This review synthesizes current evidence on peripheral BDNF levels and the Val66Met polymorphism as potential biomarkers of age-related cognitive decline and neurodegeneration and critically analyze biological mechanisms linking BDNF to neurodegeneration.
Abstract
Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, synaptic plasticity, and cognitive function. Age-related decline in BDNF signaling has been implicated in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and mild cognitive impairment. However, the prognostic value of circulating BDNF and its genetic variants remains controversial due to inconsistent findings across studies. This review synthesizes current evidence on peripheral BDNF levels and the Val66Met polymorphism as potential biomarkers of age-related cognitive decline and neurodegeneration. We critically analyze biological mechanisms linking BDNF to neurodegeneration, including its interaction with amyloid-beta and tau pathology. We further examine factors underlying discrepant results: demographic characteristics, comorbidities, lifestyle factors, pharmacological interventions, and methodological variability. Despite these challenges, BDNF remains a promising diagnostic factor. Nevertheless, standardizing preanalytical protocols and accounting for patient heterogeneity are essential to unlock its diagnostic potential.
Alzheimer’s disease (AD), the most common cause of dementia in older adults, is characterized by progressive cognitive decline, synaptic dysfunction, and neuronal loss. Among the multifactorial mechanisms implicated in AD, reciprocal interactions between brain-derived neurotrophic factor (BDNF) and amyloid-β (Aβ) have attracted increasing attention as a convergent axis linking amyloid pathology to impaired neurotrophic support. BDNF promotes neuronal resilience, synaptic plasticity, and cognitive function primarily through the activation of its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and downstream signaling pathways, including PI3K-Akt and MAPK/ERK. Human postmortem and biomarker studies mainly support associations between reduced BDNF signaling, synaptic dysfunction, and AD-related pathology. In contrast, cell-based and animal studies provide mechanistic evidence that BDNF/TrkB signaling may influence amyloid precursor protein (APP) processing and neuronal resistance to Aβ-induced stress. Conversely, mechanistic studies indicate that Aβ accumulation can suppress CREB-dependent BDNF expression, disturb BDNF transport, and impair TrkB receptor function. Thus, the BDNF–Aβ relationship is better interpreted as a stage- and context-dependent pathogenic coupling rather than a simple causal loop. This review synthesizes evidence from human studies, animal models, and cellular systems to clarify how BDNF–Aβ dysregulation contributes to AD progression and to discuss the translational potential of BDNF-oriented interventions.
Fangfang Liu, Yuanmao Huang, Aiping Wang et al.· Frontiers in Molecular Neuro...· 0 citations
Elevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment, and should be considered exploratory and require validation in larger studies.
I. López-Dequidt, Y. Leira, S. Cinza-Sanjurjo et al.· Journal of Alzheimer's Disea...· 0 citations
Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit.
Abstract
Alzheimer’s disease (AD) represents the leading cause of dementia worldwide, accounting for approximately 70% of all dementia cases, and is characterized by progressive cognitive decline arising from complex interactions among molecular, genetic, environmental, and systemic factors. This review integrates current mechanistic insights with evolving diagnostic and therapeutic approaches. Central pathogenic processes include amyloid-β (Aβ) aggregation, tau hyperphosphorylation and propagation, neuroimmune dysregulation, synaptic failure, and network-level circuit disruption. Genetic and epigenetic contributors such as APOE genotype, aging-related inflammatory signaling, oxidative stress, and lifestyle-associated risk factors further modify susceptibility and disease trajectory. Recent advances in fluid biomarkers, amyloid and tau molecular imaging, and digital phenotyping—such as AI-driven cognitive assessments, gait analysis, voice analytics, and passive activity monitoring—have improved early detection and patient stratification. Emerging therapeutic strategies include disease-modifying agents, neuroprotective interventions, neurotrophin mimetics, and hormesis-based lifestyle approaches such as structured exercise, caloric modulation, and intermittent fasting. Precision-medicine trial designs and biomarker-guided therapeutic selection are transforming clinical research. At the clinical and public health level, caregiver-centered care models, community-based support systems, and multidomain prevention strategies emphasize the need for equitable, culturally informed dementia care. Future progress will depend on large-scale, diverse cohort studies, multi-omics integration, single-cell brain atlases, and AI-supported neuropathology pipelines to enable prevention and intervention during the preclinical window. This review highlights the importance of bridging mechanistic research with real-world clinical practice to generate impactful diagnostic, therapeutic, and policy outcomes.
Keywords: Alzheimer’s disease, amyloid-β and tau pathology, neurodegeneration, biomarkers and digital phenotyping, precision medicine.
Sayed Hussain Amiri, Arman Qudosy, Sayed Mohammad Jawad Wasiq et al.· Afghanistan Journal of Basic...· 0 citations
Cognitive dysfunction is one of the most disabling non-motor manifestations of Parkinson's disease (PD), progressing from mild cognitive impairment to Parkinson's disease dementia. Although multiple pathological processes have been individually implicated, the mechanisms linking neurotransmitter deficits, proteinopathies, circuit vulnerability, and neurodegeneration remain insufficiently integrated. Here, we synthesize current evidence on the pathophysiology of cognitive impairment in PD, emphasizing the convergence of dopaminergic, cholinergic, noradrenergic and serotonergic dysfunction with α-synuclein, tau and amyloid-β pathology. We highlight the hippocampus – particularly the CA2 subregion – as a critical anatomical hub connecting synaptic dysfunction, memory impairment, and dementia progression. Accumulating evidence identifies oxidative stress and neuroinflammation as central drivers across these pathological domains. Among endogenous sources of reactive oxygen species, NADPH oxidases (NOX), especially Nox4, emerge as key regulators of redox imbalance, protein aggregation and glial–neuronal interactions. Increased Nox4 activity correlates with hippocampal damage and cognitive decline, whereas experimental inhibition of Nox4 preserves synaptic integrity and improves memory performance in preclinical models. By integrating molecular, cellular and systems-level findings, this review positions redox dysregulation – and NOX-dependent signaling in particular – as a unifying mechanism underlying cognitive decline in PD, and discusses emerging therapeutic strategies targeting redox pathways, highlighting NOX modulation as a promising approach to modify the course of Parkinson's disease-associated cognitive impairment.
Ana Rita Curto, A. A. Silva, M. Fiadeiro et al.· Redox Biology· 0 citations
Graphical Abstract This is a visual representation of the abstract. Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.
I. Farzeen, Muhammad Muzammil Nazir, Zunaira Jaan et al.· Journal of Alzheimer's Disea...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
