Journal of Dementia
Open Access

Alzheimer’s disease; Amyloid-beta; Tau protein; Neurodegeneration; Neuroinflammation; Oxidative stress; Therapeutic strategies.

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions worldwide. It is a progressive neurodegenerative disorder characterized by cognitive impairment, memory loss, and behavioral disturbances. AD presents a significant challenge to healthcare systems, necessitating a deeper understanding of its underlying pathophysiology for effective intervention. The primary pathological hallmarks of AD include extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. These abnormalities contribute to synaptic dysfunction, neuronal loss, and widespread brain atrophy, particularly in the hippocampus and cortex. Over time, neuroinflammation and oxidative stress further exacerbate neuronal damage, amplifying disease progression. Amyloid pathology stems from the aberrant processing of amyloid precursor protein (APP) by beta- and gamma-secretases, generating toxic Aβ peptides that aggregate into plaques. These plaques disrupt synaptic communication, trigger neuroinflammatory responses, and induce oxidative damage. Concurrently, tau pathology involves the hyperphosphorylation of tau protein, leading to microtubule instability, NFT formation, and neuronal cytoskeletal dysfunction. The interplay between amyloid and tau pathologies accelerates AD progression. Aβ accumulation is thought to initiate tau hyperphosphorylation, while tau pathology exacerbates synaptic dysfunction and neurodegeneration. Recent findings suggest that neuroinflammation, mediated by activated microglia and astrocytes, plays a pivotal role in disease advancement. Additionally, genetic factors, such as mutations in APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2), as well as the presence of the apolipoprotein E (APOE) ε4 allele, contribute to AD susceptibility. Despite extensive research, no definitive cure for AD exists. Current therapeutic approaches aim to mitigate amyloid and tau pathologies, reduce neuroinflammation, and promote neuronal survival. Advances in biomarker discovery and imaging techniques have improved early diagnosis, allowing for timely intervention. Further research into the molecular mechanisms of amyloid and tau pathways holds promise for the development of targeted treatments and disease-modifying therapies [1-6].

Method

This review synthesizes current research on the pathophysiology of Alzheimer’s disease, emphasizing the amyloid and tau pathways. A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Google Scholar. Articles published within the last two decades were prioritized, with a focus on molecular mechanisms, genetic influences, and potential therapeutic strategies. Inclusion criteria comprised peer-reviewed studies, clinical trials, and meta-analyses examining amyloid-beta aggregation, tau phosphorylation, neuroinflammation, and related neurodegenerative processes. Studies investigating genetic risk factors, biomarkers, and emerging treatments were also considered. Exclusion criteria included articles lacking peer review, studies with insufficient methodological rigor, and publications not primarily focused on Alzheimer’s disease pathophysiology. Data were extracted and analyzed to identify key findings, trends, and gaps in current knowledge. Additionally, relevant clinical trial data were reviewed to assess the efficacy of amyloid-targeting agents, tau inhibitors, and neuroprotective therapies. The interaction between amyloid and tau pathologies, as well as their implications for disease progression, were critically examined [7].

Results

Analysis of the literature revealed a strong link between amyloid-beta pathology and tau dysfunction in Alzheimer’s disease. Studies demonstrated that Aβ accumulation precedes tau hyperphosphorylation, suggesting a sequential pathological process. Postmortem brain analyses confirmed the presence of amyloid plaques in early disease stages, followed by widespread tau pathology in advanced cases. Neuroinflammatory responses were consistently identified as key contributors to AD progression. Microglial activation and astrocytic reactivity were found to exacerbate neuronal damage through the release of proinflammatory cytokines and oxidative stress mediators. Genetic studies reinforced the role of APOE ε4 in promoting amyloid aggregation and tau dysfunction. Therapeutic interventions targeting amyloid and tau yielded mixed results. While monoclonal antibodies such as aducanumab reduced Aβ burden, their clinical efficacy remained inconclusive. Tau-targeting drugs showed promise in preclinical models but faced challenges in clinical trials due to blood-brain barrier limitations and adverse effects.

Discussion

The amyloid and tau pathways remain central to Alzheimer’s disease pathology, yet their exact relationship continues to be debated. While amyloid accumulation appears to initiate tau pathology, tau dysfunction is more closely correlated with cognitive decline. This suggests that targeting both pathways may be necessary for effective treatment. Neuroinflammation and oxidative stress amplify the pathological cascade, making them additional therapeutic targets. Strategies aimed at modulating microglial activity and reducing oxidative damage could complement amyloid- and tau-targeted approaches. Despite the failure of many anti-amyloid therapies, ongoing research into alternative mechanisms, such as synaptic preservation and mitochondrial protection, provides hope for future treatments. Additionally, early detection through biomarkers and imaging techniques can facilitate timely intervention, potentially altering disease progression [8].

Conclusion

Understanding the complex interplay between amyloid and tau pathologies in Alzheimer’s disease is critical for developing effective treatments. Amyloid-beta aggregation and tau hyperphosphorylation drive neurodegeneration, while neuroinflammation and oxidative stress further contribute to disease progression. Current therapeutic strategies targeting amyloid and tau have faced challenges, necessitating a broader approach that includes neuroprotective and anti-inflammatory interventions. Advances in early detection and biomarker research hold promise for improving disease management. Future studies should focus on identifying synergistic treatments that address multiple pathological pathways, ultimately paving the way for more effective interventions against Alzheimer’s disease.

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