Ebook: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?

Alzheimer’s disease (AD), the most common form of dementia among older adults, is still a major scientific and clinical challenge, particularly regarding its early diagnosis and treatment. Over decades, significant efforts have been made to find the cause(s), pathogenic mechanisms, biomarkers for the early detection, and treatment of AD. Based on the growing knowledge about the multiple mechanisms involved in AD pathophysiology, many therapeutic interventions have been developed to target pathological events that are believed to play a crucial role in the course of the disease. Theoretically, those therapeutic interventions have the potential to stop or at least slow down structural and functional brain alterations providing sustainable improvements in cognitive function.

Over the past three decades, researchers have mainly focused on approaches aimed to decrease amyloid-β, considered by many as the cause of AD. However, those therapies failed due to lack of clinically meaningful efficacy and/or to serious side-effects. Nevertheless, those studies generated data that helped in the creation of new anti-amyloid treatments. On the other hand, the failure of those therapies led many researchers to explore the efficacy of strategies aimed at tackling other players in AD pathophysiology or its risk factors.

This book, which is divided into 6 parts, discusses the past and present clinical trials in AD based on pharmacological and non-pharmacological/lifestyle strategies, with varying degrees of success.

Part 1 focusses on pharmacological strategies aimed at the two proteins associated with AD, amyloid-β and tau. The therapeutic effects of amyloid-β and tau immunotherapies, which modulate the immune system response to the presence of these two proteins, are discussed. The effects promoted by the inhibitors of β-secretase (BACE), a critical enzyme involved in amyloid-β biosynthesis, and of glutaminyl cyclase, which is responsible for the formation of the toxic pyroform of amyloid-β are also debated. The therapeutic efficacy of CT1812, a small-molecule antagonist of the sigma 2 receptor, which reduces the affinity of oligomeric amyloid-β for neuronal receptors, interfering with Aβ-induced synaptic toxicity, is also discussed. Part 1 finishes discussing the ameliorative effects associated with the inhibition, promoted by Leucettinib-21, of the tyrosine phosphorylation-regulated kinase-1A (Dyrk1a), which phosphorylates the amyloid-β precursor protein and tau.

Besides amyloid-β and tau proteins, several other therapeutic targets for AD have been identified.

Part 2 of the book is devoted to discussing a broad range of therapeutic strategies including metal-targeting agents and antioxidants since metals toxicity and oxidative stress are interlinked and consistent features of AD. Moreover, the potential efficacy of CMS121, a flavonoid fisetin-derivative that targets oxytosis/ferroptosis, is discussed. The ameliorative effects promoted by molecules aimed at improving sleep and, consequently, cognition are also debated. The modulation of AD pathophysiology by phytoestrogens and hormone therapy is also approached in part 2.

Part 3 deals with repurposed drugs, particularly antidiabetics and lipid lowering-therapies due to the similarities found between type 2 diabetes and AD and the connection found between excessive levels of triglycerides and cholesterol and increased risk of developing AD, respectively.

The challenges, advances, and therapeutic effects of stem cells and gene therapies for AD are detailed and discussed in part 4 of the book.

Part 5 debates the therapeutic effects of non-pharmacological approaches particularly of specific diets, namely ketogenic diets, and omega 3 and nicotinamide adenine dinucleotide (NAD+) supplements as well as the benefits promoted by physical exercise, yoga, and acupuncture.

Finally, part 6 of the book discusses the benefits promoted by brain stimulation, a technique that modulates brain activity. Additionally, the crucial usefulness of several imaging techniques (positron emission tomography, computed tomography, magnetic resonance imaging) is discussed, putting the focus on their ability to assess the response of demented individuals to treatments.

We are very grateful to the contributors for bringing their expertise and perspectives to these topics.

Paula I. Moreira, Ph.D.

University of Coimbra, Coimbra, Portugal

Jesus Avila, Ph.D.

Centro de Biologia Molecular (CSIC-UAM), Madrid, Spain

Daniela Galimberti, Ph.D.

University of Milan, Milan, Italy

Miguel A. Pappolla, M.D., Ph.D.

University of Texas Medical Branch, Galveston, TX, USA

Germán Plascencia-Villa, Ph.D.

The University of Texas at San Antonio, San Antonio, TX, USA

Aaron A. Sorensen, B.S., M.A.

Medical Decision Logic, Baltimore, MD, USA

Xiongwei Zhu, Ph.D.

Case Western Reserve University, Cleveland, OH, USA

George Perry, Ph.D.

The University of Texas at San Antonio, San Antonio, TX, USA

Background:

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as “probable AD”, and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD.

Objective:

This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD.

Methods:

Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval.

Results:

This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies.

Conclusions:

We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.

Alzheimer’s disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid. The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological cascade that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical trials of monoclonal antibodies targeting amyloid-β have shown mixed results, highlighting the need for further research into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes, including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes.

The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer’s disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-β protein precursor (AβPP) into amyloid-β peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-β production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer’s disease. Aside from AβPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody.

Disease-modifying therapies (DMT) for Alzheimer’s disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.

Background:

Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer’s disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD.

Objective:

Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ.

Methods:

Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment.

Conclusions:

Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.

Alzheimer’s disease (AD) and Down syndrome (DS) share a common therapeutic target, the dual-specificity, tyrosine phosphorylation activated kinase 1A (DYRK1A). Abnormally active DYRK1A is responsible for cognitive disorders (memory, learning, spatial localization) observed in both conditions. In DS, DYRK1A is overexpressed due to the presence of the DYRK1A gene on chromosome 21. In AD, calcium-activated calpains cleave full-length DYRK1A (FL-DYRK1A) into a more stable and more active, low molecular weight, kinase (LMW-DYRK1A). Genetic and pharmacological experiments carried out with animal models of AD and DS strongly support the idea that pharmacological inhibitors of DYRK1A might be able to correct memory/learning disorders in people with AD and DS. Starting from a marine sponge natural product, Leucettamine B, Perha Pharmaceuticals has optimized, through classical medicinal chemistry, and extensively characterized a small molecule drug candidate, Leucettinib-21. Regulatory preclinical safety studies in rats and minipigs have been completed and formulation of Leucettinib-21 has been optimized as immediate-release tablets. Leucettinib-21 is now undergoing a phase 1 clinical trial (120 participants, including 12 adults with DS and 12 patients with AD). The therapeutic potential of DYRK1A inhibitors in AD and DS is presented.

Background:

Alzheimer’s disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ) deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials.

Objective:

The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD.

Methods:

Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (unmapped: uri http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript.

Results:

CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome.

Conclusions:

CT1812 safely works to displace Aβ; however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing.

The tau protein undergoes pathological changes in Alzheimer’s disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of some antibodies targeting amyloid-β in Alzheimer’s disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer’s disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell.

One pathological feature of Alzheimer’s disease (AD) is the dysregulated metal ions, e.g., zinc, copper, and iron in the affected brain regions. The dysregulation of metal homeostasis may cause neurotoxicity and directly addressing these dysregulated metals through metal chelation or mitigating the downstream neurotoxicity stands as a pivotal strategy for AD therapy. This review aims to provide an up-to-date comprehensive overview of the application of metal chelators and drugs targeting metal-related neurotoxicity, such as antioxidants (ferroptotic inhibitors), in the context of AD treatment. It encompasses an exploration of their pharmacological effects, clinical research progress, and potential underlying mechanisms.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease’s neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability—epitomized by the dictum “no on-site protection, no protection”—and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success.

Old age is the major risk factor for sporadic Alzheimer’s disease (AD). However, old age-related changes in brain physiology have generally not been taken into consideration in developing drug candidates for the treatment of AD. This is at least partly because the role of these age-related processes in the development and progression of AD are still not well understood. Nevertheless, we and others have described an association between the oxytosis/ferroptosis non-apoptotic regulated cell death pathway and aging. Based on this association, we incorporated protection against this pathway as part of a cell-based phenotypic screening approach to identify novel drug candidates for the treatment of AD. Using this approach, we identified the fisetin derivative CMS121 as a potent neuroprotective molecule that is able to maintain cognitive function in multiple pre-clinical models of AD. Furthermore, we identified a key target of CMS121 as fatty acid synthase, a protein which had not been previously considered in the context of AD. Herein, we provide a comprehensive description of the development of CMS121, its preclinical activities, and the results of the toxicology testing that led to its IND approval.

There are currently no effective treatments to prevent, halt, or reverse Alzheimer’s disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field.

Alzheimer’s disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Background:

There is a continued debate on whether menopausal hormone therapy (MHT) protects women against Alzheimer’s disease (AD). It is also unclear whether phytoestrogen could be an alternative treatment for AD.

Objective:

To investigate whether mixed study findings may be due to differences in age at initiation of MHT and duration of prescription of different types of MHT using meta-analyses.

Methods:

After a systematic literature search, meta-analyses were carried out using Cochrane Revman 5.4.1.software including data from large nationwide studies of registered medically diagnosed AD and prescribed MHT. These analyses were stratified for duration and type of treatment, by age at start of prescription of therapy. Insufficient quality data were available for phytoestrogen treatment and AD meta-analyses.

Results:

A total of 912,157 women were included from five registries, of whom 278,495 had developed AD during follow-up. Meta-analyses suggested a small increased AD risk after 5–10 years prescription of combination MHT regardless of age, and over 10 years only in women younger than 60 years of age. No association was seen for estrogen alone for women younger than 60 years of age, but AD risk did increase for women over 60 years of age for up to 5 years of MHT prescriptions.

Conclusions:

Combination MHT should probably be prescribed for less than 5 years after menopause to reduce risk for AD, while estrogen alone should not be prescribed to women over 60. For phytoestrogen, small treatment trials suggested some benefit of tempeh (fermented soy), which should be investigated further.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made.

Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer’s disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed.

Alzheimer’s disease is recognized as a complex condition influenced by multiple factors, necessitating a similarly multifaceted approach to treatment. Ideally, interventions should prioritize averting the progression to dementia. Given the chronic nature of the disease, long-term management strategies are required. Within this framework, lifestyle modifications and dietary supplements emerge as appealing options due to their minimal toxicity, limited side effects, and cost-effectiveness. This study presents findings from a double-blind, placebo-controlled bicentric pilot clinical trial, demonstrating the significant cognitive preservation associated with genistein, a phytoestrogen found in soy and various other dietary sources, among individuals with prodromal Alzheimer’s disease. Our prior investigation utilizing APP/PS1 mice elucidated the specific mechanisms through which genistein operates, including anti-amyloid-β, antioxidant, anti-inflammatory, and antiapoptotic effects. These findings underscore the potential of identifying bioactive compounds from dietary sources for the management of Alzheimer’s disease.

Extracts made from plants are complex mixtures of substances with varying compositions depending on the plant material and method of manufacture. This complexity makes it difficult for scientists and clinicians to interpret findings from pharmacological and clinical research. We performed a narrative review summarizing information on ginkgo biloba leaf extract, its composition, pharmacological data and clinical evidence supporting its administration for the treatment of Alzheimer’s disease (AD). Medicinal products containing ginkgo biloba leaf extract which are manufactured in compliance with the requirements of the European Pharmacopoeia are approved as medicinal products for the treatment of dementia and related conditions by drug regulatory agencies in Europe, Asia and South America. As multicomponent mixtures, they may affect various targets in the pathogenesis of AD, the most common form of dementia. Pharmacodynamic studies demonstrate the effects of EGb 761 and individual constituents on various pathophysiological features of experimentally induced cognitive impairment and neurodegeneration that could contribute to its clinical efficacy. The safety and efficacy in the treatment of AD and cognitive decline has been studied in randomized, placebo-controlled clinical trials. Most of the studies that investigate the effects of ginkgo biloba extract (GbE) used the special extract EGb 761, which makes it the best-researched plant preparation worldwide. It is therefore the only herbal alternative to standard-of-care anti-dementia drugs. However, the mechanism of action has not been fully elucidated yet, and the clinical studies in AD show heterogeneity.

Drug repurposing is a methodology used to identify new clinical indications for existing drugs developed for other indications and has been successfully applied in the treatment of numerous conditions. Alzheimer’s disease (AD) may be particularly well-suited to the application of drug repurposing methods given the absence of effective therapies and abundance of multi-omic data that has been generated in AD patients recently that may facilitate discovery of candidate AD drugs. A recent focus of drug repurposing has been in the application of pharmacoepidemiologic approaches to drug evaluation. Here, real-world clinical datasets with large numbers of patients are leveraged to establish observational efficacy of candidate drugs for further evaluation in disease models and clinical trials. In this review, we provide a selected overview of methods for drug repurposing, including signature matching, network analysis, molecular docking, phenotypic screening, semantic network, and pharmacoepidemiological analyses. Numerous methods have also been applied specifically to AD with the aim of nominating novel drug candidates for evaluation. These approaches, however, are prone to numerous limitations and potential biases that we have sought to address in the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study, a multi-step framework for selection and validation of potential drug candidates that has demonstrated the promise of STAT3 inhibitors and re-evaluated evidence for other drug candidates, such as phosphodiesterase inhibitors. Taken together, drug repurposing holds significant promise for development of novel AD therapeutics, particularly as the pace of data generation and development of analytical methods continue to accelerate.

Functional impairments in the brain’s insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer’s disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson’s disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.

Background:

Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer’s disease (AD) and Alzheimer’s disease related disorders (ADRD).

Objective:

This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes.

Methods:

This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes. We used PubMed as the main database for our literature search with a focus on English language human studies including observational studies and clinical trials. We prioritized studies published from 2013 until February 15, 2024.

Results:

Observational human studies are conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia.

Conclusions:

Clinical trial results are needed to establish the effect of metformin on the risk of AD and ADRD.