Current Alzheimer Research - Volume 20, Issue 12, 2023

There shall probably be no “magic bullet” for Alzheimer’s; rather, we should be pursuing a “magic shotgun blast” that will target multiple complementary therapeutic receptors. Although protein misfolding/oligomerization will probably be one of these targets, this alone is insufficient and will require the co-administration of other therapeutic entities engaging targets, such as immunopathy, gliopathy, mitochondriopathy, synaptotoxicity or others. Although polypharmacy is emerging as the preferred therapeutic route, many questions remain unanswered. Should this be a cocktail of biologics, a concoction of small molecules, or a judicious combination of both? Biologics and small molecule drugs display both strengths and weaknesses. When addressing a disease as complex and globally important as Alzheimer’s, there should be room for the continuing development of both of these therapeutic classes. Each has much to offer, and when used with their advantages and disadvantages in clear focus, an ultimate solution will probably require contributions from both.

The prevalence of Alzheimer's disease (AD) is increasing as the elderly population, which hurts elderly people's cognition and capacity for self-care. The process of mitophagy involves the selective clearance of ageing and impaired mitochondria, which is required to preserve intracellular homeostasis and energy metabolism. Currently, it has been discovered that mitophagy abnormalities are intimately linked to the beginning and progression of AD. This article discusses the mechanism of mitophagy, abnormal mitophagy, and therapeutic effects in AD. The purpose is to offer fresh perspectives on the causes and remedies of AD.

Discoveries in the field of medical sciences are blooming rapidly at the cost of voluminous efforts. Presently, multidisciplinary research activities have been especially contributing to catering cutting-edge solutions to critical problems in the domain of medical sciences. The modern age computing resources have proved to be a boon in this context. Effortless solutions have become a reality, and thus, the real beneficiary patients are able to enjoy improved lives. One of the most emerging problems in this context is Alzheimer’s disease, an incurable neurological disorder. For this, early diagnosis is made possible with benchmark computing tools and schemes. These benchmark schemes are the results of novel research contributions being made intermittently in the timeline. In this review, an attempt is made to explore all such contributions in the past few decades. A systematic review is made by categorizing these contributions into three folds, namely, First, Second, and Third Generations. However, priority is given to the latest ones as a handful of literature reviews are already available for the classical ones. Key contributions are discussed vividly. The objectives set for this review are to bring forth the latest discoveries in computing methodologies, especially those dedicated to the diagnosis of Alzheimer’s disease. A detailed timeline of the contributions is also made available. Performance plots for certain key contributions are also presented for better graphical understanding.

Background: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized by cognitive and behavioral impairments significantly hindering social and occupational functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between these medications and Bmal1 remains insufficiently explored. Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1, this research explores the potential synergistic efficacy of combining these pharmaceutical agents with melatonin for AD treatment. Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles. Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate notably similar binding energy values to melatonin, interacting within the Bmal1 binding site through analogous amino acid residues and functional groups. Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects.

Background: Alzheimer's Disease (AD) is the most prevalent type of dementia. The early change of gut microbiota is a potential biomarker for preclinical AD patients. Objective: The study aimed to explore changes in gut microbiota characteristics in preclinical AD patients, including those with Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI), and detect the correlation between gut microbiota characteristics and cognitive performances. Methods: This study included 117 participants [33 MCI, 54 SCD, and 30 Healthy Controls (HC)]. We collected fresh fecal samples and blood samples from all participants and evaluated their cognitive performance. We analyzed the diversity and structure of gut microbiota in all participants through qPCR, screened characteristic microbial species through machine learning models, and explored the correlations between these species and cognitive performances and serum indicators. Results: Compared to the healthy controls, the structure of gut microbiota in MCI and SCD patients was significantly different. The three characteristic microorganisms, including Bacteroides ovatus, Bifidobacterium adolescentis, and Roseburia inulinivorans, were screened based on the best classification model (HC and MCI) having intergroup differences. Bifidobacterium adolescentis is associated with better performance in multiple cognitive scores and several serum indicators. Roseburia inulinivorans showed negative correlations with the scores of the Functional Activities Questionnaire (FAQ). Conclusion: The gut microbiota in patients with preclinical AD has significantly changed in terms of composition and richness. Correlations have been discovered between changes in characteristic species and cognitive performances. Gut microbiota alterations have shown promise in affecting AD pathology and cognitive deficit.