Neurodegeneration in Alzheimer’s Disease: Integrating Mechanism with Translational Therapeutic Strategies

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the world, which has a gradual deterioration of memory, thinking and autonomy. The AD pathogenesis is a multifaceted and intricate interaction between molecular/cellular processes like amyloid-ß (Aß) aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, vascular changes, and genetic predisposing factors (APOE 4 allele). The amyloid cascade proposal suggests that when there is an anomaly in the handling of amyloid precursor protein, it will cause aggregation of Aß, which will culminate into the development of toxic oligomers and as well as extracellular plaques, and the eventual destruction of neurons. Tau pathology is also associated with a further role in neurodegeneration by causing intracellular neurofibrillary tangles and impairment of transport via axons. The studies on biomarkers obtained in recent years, such as cerebrospinal fluid biomarkers, plasma phosphorylated tau, and neuroimaging, such as structural MRI, have greatly augmented the exquisite rooting of the disease by detecting and classifying in its initial phases using AT(N) biomarker framework. Symbolic treatment has changed to disease-modifying treatment designed to inhibit the cholinergic system, glutamatergic system, anti-amyloid monoclonal antibodies, anti-tau therapy, and neuroinflammatory and metabolic dysfunction modulators. New technologies such as gene-editing, stem cell-therapy, exosome-therapy, digital-neuromodulation technologies etc also add to the translational therapeutic landscape. Moreover, multidomain lifestyle intervention, cognitive engagement, and any preventive approach to vascular risk management can be vital to eliminate the risk and development of diseases. Irrespective of these developments, there are still major challenges in translational research, such as heterogeneity of diseases, evaluation limitations of preclinical models, and inability to intervene clinically promptly. Precision medicine methods with multimodal biomarkers, early-stage diagnostics, and combination therapy should be considered in the future research to enhance the clinical outcomes and decrease the worldwide Alzheimer disease burden.