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

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