Journal of Alzheimer's Disease - Volume 96, issue 3

Authors: Černotová, Daniela | Hrůzová, Karolína | Levčík, David | Svoboda, Jan | Stuchlík, Aleš

Article Type: Review Article

Abstract: Finding a cure for Alzheimer’s disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this …review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits. Show more

Keywords: Alzheimer’s disease, animal models, dementia, hippocampus, oxytocin, parvalbumin interneurons, social cognition, social memory

DOI: 10.3233/JAD-230333

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 861-875, 2023

Authors: Mani, Shalini | Dubey, Rajni | Lai, I-Chun | Babu, M. Arockia | Tyagi, Sakshi | Swargiary, Geeta | Mody, Deepansh | Singh, Manisha | Agarwal, Shriya | Iqbal, Danish | Kumar, Sanjay | Hamed, Munerah | Sachdeva, Punya | Almutary, Abdulmajeed G. | Albadrani, Hind Muteb | Ojha, Shreesh | Singh, Sandeep Kumar | Jha, Niraj Kumar

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential …strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α -synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD. Show more

Keywords: Alzheimer’s disease, antioxidants, neuroprotection, oxidative stress, therapeutics, vitamins

DOI: 10.3233/JAD-220700

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 877-912, 2023

Authors: Naismith, Sharon L. | Michaelian, Johannes C. | Santos, Cherry | Mehrani, Inga | Robertson, Joanne | Wallis, Kasey | Lin, Xiaoping | Ward, Stephanie A. | Martins, Ralph | Masters, Colin L. | Breakspear, Michael | Ahern, Susannah | Fripp, Jurgen | Schofield, Peter R. | Sachdev, Perminder S. | Rowe, Christopher C.

Article Type: Review Article

Abstract:  In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia’s leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics , and Screening for Trials . Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now …has a national Registry for Mild Cognitive Impairment and dementia with 55 participating clinical sites, an extensive map of memory clinic services, national Memory and Cognition Clinic Guidelines and specialized screening for trials sites in five states. This paper provides an overview of ADNeT’s achievements to date and future directions. With the increase in dementia cases expected over coming decades, and with recent advances in plasma biomarkers and amyloid lowering therapies, the nationally coordinated initiatives and partnerships ADNeT has established are critical for increased national prevention efforts, co-ordinated implementation of emerging treatments for Alzheimer’s disease, innovation of early and accurate diagnosis, driving continuous improvements in clinical care and patient outcome and access to post-diagnostic support and clinical trials. For a heterogenous disorder such as dementia, which is now the second leading cause of death in Australia following cardiovascular disease, the case for adequate investment into research and development has grown even more compelling. Show more

Keywords: ADNeT, Alzheimer’s disease, Australian Dementia Network, clinical quality registry, clinical trials, dementia, diagnosis, health services, memory clinic, mild cognitive impairment

DOI: 10.3233/JAD-230854

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 913-925, 2023

Authors: Yang, Jiahui | Shi, Xiaohua | Wang, Yingying | Ma, Ming | Liu, Hongyu | Wang, Jiaoqi | Xu, Zhongxin

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings …from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients. Show more

Keywords: Alzheimer’s disease, ferroptosis, multi-target, neuroinflammation, thiazolidinediones

DOI: 10.3233/JAD-230593

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 927-945, 2023

Authors: Frederiksen, Kristian Steen | Lanctôt, Krista L. | Weidner, Wendy | Hahn-Pedersen, Julie Hviid | Mattke, Soeren

Article Type: Systematic Review

Abstract: Background: Many individuals with Alzheimer’s disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments. Objective: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD. Methods: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical …health of care partners, and the economic or financial burden of AD. Results: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost. Conclusions: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions. Show more

Keywords: Alzheimer’s disease, caregivers, financial stress, quality of life

DOI: 10.3233/JAD-230487

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 947-966, 2023

Authors: Healy, Elizabeth

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) plagues 6.5 million Americans 65+, yet treatments are lacking. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been developed to address the expansive impact of dementias on the general public. This systematic review evaluated the impact of the MIND diet on cognition in those with pathologies across the dementia spectrum. Objective: To evaluate the application of the MIND diet for prevention and/or treatment of dementia. Methods: PubMed was used to conduct a search using the MIND diet and terms related to cognition. Articles were excluded if they were published prior to …2018, studied a population without dementia or significant risk factors, or did not include those 65 + . The overall quality of each source was analyzed based on the cognitive test(s) used, the selection of subjects, and the sample size. Results: The search generated 33 papers, which yielded 11 articles after screening. Of these studies, one was conducted on those with mild cognitive impairment, one with AD, two with general dementia, and seven with at-risk individuals. All the studies found a positive correlation between adherence and some form of cognitive functioning, but results were mixed for specific cognitive domains. Conclusions: These findings suggest that the MIND diet may be a useful long-term treatment option for those with various dementia pathologies. However, more research is needed on subjects with onset dementias. Additionally, there is a need for more research into the mechanisms behind the common comorbidities. Show more

Keywords: Alzheimer’s disease, cognition, cognitive decline, dementia, global cognition score, Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, nutrition

DOI: 10.3233/JAD-230651

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 967-977, 2023

Authors: Salhi, Leila | Al Taep, Yaman | Salmon, Eric | Van Hede, Dorien | Lambert, France

Article Type: Systematic Review

Abstract: Background: The negative effects of periodontitis on systemic diseases, including diabetes, cardiovascular diseases, and Alzheimer’s disease (AD), have been widely described. Objective: This systematic review aimed to gather the current understanding of the pathophysiological mechanisms linking periodontitis to AD. Methods: An electronic systematic search of the PubMed/MEDLINE, Scopus, and Embase databases was performed using the following PECO question: How can periodontitis or periodontal bacteria influence Alzheimer’s disease features?”. Only preclinical studies exploring the biological links between periodontitis and AD pathology were included. This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO), and …the Syrcle and Camarades protocols were used to assess the risk of bias. Results: After a systematic screening of titles and abstracts (n  = 3,307), thirty-six titles were selected for abstract reading, of which 13 were excluded (k = 1), resulting in the inclusion of 23 articles. Oral or systemic exposure to periodontopathogens or their byproducts is responsible for both in situ brain manifestations and systemic effects. Significant elevated rates of cytokines and amyloid peptides (Aβ) and derivate products were found in both serum and brain. Additionally, in infected animals, hyperphosphorylation of tau protein, hippocampal microgliosis, and neuronal death were observed. Exposure to periodontal infection negatively impairs cognitive behavior, leading to memory decline. Conclusions: Systemic inflammation and brain metastatic infections induced by periodontal pathogens contribute to neuroinflammation, amyloidosis, and tau phosphorylation, leading to brain damage and subsequent cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, periodontal bacteria, periodontitis, periodontitis systemic effect, tau protein

DOI: 10.3233/JAD-230478

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 979-1010, 2023

Authors: Shinagawa, Hijiri | Ohuchi, Kazuki | Goto, Yuya | Hashimoto, Kohei | Kijima, Hideki | Maekawa, Shogo | Kurita, Hisaka | Inden, Masatoshi

Article Type: Short Communication

Abstract: Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer’s disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson’s disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these …proteins. Show more

Keywords: Alzheimer’s disease, amyloid-β, retromer, vacuolar protein-sorting protein

DOI: 10.3233/JAD-230686

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1011-1017, 2023

Authors: Borroni, Barbara | Urso, Daniele | Zecca, Chiara | Binetti, Giuliano | Fostinelli, Silvia | Benussi, Luisa | Ghidoni, Roberta | Tarantino, Barbara | Rivolta, Jasmine | Dell’Abate, Maria Teresa | Alberici, Antonella | Logroscino, Giancarlo

Article Type: Short Communication

Abstract: Population-based registries represent a unique sample to estimate survival. The aim of the present study was to assess survival rates and predictors of outcome in incidental frontotemporal lobar degeneration (FTLD). Incident cases with FTLD, included between January 1, 2017 to December 31, 2017, have been followed for five years. Median survival was 8.16 years from disease onset and 5.38 years from diagnosis. Survival rates did not differ between phenotypes. Shorter disease duration from onset to diagnosis was associated with poorer outcome (p  = 0.01). FTLD is a relatively homogeneous disease in terms of survival. Future multinational population-based studies are needed to …confirm these findings. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, frontotemporal dementia, primary progressive aphasia, survival

DOI: 10.3233/JAD-230676

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1019-1024, 2023

Authors: Kalia, Vrinda | Kulick, Erin R. | Vardarajan, Badri | Gu, Yian | Manly, Jennifer J. | Elkind, Mitchell S.V. | Kaufman, Joel D. | Jones, Dean P. | Baccarelli, Andrea A. | Mayeux, Richard | Kioumourtzoglou, Marianthi-Anna | Miller, Gary W.

Article Type: Research Article

Abstract: Background: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations. Objective: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5μm in aerodynamic diameter (PM2.5 ), PM less than 10μm in aerodynamic diameter (PM10 ), and nitrogen dioxide (NO2 ) in an ethnically diverse, older population. Methods: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project …in New York City, collected from 1995–2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis. Results: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2 . PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer’s disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. Conclusions: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population. Show more

Keywords: Aging population, air pollution, Alzheimer’s disease, dementia, metabolomics, nitrogen dioxide, particulate matter

DOI: 10.3233/JAD-230122

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1025-1040, 2023