Supplement: Therapeutic Trials in Alzheimer's Disease: Where Are We Now? (Guest Editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu, and George Perry)
Page S1
Preface
Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, German Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu, and George Perry
Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?
Part 1: Therapies Targeting Amyloid and Tau Proteins
Pages S3-S22
Review
Keith Noorda, Kevin Noorda, Marwan N. Sabbagh, John Bertelson, Jonathan Singer, Boris Decourt
Amyloid-Directed Antibodies: Past, Present, and Future
Abstract: 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.
Pages S23-S39
Review
Kshitij Vashisth*, Shivani Sharma, Shampa Ghosh*, M. Arockia Babu, Soumya Ghosh, Danish Iqbal, Mehnaz Kamal, Abdulmajeed G. Almutary, Saurabh Kumar Jha, Shreesh Ojha, Rakesh Bhaskar, Niraj Kumar Jha, Jitendra Kumar Sinha *These authors contributed equally to this work.
Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions
Abstract: 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.
Pages S41-S52
Review
Elyse A. Watkins, Robert Vassar
BACE Inhibitor Clinical Trials for Alzheimer’s Disease
Abstract: 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.
Pages S53-S78
Review
Judite R.M. Coimbra, Rosa Resende, José B.A. Custódio, Jorge A.R. Salvador, Armanda E. Santos
BACE1 Inhibitors for Alzheimer’s Disease: Current Challenges and Future Perspectives
Abstract: 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 evidence that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Evidence from basic research, human genetic and biomarker studies, pinpoint 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.
Pages S79-S93
Howard H. Feldman, Karen Messer, Yuqi Qiu, Marwan Sabbagh, Douglas Galasko, R. Scott Turner, Oscar Lopez, Amanda Smith, January Durant, Jody-Lynn Lupo, Carolyn Revta, Archana Balasubramanian, Kerstin Kuehn-Wache, Tanja Wassmann, Sylvia Schell-Mader, Diane M. Jacobs, David P. Salmon, Gabriel Léger, Mari L. DeMarco, Frank Weber, for the ADCS VIVA-MIND Study Group
Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Abstract: 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.
Pages S95-S113
Review
Laurent Meijer, Emilie Chretien, Denis Ravel
Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer’s Disease and Down Syndrome
Abstract: 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.
Pages S115-S128
Systematic Review
Premrutai Thitilertdecha, James Michael Brimson
CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer’s Disease Treatment: A Systematic Review of Available Clinical Data
Abstract: 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 (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.
Pages S129-S140
Review
Einar M. Sigurdsson
Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Status of Trials and Insights from Preclinical Studies
Abstract: 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.
Part 2: Beyond Amyloid and Tau Proteins-Targeted Strategies
Pages S141-S154
Review
Bin Du*, Kang Chen*, Weiwei Wang, Peng Lei *These authors contributed equally to this work.
Targeting Metals in Alzheimer's Disease: An Update
Abstract: 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.
Pages S155-S178
Review
Miguel A. Pappolla, Ralph N. Martins, Burkhard Poeggeler, Rawhi A. Omar, George Perry
Oxidative Stress in Alzheimer's Disease: The Shortcomings of Antioxidant Therapies
Abstract: 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.
Pages S179-S192
Review
Antonio Currais, William Raschke, Pamela Maher
CMS121, a Novel Drug Candidate for the Treatment of Alzheimer’s Disease and Age-Related Dementia
Abstract: 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.
Pages S193-S204
Review
Marilyn J. Steinbach, Natalie L. Denburg
Melatonin in Alzheimer’s Disease: Literature Review and Therapeutic Trials
Abstract: 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 benefits 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.
Pages S205-S215
Estelle Eyob*, Jacob S. Shaw*, Arnold Bakker, Cynthia Munro, Adam Spira, Mark Wu, Jill A. Rabinowitz, Matthew Peters, Sarah Wanigatunga, Vadim Zipunnikov, Richard Thompson, M. Haroon Burhanullah, Jeannie-Marie Leoutsakos, Paul Rosenberg, Barry Greenberg *These authors contributed equally to this work.
A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (REST)
Abstract: 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.
Pages S217-S234
Review
M.J. Kuck, Ahmet Begde, Katie Hawkins, Eef Hogervorst
Alzheimer’s Disease and (Phyto)Estrogen Treatment: Modification of Effects by Age, Type of Treatment, and Duration of Use
Abstract: 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.
Pages S235-S261
Review
Jessica Sayfullaeva*, John McLoughlin*, Andrea Kwakowsky *These authors contributed equally to this work.
Hormone Replacement Therapy and Alzheimer’s Disease: Current State of Knowledge and Implications for Clinical Use
Abstract: 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.
Pages S263-S274
Review
Miao-Kun Sun, Daniel L. Alkon
Treating Alzheimer’s Disease: Focusing on Neurodegenerative Consequences
Abstract: 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.
Pages S275-S283
Review
José Viña, Consuelo Borrás, Cristina Mas-Bargues
Genistein, a Phytoestrogen, Delays the Transition to Dementia in Prodromal Alzheimer’s Disease Patients
Abstract: 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.
Pages S285-S298
Review
Xavier Morató, Juan Pablo Tartari, Vanesa Pytel, Mercè Boada
Pharmacodynamic and Clinical Effects of Ginkgo Biloba Extract EGb 761 and Its Phytochemical Components in Alzheimer’s Disease
Abstract: 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.
Part 3: Drug Repurposing
Pages S299-S315
Review
Jackson A. Roberts, Vijay R. Varma, Attila Jones, Madhav Thambisetty
Drug Repurposing for Effective Alzheimer’s Disease Medicines: Existing Methods and Novel Pharmacoepidemiological Approaches
Abstract: 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.
Pages S317-S343
Review
Suzanne M. de la Monte
Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?
Abstract: 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 impairments 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.
Pages S345-S356
Review
Mouna Tahmi, Richard Benitez, Jose A. Luchsinger
Metformin as a Potential Prevention Strategy for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias
Abstract: 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.
Pages S357-S370
Review
Harry Crook, Paul Edison
Incretin Mimetics as Potential Disease Modifying Treatment for Alzheimer’s Disease
Abstract: Alzheimer’s disease is a devastating neurodegenerative condition that exerts a significant global burden. Despite recent efforts, disease modifying therapies remain extremely limited, with a tremendous proportion of patients having to rely on symptomatic treatment only. Epidemiological and pathological overlaps exist between Alzheimer’s disease and diabetes mellitus type 2, with people with diabetes mellitus type 2 at a significantly increased risk of developing Alzheimer’s disease in the future. Incretin mimetics, also known as GLP-1/GIP receptor agonists, are useful tools licensed for the treatment of diabetes mellitus type 2 which have recently been the subject of news coverage for their off-label use as weight loss medications. Emerging evidence highlights the possible neuroprotective function of incretin mimetics in models of Alzheimer’s disease as well as in clinical studies. This review details the pre-clinical and clinical studies that have explored the effectiveness of incretin mimetics to alleviate Alzheimer’s disease associated pathology and cognitive impairment, while also highlighting the progress made to examine the effectiveness of these molecules in Parkinson’s disease. Should clinical trials prove effective, incretin mimetics may be able to be repurposed and become useful novel tools as disease-modifying treatments for Alzheimer’s disease and other neurodegenerative diseases.
Pages S371-S393
Review
Miguel A. Pappolla, Lorenzo Refolo, Kumar Sambamurti, Daniel Zambon, Karen Duff
Hypercholesterolemia and Alzheimer’s Disease: Unraveling the Connection and Assessing the Efficacy of Lipid-Lowering Therapies
Abstract: This article examines the relationship between cholesterol levels and Alzheimer’s disease (AD), beginning with the early observation that individuals who died from heart attacks often had brain amyloid deposition. Subsequent animal model research proved that high cholesterol could hasten amyloid accumulation. In contrast, cholesterol-lowering treatments appeared to counteract this effect. Human autopsy studies reinforced the cholesterol-AD connection, revealing that higher cholesterol levels during midlife significantly correlated with higher brain amyloid pathology. This effect was especially pronounced in individuals aged 40 to 55. Epidemiological data supported animal research and human tissue observations and suggested that managing cholesterol levels in midlife could reduce the risk of developing AD. We analyze the main observational studies and clinical trials on the efficacy of statins. While observational data often suggest a potential protective effect against AD, clinical trials have not consistently shown benefit. The failure of these trials to demonstrate a clear advantage is partially attributed to multiple factors, including the timing of statin therapy, the type of stain and the appropriate selection of patients for treatment. Many studies failed to target individuals who might benefit most from early intervention, such as high-risk patients like APOE4 carriers. The review addresses how cholesterol is implicated in AD through various biological pathways, the potential preventive role of cholesterol management as suggested by observational studies, and the difficulties encountered in clinical trials, particularly related to statin use. The paper highlights the need to explore alternate therapeutic targets and mechanisms that escape statin intervention.
Part 4: Stem Cells and Gene Therapy
Pages S395-S416
Review
Miguel. A. Pappolla, Ping Wu, Xiang Fang, Burkhard Poeggeler, Kumar Sambamurti, Thomas Wisniewski, George Perry
Stem Cell Interventions in Neurology: From Bench to Bedside
Abstract: Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson’s disease, and Alzheimer’s disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.
Pages S417-S431
Review
Fabiana Morroni, Antonella Caccamo
Advances and Challenges in Gene Therapy for Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD.
Pages S433-S441
Review
Mark H. Tuszynski
Growth Factor Gene Therapy for Alzheimer’s Disease
Abstract: Nervous system growth factors are natural proteins of the brain that influence neuronal survival and function throughout life, from embryonic development to old age. In animal models of Alzheimer’s disease (AD), the growth factor brain derived neurotrophic factor (BDNF) prevents neuronal death, activates neuronal function, builds new synapses and improves learning and memory. Accordingly, we are determining whether gene delivery of BDNF in patients with AD will slow disease progression and improve memory. In a previous clinical trial of nerve growth factor (NGF) gene therapy in AD patients (NCT00017940, June 2001), we learned that growth factors can unequivocally elicit classic trophic responses from degenerating neurons in AD. Experience gained from the earlier NGF gene therapy trial is guiding our effort to optimize gene delivery of BDNF in our present clinical program (NCT05040217, June 2021).
Part 5: Diet and Lifestyle Interventions
Pages S443-S453
Review
Renata Gabuzyan, Christopher Lee, Haakon B. Nygaard
Ketogenic Approaches for the Treatment of Alzheimer’s Disease
Abstract: Dementia represents one of the largest and most urgent public health problems across the globe. Modeling projections have estimated that delaying the onset of Alzheimer’s disease (AD) by 6 months would reduce the prevalence by 5%, while a delay of 12 months would reduce the prevalence by 10%. One approach to achieving a delay in the onset of AD is to investigate lifestyle interventions that could be widely implemented with a favorable risk-benefit relationship and socioeconomic profile. Amongst such interventions, there is increasing evidence to support the use of ketogenic interventions in AD. Indeed, it is well known that cerebral glucose metabolism is impaired in AD, even at a preclinical stage, and a growing body of literature suggests that these findings may represent a primary pathogenic mechanism leading to neurodegeneration. Ketones are readily taken up by the brain and can serve as an alternative energy source for neurons and glia, hypothetically bypassing the glucose uptake deficit in AD. In this invited review we discuss the preclinical as well as clinical work aiming to increase ketones as a primary intervention in AD, including variations of the ketogenic diet, medium chain triglyceride supplementation, and newer, more experimental approaches.
Pages S455-S466
Hussein N. Yassine, A. Sofia Carrasco, Daniel S. Badie
Designing Newer Omega-3 Supplementation Trials for Cognitive Outcomes: A Systematic Review Guided Analysis
Abstract: Background: Epidemiology cohorts reveal associations between levels or intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) and lower Alzheimer’s disease (AD) risk. However, the results of randomized clinical trials have been inconsistent. Objective: A systematic review was performed to understand the effects of n-3 PUFA supplementation on cognition in adults. The objective was to present suggestions for new study designs to translate epidemiological findings into effective clinical trials. Methods: A database search was conducted on PubMed (MEDLINE) and Web of Science to retrieve articles published between 2000 and 2023 that evaluated the effects of n-3 PUFA supplementation on cognitive function. Subsequently, the search results were filtered to collect randomized controlled trials with 100 or more participants, n-3 PUFA supplementation was one of the interventions, cognition was an outcome of interest, and participants were at least 18 years of age. Results: A total of 24 articles met the inclusion criteria. In 5 of the 24 studies reviewed, supplementation with n-3 PUFAs improved cognition. All four trials in persons with AD reported null outcomes. Most of the n-3 PUFA studies in cognitively normal individuals or participants with mild cognitive impairment were null, not powered to detect small effect sizes, or selected participants without dementia risk factors. Conclusions: We recommend that newer n-3 PUFA supplement trials targeting AD prevention be personalized. For the general population, the null hypothesis appears to be correct, and future interventions are needed to identify and test dietary patterns that include PUFA-rich foods, rather than supplements.
Pages S467-S477
Review
Mohammed Alghamdi, Nady Braidy
Supplementation with NAD+ Precursors for Treating Alzheimer’s Disease: A Metabolic Approach
Abstract: Background: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases. Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR. Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.
Pages S479-S501
Review
Xi Chen, Karen Walton, Henry Brodaty, Karen Chalton
Polyphenols and Diets as Current and Potential Nutrition Senotherapeutics in Alzheimer’s Disease: Findings from Clinical Trials
Abstract: Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer’s disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to further investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed.
Pages S503-S520
Review
Haixia Li, Qiongyao Xiang, Rujing Ren, Gang Wang
Acupuncture as a Complementary Therapy for Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a significant global medical concern due to the aging population. AD is featured by gradual cognitive impairment, impacting daily functioning and causing behavioral and personality changes, causing disruptive psychiatric symptoms. While pharmacological interventions are the primary clinical approach, their efficacy is variable and limited. Acupuncture, with its distinctive theoretical framework and treatment approach, has garnered attention as a non-pharmacological intervention for AD through extensive preclinical and clinical research. Neurobiological investigations into the machinery of acupuncture in AD have provided compelling evidence of its therapeutic efficacy and unique advantages. This review commences with an in-depth exploration of acupuncture’s clinical applications, emphasizing its various parameters and its potential combination with first-line drugs and other therapies in the context of AD. Subsequently, we delve into the underlying therapeutic mechanisms of acupuncture in AD. Finally, we summarize these aspects, highlight current study limitations, and offer recommendations for future research. Taken together, in a rapidly aging society, both clinical application and mechanistic exploration of acupuncture in AD treatment have gained momentum. This trajectory suggests that acupuncture will continue to make significant strides in AD therapeutics as research progresses.
Pages S521-S535
Review
Adriel Brown, Peter J. Bayley
The Therapeutic Potential of Yoga for Alzheimer's Disease: A Critical Review
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, significantly impacting the quality of life of affected individuals and their caregivers. While pharmacological treatments offer limited relief, nonpharmacological interventions, like yoga, have gained attention for their potential therapeutic benefits. This critical review synthesizes findings from various studies on the feasibility, adherence, physical function, cognitive improvements, inflammatory markers, neuroprotection, and mood and behavioral changes associated with yoga interventions for older adults with AD. Despite these promising results, further research with randomized controlled trials, larger sample sizes, control groups, longitudinal follow-ups, standardized protocols, and diverse populations is necessary to confirm these benefits and understand the long-term effects of yoga on AD progression. This critical review highlights yoga's potential as a valuable nonpharmacological intervention in the holistic management of AD.
Pages S537-S544
Review
Nizhuan Wang*, Hsu-Chih Tai*, I-Shiang Tzeng *These authors contributed equally to this work.
Non-Pharmacological Exercise Randomized Controlled Trials in Alzheimer’s Disease
Abstract: This narrative review aimed to summarize evidence on responses to exercise in pre-clinical Alzheimer’s disease (AD) and on how long-term exercise programs work to improve neuropsychiatric symptoms and cognitive performance. We conducted a narrative review of the body of research on the benefits of long-term exercise programs in improving cognitive performance and reducing neuropsychiatric scores in patients with AD. Long-term exercise therapy appears to improve blood flow, increase hippocampal volume, and promote neurogenesis in patients with AD. Higher levels of physical activity are associated with a lower chance of developing the disease, and most prospective studies have shown that physical inactivity is one of the most prevalent modifiable risk factors for the development of AD. Exercise appears to be beneficial in improving cognitive function, a neuropsychiatric symptom of AD. Exercise has been shown to have fewer side effects, such as non-pharmacological effects and better adherence than medication. In this review, experts provided a snapshot and authoritative summary of evidence for non-pharmacological exercise in patients with AD based on the best synthesis efforts, identified the main knowledge gaps and relevant barriers, and provided directions for future research. Furthermore, experts in randomized trial designs provided practical details and recommendations for researchers working in this area, underscoring the importance of relevant topics.
Part 6: Brain Stimulation and Imaging
Pages S545-S565
Review
Alberto Benussi, Barbara Borroni
Brain Stimulation in Alzheimer’s Disease Trials
Abstract: Alzheimer's disease (AD) continues to lack definitive curative therapies, necessitating an urgent exploration of innovative approaches. This review provides a comprehensive analysis of recent clinical trials focusing on invasive and non-invasive brain stimulation techniques as potential interventions for AD. Deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) are evaluated for their therapeutic efficacy, safety, and applicability. DBS, though invasive, has shown promising results in mitigating cognitive decline, but concerns over surgical risks and long-term effects persist. On the other hand, non-invasive methods like rTMS, tDCS, and tACS have demonstrated potential in enhancing cognitive performance and delaying disease progression, with minimal side effects, but with varied consistency. The evidence hints towards an individualized, patient-centric approach to brain stimulation, considering factors such as disease stage, genetic traits, and stimulation parameters. The review also highlights emerging technologies and potential future directions, emphasizing the need for larger, multi-center trials to confirm preliminary findings and establish robust clinical guidelines. In conclusion, while brain stimulation techniques present a promising avenue in AD therapy, further research is imperative for more comprehensive understanding and successful clinical implementation. Through this review, we aim to catalyze the scientific discourse and stimulate further investigation into these novel interventions for AD.
Pages S567-S578
Review
Mohammed Alghamdi, Nady Braidy
Functional Magnetic Resonance Imaging in Alzheimer’s Disease Drug Trials: A Mini-Review
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative pathology that leads to cognitive decline and dementia, particularly in older adults. It disrupts brain structure and function, with neurotoxic amyloid-β (Aβ) plaques being a primary pathological hallmark. Pharmacotherapeutic trials targeting Aβ and other AD pathological features aim to slow disease progression. Functional magnetic resonance imaging (fMRI) is a non-invasive tool that visualizes brain functional activity, aiding in evaluating the efficacy of AD drugs in clinical trials. Objective: This mini-review explores the role of fMRI in evaluating the impact of AD pharmacotherapeutic clinical trials conducted in the past seven years. Methods: Literature was systematically searched using two databases. The risk of bias was assessed with the Revised Cochrane risk-of-bias tool (RoB-2) for randomized clinical trials (RCTs). Results: Four studies using fMRI to investigate AD drug efficacy were included. Cholinesterase, glutamatergic, and serotonergic drugs showed significant positive effects on brain functional activity, especially within the default mode network. Functional connectivity (FC) changes due to drug intake were linked to cerebellar and cholinergic decline in AD, correlating with improved global cognition and fMRI task performance. Conclusions: Recent RCTs demonstrate fMRI's ability to reveal longitudinal FC pattern changes in response to AD drug treatments across disease stages. Positive FC changes in distinct brain regions suggest potential compensatory mechanisms from drug intake. However, these drugs have limited efficacy, necessitating further research to enhance specific pharmacological interventions for clinical application.
Pages S579-S601
Review
Poul F. Høilund-Carlsen, Abass Alavi, Jorge R. Barrio
PET/CT/MRI in Clinical Trials of Alzheimer's Disease
Abstract: With the advent of PET imaging in 1976, 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET became the preferred method for in vivo investigation of cerebral processes, including regional hypometabolism in Alzheimer’s disease. With the emergence of amyloid-PET tracers, [11C]Pittsburgh Compound-B in 2004 and later [18F]florbetapir, [18F]florbetaben, and [18F]flumetamol, amyloid-PET has replaced FDG-PET in Alzheimer's disease anti-amyloid clinical trial treatments to ensure “amyloid positivity” as an entry criterion, and to measure treatment-related decline in cerebral amyloid deposits. MRI has been used to rule out other brain diseases and screen for 'amyloid-related imaging abnormalities' (ARIAs) of two kinds, ARIA-E and ARIA-H, characterized by edema and micro-hemorrhage, respectively, and, to a lesser extent, to measure changes in cerebral volumes. While early immunotherapy trials of Alzheimer's disease showed no clinical effects, newer monoclonal antibody trials reported decreases of 27% to 85% in the cerebral amyloid-PET signal, interpreted by the Food and Drug Administration as amyloid removal expected to result in a reduction in clinical decline. However, due to the lack of diagnostic specificity of amyloid-PET tracers, amyloid positivity cannot prevent the inclusion of non-Alzheimer's patients and even healthy subjects in these clinical trials. Moreover, the "decreasing amyloid accumulation" assessed by amyloid-PET imaging has questionable quantitative value in the presence of treatment-related brain damage (ARIAs). Therefore, future Alzheimer's clinical trials should disregard amyloid-PET imaging and focus instead on assessment of regional brain function by FDG-PET and MRI monitoring of ARIAs and brain volume loss in all trial patients.
Pages S603-S628
Review
Elizabeth Katherine Anna Triumbari*, Agostino Chiaravalloti*, Orazio Schillaci, Nicola Biagio Mercuri, Claudio Liguori *These authors contributed equally to this work.
Positron Emission Tomography/Computed Tomography Imaging in Therapeutic Clinical Trials in Alzheimer’s Disease: An Overview of the Current State of the Art of Research
Abstract: The integration of positron emission tomography/computed tomography (PET/CT) has revolutionized the landscape of Alzheimer's disease (AD) research and therapeutic interventions. By combining structural and functional imaging, PET/CT provides a comprehensive understanding of disease pathology and response to treatment assessment. PET/CT, particularly with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), facilitates the visualization of glucose metabolism in the brain, enabling early diagnosis, staging, and monitoring of neurodegenerative disease progression. The advent of amyloid and tau PET imaging has further propelled the field forward, offering invaluable tools for tracking pathological hallmarks, assessing treatment response, and predicting clinical outcomes. While some therapeutic interventions targeting amyloid plaque load showed promising results with the reduction of cerebral amyloid accumulation over time, others failed to demonstrate a significant impact of anti-amyloid agents for reducing the amyloid plaques burden in AD brains. Tau PET imaging has conversely fueled the advent of disease-modifying therapeutic strategies in AD by supporting the assessment of neurofibrillary tangles of tau pathology deposition over time. Looking ahead, PET imaging holds immense promise for studying additional targets such as neuroinflammation, cholinergic deficit, and synaptic dysfunction. Advances in radiotracer development, dedicated brain PET/CT scanners, and Artificial Intelligence-powered software are poised to enhance the quality, sensitivity, and diagnostic power of molecular neuroimaging. Consequently, PET/CT remains at the forefront of AD research, offering unparalleled opportunities for unravelling the complexities of the disease and advancing therapeutic interventions, although it is not yet enough alone to allow patients’ recruitment in therapeutic clinical trials.
