Insights into the Pathophysiology of Alzheimer’s Disease and Potential Therapeutic Targets: A Current Perspective

Abstract

The aging population increases steadily because of a healthy lifestyle and medical advancements in healthcare. However, Alzheimer’s disease (AD) is becoming more common and problematic among older adults. AD-related cases show an increasing trend annually, and the younger age population may also be at risk of developing this disorder. AD constitutes a primary form of dementia, an irreversible and progressive brain disorder that steadily damages cognitive functions and the ability to perform daily tasks. Later in life, AD leads to death as a result of the degeneration of specific brain areas. Currently, the cause of AD is poorly understood, and there is no safe and effective therapeutic agent to cure or slow down its progression. The condition is entirely preventable, and no study has yet demonstrated encouraging findings in terms of treatment. Identifying this disease’s pathophysiology can help researchers develop safe and efficient therapeutic strategies to treat this ailment. This review outlines and discusses the pathophysiology that resulted in the development of AD including amyloid-β plaques, tau neurofibrillary tangles, neuroinflammation, oxidative stress, cholinergic dysfunction, glutamate excitotoxicity, and changes in neurotrophins levels based on the literature search from Scopus, PubMed, ScienceDirect, and Google Scholar. Potential therapeutic strategies are discussed to provide more insights into AD mechanisms by developing some possible pharmacological agents for its treatment.

Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole‐brain modeling

“…indicating hypoexcitation, whole-brain models informed with neurotransmitters and neuromodulator receptor expression could be used to test pharmacological interventions that may restore a healthy E/I balance in patients. Possible candidates include cholinergic drugs 107,128 and psychedelics, 129 which have been found to restore normal brain function in other disorders. 130 From a more methodological perspective, our work provides valuable computational tools for studying whole-brain dynamics in both health and disease, 11 and we have made these tools publicly available alongside this publication.…”

Amyloid‐beta (Aβ)‐targeting monoclonal antibody trials in early Alzheimer's disease—Clinical outcome with gantenerumab

“…Despite the unequivocal role of Aβ in AD pathogenesis, it is unclear if Aβ functions as the predominant driving force in AD pathology, and has a greater effect compared to the contributions of pathogenic tau or neuroimmune responses. The pathophysiologic heterogeneity and involvement of other microenvironmental and individual variability in responding to the amyloid load, may explain the differences in the trial results 5 . In the clinical trial of donanemab, significant clinical benefits were observed in the participants in the low/medium tau group presenting stable scores of the CDR‐SB at 1 year, but this was not noticed in the high tau group 6 .…”

“…The pathophysiologic heterogeneity and involvement of other microenvironmental and individual variability in responding to the amyloid load, may explain the differences in the trial results. 5 In the clinical trial of donanemab, significant clinical benefits were observed in the participants in the low/medium tau group presenting stable scores of the CDR-SB at 1 year, but this was not noticed in the high tau group. 6 Hence, clinical and genetic heterogeneity in the AD population, coupled with variable intrinsic rate of AD decline could account for the negative findings in the gantenerumab clinical trials, which may represent a potential type II error.…”

Update on new trends and progress of natural active ingredients in the intervention of Alzheimer's disease, based on understanding of traditional Chinese and Western relevant theories: A review

“…As the disease progresses, social, occupational, and life functions will be severely affected, more severely, patients will die of complications within 10–20 years after onset. Based on this, AD and other dementias were considered as the seventh leading cause of death globally, with a dramatic 174% increase from 2000 (Kumaran et al, 2023).…”

“…were considered as the seventh leading cause of death globally, with a dramatic 174% increase from 2000 (Kumaran et al, 2023).…”