Journal of Alzheimer's Disease - Volume 101, issue s1

Authors: Pappolla, Miguel A. | Martins, Ralph N. | Poeggeler, Burkhard | Omar, Rawhi A. | Perry, George

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, clinical trials, DASH diet, Mediterranean diet, melatonin, MIND diet, oxidative stress, resveratrol, vitamin E, vitamin C

DOI: 10.3233/JAD-240659

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S155-S178, 2024

Authors: Currais, Antonio | Raschke, William | Maher, Pamela

Article Type: Review Article

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. Show more

Keywords: Acetyl CoA, Alzheimer’s disease, AMP-activated kinase, fatty acid synthase, mitochondria, oxytosis/ferroptosis

DOI: 10.3233/JAD-231062

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S179-S192, 2024

Authors: Steinbach, Marilyn J. | Denburg, Natalie L.

Article Type: Review Article

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 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. Show more

Keywords: Aging, Alzheimer’s disease, circadian rhythm, clinical trials, dementia, melatonin, sleep

DOI: 10.3233/JAD-230760

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S193-S204, 2024

Authors: Eyob, Estelle | Shaw, Jacob S. | Bakker, Arnold | Munro, Cynthia | Spira, Adam | Wu, Mark | Rabinowitz, Jill A. | Peters, Matthew | Wanigatunga, Sarah | Zipunnikov, Vadim | Thompson, Richard | Burhanullah, M. Haroon | Leoutsakos, Jeannie-Marie | Rosenberg, Paul | Greenberg, Barry

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, circadian rhythms, hippocampus, mild cognitive impairment, sleep, trazodone

DOI: 10.3233/JAD-230635

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S205-S215, 2024

Authors: Kuck, M.J. | Begde, Ahmet | Hawkins, Katie | Hogervorst, Eef

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease risk, estrogen, hormone therapy, memory, menopause, meta-analyses

DOI: 10.3233/JAD-231415

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S217-S234, 2024

Authors: Sayfullaeva, Jessica | McLoughlin, John | Kwakowsky, Andrea

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, cognition, dementia, estradiol, estrogen, hormone replacement therapy, hormone therapy, memory

DOI: 10.3233/JAD-240899

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S235-S261, 2024

Authors: Sun, Miao-Kun | Alkon, Daniel L.

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, cognitive therapy, meaningful clinical benefit, neuroinflammation, neuropharmacology, protein kinase Cɛ

DOI: 10.3233/JAD-240479

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S263-S274, 2024

Authors: Viña, José | Borrás, Consuelo | Mas-Bargues, Cristina

Article Type: Review Article

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. Show more

Keywords: Aging, Alzheimer’s disease, dementia, genistein, soya supplements, treatment.

DOI: 10.3233/JAD-240308

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S275-S283, 2024

Authors: Morató, Xavier | Tartari, Juan Pablo | Pytel, Vanesa | Boada, Mercè

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease clinical studies, EGb 761, Ginkgo biloba L. extract, pharmacological studies

DOI: 10.3233/JAD-231372

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S285-S298, 2024

Authors: Roberts, Jackson A. | Varma, Vijay R. | Jones, Attila | Thambisetty, Madhav

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, clinical trials, drug repositioning, drug repurposing, metabolomics, pharmacoepidemiology, proteomics

DOI: 10.3233/JAD-240680

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S299-S315, 2024

Authors: de la Monte, Suzanne M.

Article Type: Review Article

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 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. Show more

Keywords: Alzheimer’s disease, diabetes drugs, incretin, insulin resistance, insulin sensitizer, intranasal insulin, neurodegeneration, PPAR agonist, type 3 diabetes, vascular dementia

DOI: 10.3233/JAD-240069

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S317-S343, 2024

Authors: Tahmi, Mouna | Benitez, Richard | Luchsinger, José A.

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, dementia, diabetes, metformin

DOI: 10.3233/JAD-240495

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S345-S356, 2024

Authors: Crook, Harry | Edison, Paul

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, drug repositioning, gastric inhibitory polypeptide, glucagon-like peptide-1, type 2 diabetes mellitus

DOI: 10.3233/JAD-240730

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S357-S370, 2024

Authors: Pappolla, Miguel A. | Refolo, Lorenzo | Sambamurti, Kumar | Zambon, Daniel | Duff, Karen

Article Type: Review Article

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 statin 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. Show more

Keywords: Alzheimer’s disease, amyloid, cholesterol, clinical trials, hypercholesterolemia, lipids, statins

DOI: 10.3233/JAD-240388

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S371-S393, 2024

Authors: Pappolla, Miguel A. | Wu, Ping | Fang, Xiang | Poeggeler, Burkhard | Sambamurti, Kumar | Wisniewski, Thomas | Perry, George

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, regenerative medicine, stem cells, stroke, traumatic brain injury

DOI: 10.3233/JAD-230897

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S395-S416, 2024

Authors: Morroni, Fabiana | Caccamo, Antonella

Article Type: Review Article

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.

Keywords: Adeno associated virus, Alzheimer’s disease, amyloid-β, neurotrophins, tau

DOI: 10.3233/JAD-230783

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S417-S431, 2024

Authors: Tuszynski, Mark H.

Article Type: Review Article

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). Show more

Keywords: Alzheimer’s disease, brain derived neurotrophic factor, clinical trial, gene therapy, intraparenchymal, intrathecal, mild cognitive impairment, MRI guidance, nerve growth factor, systemic

DOI: 10.3233/JAD-240545

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S433-S441, 2024

Authors: Gabuzyan, Renata | Lee, Christopher | Nygaard, Haakon B.

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, clinical trial, ketogenic diet, medium chain triglyceride, mouse model

DOI: 10.3233/JAD-240186

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S443-S453, 2024

Authors: Yassine, Hussein N. | Carrasco, A. Sofia | Badie, Daniel S.

Article Type: Research Article

Abstract: Background: Epidemiology cohorts reveal associations between levels or intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) and a lower risk of Alzheimer’s disease (AD). 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 food rather than supplements. Show more

Keywords: Alzheimer’s disease, cognitive function, omega-3, supplementation

DOI: 10.3233/JAD-231467

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S455-S466, 2024

Authors: Alghamdi, Mohammed | Braidy, Nady

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, NAD+, nicotinamide, sirtuins

DOI: 10.3233/JAD-231277

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S467-S477, 2024

Authors: Chen, Xi | Walton, Karen | Brodaty, Henry | Chalton, Karen

Article Type: Review Article

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 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. Show more

Keywords: Alzheimer’s disease, cellular senescence, cognition, mild cognitive impairment, nutrition senotherapeutics, senolytic agent

DOI: 10.3233/JAD-231222

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S479-S501, 2024

Authors: Li, Haixia | Xiang, Qiongyao | Ren, Rujing | Wang, Gang

Article Type: Review Article

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. Show more

Keywords: Acupuncture, Alzheimer’s disease, neuronal plasticity, therapeutics

DOI: 10.3233/JAD-231250

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S503-S520, 2024

Authors: Brown, Adriel | Bayley, Peter J.

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, clinical trials, dementia, interventions, mind-body, yoga

DOI: 10.3233/JAD-240719

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S521-S535, 2024

Authors: Wang, Nizhuan | Tai, Hsu-Chih | Tzeng, I-Shiang

Article Type: Review Article

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. Show more

Keywords: Aerobic physical activity, Alzheimer’s disease, exercise, non-pharmacological treatment

DOI: 10.3233/JAD-240418

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S537-S544, 2024

Authors: Benussi, Alberto | Borroni, Barbara

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, brain stimulation, deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial alternating current stimulation, transcranial direct current stimulation

DOI: 10.3233/JAD-230535

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S545-S565, 2024

Authors: Alghamdi, Mohammed | Braidy, Nady

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, brain networks, clinical trials, cognitive decline, functional connectivity, magnetic resonance imaging, pharmacotherapy

DOI: 10.3233/JAD-231276

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S567-S578, 2024

Authors: Høilund-Carlsen, Poul F. | Alavi, Abass | Barrio, Jorge R.

Article Type: Review Article

Abstract: With the advent of PET imaging in 1976, 2-deoxy-2-[18 F]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, [11 C]Pittsburgh Compound-B in 2004 and later [18 F]florbetapir, [18 F]florbetaben, and [18 F]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. Show more

Keywords: Alzheimer’s disease, amyloid-PET, amyloid-related imaging abnormalities, FDG-PET, cerebral volume, immunotherapy, MRI

DOI: 10.3233/JAD-240206

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S579-S601, 2024

Authors: Triumbari, Elizabeth Katherine Anna | Chiaravalloti, Agostino | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Review Article

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 (18 F-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. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, disease-modifying treatment, FDG, PET/CT, tau, trial

DOI: 10.3233/JAD-240349

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S603-S628, 2024