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

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