Background Loss of synaptic functionality has been recently identified as an early-stage indicator of neurological diseases. Consequently, monitoring changes in synaptic protein levels may be relevant for observing disease evolution or treatment responses in patients. Here, we have studied the relationship between fluid biomarkers of neurodegeneration and synaptic dysfunction in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and subjective cognitive decline (SCD). Methods The exploratory cohort consisted of cerebrospinal fluid (CSF) samples (n = 60) from patients diagnosed with AD (n = 20), FTD (n = 20), and SCD (n = 20) from the Amsterdam Dementia Cohort. We developed two novel immunoassays for the synaptic proteins synaptosomal-associated protein-25 (SNAP25) and vesicle-associated membrane protein-2 (VAMP2). We measured the levels of these biomarkers in CSF, in addition to neuronal pentraxin-2 (NPTX2), glutamate ionotropic receptor-4 (GluR4), and neurogranin (Ng) for this cohort. All in-house immunoassays were validated and analytically qualified prior to clinical application. CSF neurogranin (Ng) was measured using a commercially available ELISA. Results This pilot study indicated that SNAP25, VAMP2, and Ng may not be specific biomarkers for AD as their levels were significantly elevated in patients with both AD and FTD compared to SCD. Moreover, the strength of the correlations between synaptic proteins was lower in the AD and FTD clinical groups compared to SCD. SNAP25, VAMP2, and Ng correlated strongly with each other as well as with total Tau (Tau) and phosphorylated Tau (PTau) in all three clinical groups. However, this correlation was weakened or absent with NPTX2 and GluR4. None of the synaptic proteins correlated to neurofilament light (NfL) in any clinical group. Conclusion The correlation of the synaptic biomarkers with CSF Tau and PTau but the lack thereof with NfL implies that distinct pathological pathways may be involved in synaptic versus axonal degeneration. Our results reflect the diversity of synaptic pathology in neurodegenerative dementias.
Background We previously identified four Alzheimer’s disease (AD) subgroups with increasingly higher cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p-tau). These subgroups included individuals across the cognitive spectrum, suggesting p-tau subgroups could reflect distinct biological changes in AD, rather than disease severity. Therefore, in the current study, we further investigated which potential processes may be related with p-tau subgroups, by comparing individuals on CSF markers for presynaptic structure [vesicle-associated membrane protein 2 (VAMP2)], postsynaptic structure [neurogranin (NRGN)], axonal damage [neurofilament light (NfL)], and amyloid production [beta-secretase 1 (BACE1) and amyloid-beta 1–40 (Aβ40)]. Methods We selected 348 amyloid-positive (A+) individuals (53 preclinical, 102 prodromal, 193 AD dementia) and 112 amyloid-negative (A−) cognitively normal (CN) individuals from the Amsterdam Dementia Cohort (ADC). Individuals were labeled according to their p-tau subgroup (subgroup 1: p-tau ≤ 56 pg/ml; subgroup 2: 57–96 pg/ml; subgroup 3: 97–159 pg/ml; subgroup 4: > 159 pg/ml). CSF protein levels were measured with ELISA (NRGN, BACE1, Aβ40, NfL) or single-molecule array (Simoa) (VAMP2). We tested whether protein levels differed between the p-tau subgroups within A+ individuals with linear models corrected for age and sex and whether disease stage influenced these relationships. Results Among A+ individuals, higher p-tau subgroups showed a higher percentage of AD dementia [subgroup 1: n = 41/94 (44%); subgroup 2: n = 81/147 (55%); subgroup 3: n = 59/89 (66%); subgroup 4: n = 7/11 (64%)]. Relative to controls, subgroup 1 showed reduced CSF levels of BACE1, Aβ40, and VAMP2 and higher levels of NfL. Subgroups 2 to 4 showed gradually increased CSF levels of all measured proteins, either across the first three (NfL and Aβ40) or across all subgroups (VAMP2, NRGN, BACE1). The associations did not depend on the clinical stage (interaction p-values ranging between 0.19 and 0.87). Conclusions The results suggest that biological heterogeneity in p-tau levels in AD is related to amyloid metabolism and synaptic integrity independent of clinical stage. Biomarkers reflecting amyloid metabolism and synaptic integrity may be useful outcome measures in clinical trials targeting tau pathology.
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