Alzheimer’s (AD) and Parkinson’s disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca²⁺-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions.

Traumatic brain injury (TBI), a major cause of persistent cognitive impairment (CI), increases the long-term risk of developing dementia, including Alzheimer’s disease (AD). To elucidate this association, we systematically reviewed fluid biomarkers linked to post-TBI cognitive outcomes. A comprehensive search of the PubMed, Embase, and Cochrane Library databases was performed. A total of 29 clinical studies were included, reporting on several biomarkers related to neural injury and repair, AD-like pathology, and inflammation. Among these, neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1, total tau, and glial fibrillary acidic protein (GFAP) were consistently associated with CI and brain atrophy across various TBI severities and stages. Notably, certain biomarkers assessed during the acute phase (within 7 days post-injury), such as brain-derived neurotrophic factor, neuron-specific enolase, and interleukin-1β, showed significant correlations with CI. In contrast, elevated levels of GFAP and NfL measured during the recovery phase (6 months to 8 years post-injury) were significantly associated with TBI-related CI (TBI-CI). The findings also highlighted that axonal injury, glial activation, neuroinflammation, neuronal damage, and degeneration drive TBI-CI, with tau pathology and synaptic dysfunction emerging as potential bridges from TBI to AD. This review underscores the critical temporal dynamics of fluid biomarkers in TBI-CI, revealing that stage-specific biomarker profiles mirror distinct underlying pathophysiological processes. Future longitudinal studies should focus on well-characterized patient subgroups, adopt standardized diagnostic criteria, and integrate fluid biomarkers with neuroimaging and genetic data.