Journal of Alzheimer's Disease - Volume 101, issue 4

Authors: Liu, Xin Lian | Yeerlan, Jianishaya | Liu, Zhirong | Bai, Yang | Wang, Qin | Yan, YiRui | Xu, LuKe | Jia, Cui | Zhang, LuShun

Article Type: Research Article

Abstract: Background: No effective drugs currently exist to cure Alzheimer’s disease (AD) due to its complexity and the lack of understanding of the involved molecular signaling and pathways. The relationship between liver health and AD is now widely recognized. Still, molecular links and shared pathways between the liver and brain remain unclear, making the liver-brain axis in AD therapies a new area for exploration. However, bibliometric studies on this topic are lacking. Objective: This study aims to review the liver-brain axis in AD and identify future research hotspots and trends through bibliometric analysis. Methods: Articles and reviews …related to AD and liver and its related diseases were searched in the Web of Science Core Collection (WoSCC) database up to 2024. Data were processed and visually analyzed using VOSviewer, CiteSpace, and Pajek. Results: We collected 1,777 articles on AD and liver and its related diseases from 2,517 institutions across 80 countries. Keyword cluster analysis identified 11 clusters, with ‘insulin resistance,’ ‘amyloid-beta,’ ‘apolipoprotein-E,’ ‘oxidative stress,’ and ‘inflammation’ appearing most frequently, and exhibiting strong total link strength. These results indicate that these topics have been the primary focus of research on the liver-brain axis in AD. Conclusions: This study is the first to comprehensively analyze the liver-brain axis in AD using bibliometric methods. The research results identify recent research frontiers and hotspots, aiding scholars in gaining a deeper understanding of the correlation between AD and the liver. Show more

Keywords: Alzheimer’s disease, bibliometric analysis, liver, liver-brain axis, review

DOI: 10.3233/JAD-240688

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1267-1280, 2024

Authors: Park, Jiae | Oh, Jung-Pyo | Ku, Kyojin | Jin, Yeonsun | Kim, Eun Jung | Lee, Ji-Hyun

Article Type: Research Article

Abstract: Background: Drug-induced adverse symptoms affect patients’ quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer’s disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL. Objective: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and …investigate the underlying mechanisms. Methods: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes. Results: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+ ]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+ ]i levels in muscle cells. Conclusions: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+ ]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients. Show more

Keywords: Acetylcysteine, adverse effects, Alzheimer’s disease, donepezil

DOI: 10.3233/JAD-240709

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1281-1292, 2024

Authors: Pereira, Helena Rico | Diogo, Vasco Sá | Prata, Diana | Ferreira, Hugo Alexandre

Article Type: Research Article

Abstract: Background: Early detection of amyloid-β (Aβ) positivity is essential for an accurate diagnosis and treatment of Alzheimer’s disease (AD), but it is currently costly and/or invasive. Objective: We aimed to classify Aβ positivity (Aβ+) using morphometric features from magnetic resonance imaging (MRI), a more accessible and non-invasive technique, in two clinical population scenarios: one containing AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects, and another only cognitively impaired subjects (AD and MCI). Methods: Demographic, cognitive (Mini-Mental State Examination [MMSE] scores), regional morphometry MRI (volumes, areas, and thicknesses), and derived morphometric graph theory (GT) features …from all subjects (302 Aβ+, age: 73.3±7.2, 150 male; 246 Aβ–, age: 71.1±7.1, 131 male) were combined in different feature sets. We implemented a machine learning workflow to find the best Aβ+ classification model. Results: In an AD+MCI+CN population scenario, the best-performing model selected 120 features (107 GT features, 12 regional morphometric features and the MMSE total score) and achieved a negative predictive value (NPVadj ) of 68.4%, and a balanced accuracy (BAC) of 66.9%. In a AD+MCI scenario, the best model obtained NPVadj of 71.6%, and BAC of 70.7%, using 180 regional morphometric features (98 volumes, 52 areas and 29 thicknesses from temporal, parietal, and frontal brain regions). Conclusions: Although with currently limited clinical applicability, regional MRI morphometric features have clinical usefulness potential for detecting Aβ status, which may be augmented by a combination with cognitive data when cognitively normal subjects make up a substantial part of the population presenting for diagnosis. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, diagnostic imaging, machine learning

DOI: 10.3233/JAD-240366

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1293-1305, 2024

Authors: Babulal, Ganesh M. | Zha, Wenqing | Trani, Jean-Francois | Guerra, Jorge Llibre | Tee, Boon Lead | Zhu, Yiqi | Chen, Yaohua | Chen, Ling | Bubu, Michael | Josephy-Hernandez, Sylvia | Wandera, Stephen | Karanja, Wambūi | Ellajosyula, Ratnavalli | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: The significant increase in Alzheimer’s disease and related dementia prevalence is a global health crisis, acutely impacting low- and lower-middle and upper-middle-income countries (LLMICs/UMICs). Objective: The objective of this study is to identify key barriers and gaps in dementia care and research in LLMICs and UMICs. Methods: We conducted an international, cross-sectional survey among clinicians and healthcare professionals (n  = 249 in 34 countries) across LLMICs and UMICs, exploring patient demographics, use of clinical diagnosis, dementia evaluation, screening/evaluation tools, and care and treatment. Results: Significant disparities were found in diagnostic practices, access to assessments, …and access to care. On average, clinicians in LLMICs saw more patients, had less time for evaluations, lower use of formal screening and tools, and less access to biomarkers. They were also under-resourced compared to UMICs. Conclusions: The findings provide insights for policymakers, healthcare organizations, and researchers to address the complex challenges associated with dementia care in diverse settings. Addressing these challenges requires a multipronged approach involving local, national, and international stakeholders. Show more

Keywords: Alzheimer’s disease, dementia, disparity, low and middle-income countries, resources, underserved

DOI: 10.3233/JAD-240650

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1307-1320, 2024

Authors: Wu, Yanjuan | Liu, Yixuan | Liu, Yuyang | Chen, Yuntao | Lobanov-Rostovsky, Sophia | Zhang, Yuting | Liu, Yuanli | Brunner, Eric J. | French, Eric | Liao, Jing

Article Type: Research Article

Abstract: Background: Previous estimates on future socioeconomic costs of dementia in China are inconsistent, and the main drivers of these costs are unclear. Objective: This study projected future socioeconomic costs (healthcare, formal social care, and informal care costs) and value of quality adjusted life years (QALYs) lost to dementia in China and assessed drivers of socioeconomic costs. Methods: Based on our prior projection on dementia cases to 2050 by a Markov model, we forecasted future socioeconomic costs and the value of QALYs from a societal perspective, utilizing the China Health and Retirement Longitudinal Study and the Chinese …Longitudinal Healthy Longevity Survey. In our main analysis, dementia incidence increased by 2.9% annually, while sensitivity analyses considered a flat or 1.0% annual decrease in the temporal trend of dementia incidence. Furthermore, we decomposed socioeconomic costs changes (2018 US$) into population growth, population aging, dementia prevalence and average socioeconomic costs per case. Results: The annual socioeconomic costs and value of QALYs lost to dementia will reach $1,233 billion and $702 billion by 2050. If dementia incidence stays constant or decreases by 1.0% annually, the costs and QALYs would respectively decrease by 34% or 43% in 2050. Informal care is currently, and projected to remain, the largest share of socioeconomic costs. Population aging and rising dementia prevalence will mainly drive the growth in socioeconomic costs through 2050. Conclusions: Dementia casts an increasingly large economic burden on Chinese society, mainly driven by fast aging population and growing dementia prevalence. Show more

Keywords: Alzheimer’s disease, China, costs of quality of life lost, dementia, modeling studies, socioeconomic costs

DOI: 10.3233/JAD-240583

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1321-1331, 2024

Authors: Del Tredici, Kelly | Schön, Michael | Feldengut, Simone | Ghebremedhin, Estifanos | Kaufman, Sarah K. | Wiesner, Diana | Roselli, Francesco | Mayer, Benjamin | Amunts, Katrin | Braak, Heiko

Article Type: Research Article

Abstract: Background: Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-β (Aβ) deposition in Alzheimer’s disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aβ deposition as a ‘primary age-related tauopathy’ (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon’s horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART. …Objective: To test the ‘definite PART’ hypothesis. Methods: We used AT8-immunohistochemistry in 100μ m sections to examine the EC, transentorhinal cortex (TRE), and Ammon’s horn in 325 brains with tau inclusions lacking Aβ deposits (average age at death 66.7 years for females, 66.4 years for males). Results: 100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ 4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD. Conclusions: Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD. Show more

Keywords: Alzheimer’s disease, Ammon’s horn, APOE, CA2, entorhinal cortex, neurofibrillary tangles, PART hypothesis, pretangles, tau seeding, tractus perforans

DOI: 10.3233/JAD-240483

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1333-1353, 2024

Authors: Wang, Qiuchen | Fu, Mengjie | Gao, Lihui | Yuan, Xin | Wang, Ju

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is the most common form of dementia in the elderly. The drugs currently used to treat AD only have limited effects and are not able to cure the disease. Drug repositioning has increasingly become a promising approach to find potential drugs for diseases like AD. Objective: To screen potential drug candidates for AD based on the relationship between risk genes of AD and drugs. Methods: We collected the risk genes of AD and retrieved the information of known drugs from DrugBank. Then, the AD-related genes and the …targets of each drug were mapped to the human protein-protein interaction network (PPIN) to represent AD and the drugs on the network. The network distances between each drug and AD were calculated to screen the drugs proximal to AD-related genes on PPIN, and the screened drug candidates were further analyzed by molecular docking and molecular dynamics simulations. Results: We compiled a list of 714 genes associated with AD. From 5,833 drugs used for human diseases, we identified 1,044 drugs that could be potentially used to treat AD. Then, amyloid-β (Aβ) protein, the key molecule involved in the pathogenesis of AD was selected as the target to further screen drugs that may inhibit Aβ aggregation by molecular docking. We found that ergotamine and RAF-265 could bind stably with Aβ. In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability. Conclusions: Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD. Show more

Keywords: Alzheimer’s disease, drug repositioning, ergotamine, molecular docking, risk genes

DOI: 10.3233/JAD-240235

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1355-1366, 2024

Authors: Ansah, John P. | Zacharia, Hannah | Chiu, Chi-Tsun

Article Type: Research Article

Abstract: Background: The association between COVID-19 infection and the onset of dementia among adults 65 years and older has the potential to increase the burden of dementia worldwide significantly. Our research, which focuses on understanding the likely increase in the burden of dementia due to COVID-19 infection in the USA, has crucial public policy implications. By providing these insights, we aim to empower policymakers, healthcare professionals, researchers, and public health officials to make informed decisions and plan for the future. Objective: Project the prevalence of dementia in the United States while accounting for the impact of COVID-19 infection on …the onset of dementia. Methods: A dynamic multi-state population model was developed. The model was initialized with USA demographic data and estimates of age, gender, and race-specific transition rates from the Health and Retirement Study (HRS). Results: The projected increase in the burden of dementia among Americans 65 years and older is a staggering 14.838 million by 2050. However, due to the COVID-19 pandemic, we anticipate an additional 265,000 to 677,000 older adults 65 years and older will be affected by dementia. This will escalate the burden of dementia to a potential 15.103 million to 15.515 million by 2050, a significant human toll that we must be prepared for. Conclusions: The projected dementia numbers underscore the urgent need for policy and intervention in social care services and healthcare needs planning. This includes providing robust support systems for caregivers and ensuring the healthcare staff is adequately trained to meet the healthcare needs of dementia patients and their families. Show more

Keywords: Alzheimer’s diseases, dementia, multi-state population model, race and ethnicity, system dynamics

DOI: 10.3233/JAD-240177

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1367-1377, 2024

Authors: Verdelho, Ana | Correia, Manuel | Gonçalves-Pereira, Manuel | Madureira, Sofia | Vilela, Pedro | Santos, Ana Catarina | Rodrigues, Mário | Borges, Mariana | Ferro, José M. | Santa-Clara, Helena

Article Type: Research Article

Abstract: Background: Vascular cognitive impairment is frequent, in mild (mVCI) or severe forms (vascular dementia). Objective: To do a randomized controlled-trial to evaluate the impact of physical activity on cognition (primary outcome), neurocognitive measures, quality of life, functional status, and physical function (secondary outcomes), in patients with mVCI. Methods: A hundred and four patients with mVCI (mean age 71.2 years; 53 women) were randomized for a six-month intervention of moderate physical activity (60-minute sessions, 3 times/week) (n  = 53) or best-practice “usual care” (n  = 51). Comprehensive evaluations of primary and secondary outcomes included an objective measure of physical …activity through accelerometry at baseline and after intervention. Results: Mean session attendance was 58%. Adverse events were negligible. After 6 months, no significant primary outcome change was observed, either in the intervention or ‘usual care’ group. The intervention group improved significantly in some secondary outcomes in physical function - aerobic capacity (U = 403; p  = 0.000) and agility (U = 453; p  = 0.005) after 6 months. Regardless of randomization arm, a post-hoc analysis based on fulfilling at least 21.5 minutes/day of moderate or 10.7 minutes/day of vigorous physical activity (World Health Organization-WHO standards) revealed improvements. These were not only in motor capacity but also on the global measure of cognition, executive functions and memory. Conclusions: Physical activity was safe and beneficial regarding domains of physical function. No significant cognitive decline was registered over 6-months, regardless of intervention allocation. Larger samples, longer follow-ups and focus on intervention adherence are needed to fully analyze the impact of WHO recommendations for physical activity in mVCI populations. Show more

Keywords: Alzheimer’s disease, intervention, non-Alzheimer’s disease neurocognitive disorder, physical activity, prevention, vascular cognitive impairment

DOI: 10.3233/JAD-240246

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1379-1392, 2024

Authors: Rajamaki, Blair | Braithwaite, Billy | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Multimorbidity is common in older adults and complicates diagnosing and care for this population. Objective: We investigated co-occurrence patterns (clustering) of medical conditions in persons with Alzheimer’s disease (AD) and their matched controls. Methods: The register-based Medication use and Alzheimer’s disease study (MEDALZ) includes 70,718 community-dwelling persons with incident AD diagnosed during 2005-2011 in Finland and a matched comparison cohort. Latent Dirichlet Allocation was used to cluster the comorbidities (ICD-10 diagnosis codes). Modeling was performed separately for AD and control cohorts. We experimented with different numbers of clusters (also known as topics in the field …of Natural Language Processing) ranging from five to 20. Results: In both cohorts, 17 of the 20 most frequent diagnoses were the same. Based on a qualitative assessment by medical experts, the cluster patterns were not affected by the number of clusters, but the best interpretability was observed in the 10-cluster model. Quantitative assessment of the optimal number of clusters by log-likelihood estimate did not imply a specific optimal number of clusters. Multidimensional scaling visualized the variability in cluster size and (dis)similarity between the clusters with more overlapping of clusters and variation in group size seen in the AD cohort. Conclusions: Early signs and symptoms of AD were more commonly clustered together in the AD cohort than in the comparison cohort. This study experimented with using natural language processing techniques for clustering patterns from an epidemiological study. From the computed clusters, it was possible to qualitatively identify multimorbidity that differentiates AD cases and controls. Show more

Keywords: Alzheimer’s disease, ICD-10 codes, latent Dirichlet allocation, natural language processing, register-based studies, topic modeling

DOI: 10.3233/JAD-240490

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1393-1403, 2024