in differentiating AD dementia from controls (areas under the curve = 0.81–0.93). SNAP-25 and 14-3-3 zeta/delta also had the strongest associations with tau-PET, amyloid-β-PET and cortical thickness at baseline and were associated with longitudinal changes in these imaging biomarkers [β(standard error, SE) = −0.056(0.0006) to 0.058(0.005), P < 0.0001]. SNAP-25 was the strongest predictor of progression to AD dementia in non-demented individuals (hazard ratio = 2.11). In contrast, neuronal pentraxins were decreased in all neurodegenerative diseases (except for Parkinson's disease), and NPTX2 showed the strongest associations with subsequent cognitive decline [longitudinal Mini-Mental State Examination: β(SE) = 0.57(0.1), P ≤ 0.0001; and mPACC: β(SE) = 0.095(0.024), P ≤ 0.001] across the AD continuum. Interestingly, utilizing a ratio of the proteins that displayed higher levels in AD, such as SNAP-25 or 14-3-3 zeta/delta, over NPTX2 improved the biomarkers' associations with cognitive decline and brain atrophy. We found 14-3-3 zeta/delta and SNAP-25 to be especially promising as synaptic biomarkers of pathophysiological changes in AD. Neuronal pentraxins were identified as general indicators of neurodegeneration and associated with cognitive decline across various neurodegenerative dementias. Cognitive decline and brain atrophy were best predicted by ratios of SNAP-25/NPTX2 and 14-3-3 zeta/delta/NPTX2. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels. Methods: We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer' disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins. Results: CSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p < 0.001), plasma Aβ42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aβ40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MDrange, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aβ42/Aβ40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aβ status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aβ-positive (MD, 16.46 ng/ml; p = 0.009) but not Aβ-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained. Discussion: Our findings provide evidence for diurnal fluctuations in Aβ peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aβ42/Aβ40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aβ peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials. [ABSTRACT FROM AUTHOR]

BACKGROUND: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSvenous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings. METHODS: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; and phosphorylated tau (p‐tau181 and p‐tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single‐molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS: All DPSvenous and plasma analytes correlated significantly, except for Aβ42. In the validation cohort, DPSvenous GFAP, NfL, p‐tau181, and p‐tau217 differed between CSF Aβ‐positive and ‐negative individuals and were associated with worsening cognition. DISCUSSION: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood‐based biomarkers to remote settings with simplified sampling conditions, storage, and logistics. Highlights: A wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPSvenous).DPSvenous biomarkers correlated with standard procedures and cognitive status.DPSvenous biomarkers had a good diagnostic accuracy discriminating amyloid status.Our findings show the potential interchangeability of DPSvenous and plasma sampling.DPSvenous may facilitate remote and temperature‐independent sampling for AD biomarker measurement.Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD. [ABSTRACT FROM AUTHOR]

Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies., (© 2024. The Author(s).)

Background: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPS v enous ) for the diagnosis and monitoring of neurodegenerative diseases in remote settings., Methods: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; and phosphorylated tau (p-tau181 and p-tau217) were measured in paired DPS venous and ethylenediaminetetraacetic acid plasma samples with single-molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers., Results: All DPS venous and plasma analytes correlated significantly, except for Aβ42. In the validation cohort, DPS venous GFAP, NfL, p-tau181, and p-tau217 differed between CSF Aβ-positive and -negative individuals and were associated with worsening cognition., Discussion: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPS venous extends the utility of blood-based biomarkers to remote settings with simplified sampling conditions, storage, and logistics., Highlights: A wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPS venous ). DPS venous biomarkers correlated with standard procedures and cognitive status. DPS venous biomarkers had a good diagnostic accuracy discriminating amyloid status. Our findings show the potential interchangeability of DPS venous and plasma sampling. DPS venous may facilitate remote and temperature-independent sampling for AD biomarker measurement. Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)