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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Abi-Ghanem, Charly | Salinero, Abigail E. | Smith, Rachel M. | Kelly, Richard D. | Belanger, Kasey M. | Richard, Riane N. | Paul, Aaron S. | Herzog, Ava A. | Thrasher, Christina A. | Rybka, Krystyna A. | Riccio, David | Gannon, Olivia J. | Kordit, David | Kyaw, Nyi-Rein | Mansour, Febronia M. | Groom, Emily | Brooks, Heddwen L. | Robison, Lisa S. | Pumiglia, Kevin | Zuloaga, Damian G. | Zuloaga, Kristen L.
Article Type: Research Article
Abstract: Background: About two-thirds of those with Alzheimer’s disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods: First, 3-month-old AppNL-F and WT female …mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. Show more
Keywords: Alzheimer’s disease, glucose metabolism, hypothalamus, menopause, metabolic disease, obesity
DOI: 10.3233/JAD-231332
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Mattke, Soeren | Tang, Yu | Hanson, Mark | von Arnim, Christine A.F. | Frölich, Lutz | Grimmer, Timo | Onur, Oezguer A. | Perneczky, Robert | Teipel, Stefan | Thyrian, Jochen René
Article Type: Research Article
Abstract: Background: Amyloid-targeting therapies for Alzheimer’s disease (AD) might become available in Germany soon. The combination of a large pool of prevalent cases and a complex diagnostic process to determine eligibility for these treatments is likely to challenge health systems’ capacity. Objective: To analyze Germany’s healthcare system capacity to identify treatment-eligible patients in a timely and equitable manner. Methods: We modeled patients’ diagnostic journey and projects wait times due to capacity constraints for AD specialist visits and PET scans from 2024 to 2043. Model parameters were derived from published data and expert input. Results: Wait …times would be ∼50 months over the model horizon, if patients were referred to specialists based on a brief cognitive assessment in primary care. Wait times for patients with social health insurance are projected to be 1.9 times those of patients with private insurance, with peak wait times of around 76 and 40 months, respectively. Adding a blood test for the AD pathology as additional triage step would reduce wait times to below 24 months. Conclusions: In spite of having a well-resourced health system, Germany is projected to be unable to cope with the demand for biomarker-based AD diagnosis, if a disease-modifying AD treatment were introduced. As these treatments might become available by the end of 2024, decisive action, in particular dissemination of high-performing AD blood tests for triage in primary care, will be needed to prevent delays in access and potentially avoidable and inequitable disease progression. Show more
Keywords: Alzheimer’s disease, biomarker, disease-modifying treatment, health system preparedness, specialty care, diagnosis, wait times
DOI: 10.3233/JAD-240728
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Utyro, Olga | Włoczkowska-Łapińska, Olga | Jakubowski, Hieronim
Article Type: Research Article
Abstract: Background: Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer’s disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4’s association with AD was unknown. Objective: To assess GLOD4’s role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh –/– 5xFAD mouse AD model of AD. Methods: GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. …Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4 protein/mRNA, Aβ precursor protein (Aβpp)/mRNA, Atg5 , p62 , and Lc3 mRNAs were quantified. Results: GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh –/– 5xFAD mice compared to Blmh +/+ 5xFAD sibling controls, but not in Blmh –/– mice without the 5xFAD transgene compared to Blmh +/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh –/– mice of both sexes and in Blmh +/+ males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh –/– 5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5 , p62 , and Lc3 genes. Conclusions: These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits. Show more
Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, autophagy, bleomycin hydrolase, Blmh–/–5xFAD mouse, GLOD4, N2a-APPswe mouse neuroblastoma cells
DOI: 10.3233/JAD-240512
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Veronelli, Laura | Daini, Roberta | Mannino, Alice | Rossetti, Alessia | Gilardone, Giulia | Corbo, Massimo | Primativo, Silvia
Article Type: Research Article
Abstract: Background: Visuo-perceptual and visuo-attentional disorders, such as global processing deficit and simultanagnosia, are not routinely investigated in prodromal forms of typical Alzheimer’s disease, as amnestic mild cognitive impairment (MCI). Objective: This study evaluated global processing abilities through Navon’s classical paradigm in individuals with amnestic MCI and investigated the related visuo-perceptual and attentional components involved in simultanagnosia. Methods: Sixteen consecutive patients with amnestic MCI (6 single-domain, 10 multiple-domain) and 16 matched controls were requested to identify global and local elements of hierarchical Navon letters, and to name large and small solid letters. Results: While correctly …identifying solid letters, patients with multiple-domain amnestic MCI were less accurate in processing the global level of hierarchical stimuli compared to controls. Single-case analyses suggested that global processing may also be impaired in single-domain amnestic MCI. In addition, patients with pathological performance in the Navon task showed perceptual and/or visual focal attention deficits. Conclusions: Early dysfunction of holistic processing can be detected in amnestic MCI. Visuo-perceptual and/or visual focal attention mechanisms, which have been shown to be damaged in Posterior Cortical Atrophy patients with simultanagnosia, may be impaired in individuals with amnestic MCI. Investigation and identification of global processing deficits in MCI could contribute to early diagnosis and longitudinal monitoring of the disease. Show more
Keywords: Alzheimer’s disease, focal attention, global processing deficits, mild cognitive impairment, Navon, simultanagnosia, visuo-perceptual processing
DOI: 10.3233/JAD-240375
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Méndez-Barrio, Carlota | Medina-Rodríguez, Manuel | Mendoza-Vázquez, Gonzalo | García-Roldán, Ernesto | Rodrigo-Herrero, Silvia | Luque-Tirado, Andrea | Almodóvar-Sierra, Ángela | Franco-Macías, Emilio
Article Type: Research Article
Abstract: Background: Predicting which patients with prodromal AD (pAD) will imminently convert to dementia may be paramount in a memory clinical setting, especially with potential disease-modifying therapies on the horizon. Objective: To explore a practical tool for this prediction, combining cognitive tests and cerebrospinal fluid (CSF) biomarkers. Methods: We designed a longitudinal prospective, observational, and multicenter study, enrolling patients with pAD. Inclusion criteria comprised memory complaints, Mini-Mental State Examination (MMSE) score of≥22, memory impairment as indicated by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) and/or TMA-93, Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, …and positive CSF Aβ 42 /Aβ 40 ratio (<0.095, Euroimmun). The primary outcome was the conversion to dementia (CDR-GS≥1) within the first year of follow-up, referred to as “short-term conversion”. A multiple regression logistic model was adopted to design the “Predict Short-Term Conversion” (PSTC) score. Results: Between 2020 and 2022, 83 patients were recruited. The median age was 74, with 49.4% being women. Twenty-five (30.1%) patients were classified as short-term converters. The PSTC score incorporated baseline scores on MMSE (≤24 = 3, >24 = 0) and FCSRT + IR Total Recall (≤14 = 4, >14 = 0), and CSF neurofilament light chains (NfLs) concentrations (β =0.001299). The PSTC score demonstrated an area under the curve of 0.79 (95% CI: 0.71–0.91, p < 0.0001), with a cutoff value of 5.14 presenting 76% sensitivity and 80% specificity. Conclusions: The PSTC score, comprising two relatively brief cognitive test scores and NfLs CSF concentrations, could be useful for predicting short-term converters among patients diagnosed with pAD. Show more
Keywords: Alzheimer’s disease, conversion to dementia, Free and Cued Selective Reminding Test, global cognition, Mini-Mental State Examination, neurofilament light chains
DOI: 10.3233/JAD-240689
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Zhang, Xiaohong | Wang, Mingzhen | Chen, Kaiyue | Shi, Na | Cui, Xia | Yang, Zhicheng | Chen, Feifei | Lin, Xingfeng
Article Type: Research Article
Abstract: Background: Alzheimer’s disease and related dementias (ADRD) are progressive conditions. Family caregivers of patients, especially those caring for patients with ADRD exhibiting behavioral and psychological symptoms of dementia (BPSD), undergo significant physical and mental changes during long-term care. While most researchers have focused on the specific needs of family caregivers, the comprehensive understanding of these needs is limited. In this study, Alderfer’s existence, relatedness, and growth theory was used to develop an interview framework to systematically and comprehensively understand the needs of family caregivers of individuals with ADRD. Objective: The objective of this study was to understand family …caregivers’ needs in coping with BPSD in individuals with ADRD, aiming to alleviate caregivers’ stress and promote their overall well-being. Methods: This study used a hermeneutic–phenomenological interview research design. Data were collected via remote conferences involving interviews with 17 participants selected via maximum variation sampling. The Colaizzi seven-step method was utilized, and the interview contents were analyzed using NVivo 12.0 software. Results: The needs of family caregivers in coping with the BPSD of individuals with ADRD could be summarized into three themes, namely existence needs, relatedness needs, and growth needs, and 10 sub-themes. Conclusions: The study findings provide new insights into the needs of family caregivers in coping with patients exhibiting BPSD. Family caregivers experience significant negative emotions, poor caregiving experiences, heavy caregiving burdens, and a desire for professional assistance and policy support. Show more
Keywords: Alzheimer’s disease, family caregivers, hermeneutic phenomenology, needs assessment, nonprofessional home care
DOI: 10.3233/JAD-240629
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 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. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Zhang, Tan | Wang, Xin | Jester, Hannah M. | Zhou, Xueyan | Ma, Tao
Article Type: Research Article
Abstract: Background: Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. Objective: This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. Methods: A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to …examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Results: Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Conclusions: Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging. Show more
Keywords: Alzheimer’s disease, apathy-like behavior, Down syndrome, Dp16, mouse model, Ts65Dn
DOI: 10.3233/JAD-240675
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Manakkadan, Anoop | Krishnan, Dolly | Rui Xia Ang, Sheila | Sajikumar, Sreedharan
Article Type: Research Article
Abstract: Background: Impairment of synaptic plasticity along with the formation of amyloid-β (Aβ) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer’s disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2 S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2 S in AD conditions using rat hippocampal …slices and the organic molecule GYY4137, a slow releasing H2 S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aβ 42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aβ 42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro . Conclusions: GYY4137, with its slow release of H2 S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD. Show more
Keywords: Alzheimer’s disease, gaseous neurotransmitter, hippocampus, H2S, long term potentiation, synaptic plasticity, synaptic tagging and capture
DOI: 10.3233/JAD-240456
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Nowell, Joseph | Raza, Sanara | Livingston, Nicholas R. | Sivanathan, Shayndhan | Gentleman, Steve | Edison, Paul
Article Type: Research Article
Abstract: Background: Tau aggregation demonstrates close associations with hypometabolism in Alzheimer’s disease (AD), although differing pathophysiological processes may underlie their development. Objective: To establish whether tau deposition and glucose metabolism have different trajectories in AD progression and evaluate the utility of global measures of these pathological hallmarks in predicting cognitive deficits. Methods: 279 participants with amyloid-β (Aβ ) status, and T1-weighted MRI scans, were selected from the Alzheimer’s Disease Neuroimaging Initiative (http://adni.loni.usc.edu ). We created the standard uptake value ratio images using Statistical Parametric Mapping 12 for [18 F]AV1451-PET (tau) and [18 F]FDG-PET (glucose metabolism) scans. …Voxel-wise group and single-subject level SPM analysis evaluated the relationship between global [18 F]FDG-PET and [18 F]AV1451-PET depending on the Aβ status. Linear models assessed whether tau deposition or glucose metabolism better predicted clinical progression. Results: There was a dissociation between global cerebral glucose hypometabolism and global tau load in amyloid-positive AD and amyloid-negative mild cognitive impairment (MCI) (p > 0.05). Global hypometabolism was only associated with global cortical tau in amyloid-positive MCI. Voxel-level single subject tau load better predicted neuropsychological performance, Alzheimer’s disease assessment scale-cognitive (ADAS-Cog) 13 score, and one-year change compared with regional and global hypometabolism. Conclusions: A dissociation between tau pathology and glucose metabolism at a global level in AD could imply that other pathological processes influence glucose metabolism. Furthermore, as tau is a better predictor of clinical progression, these processes may have independent trajectories and require independent consideration in the context of therapeutic interventions. Show more
Keywords: Alzheimer’s disease, fluorodeoxyglucose F18, positron-emission tomography, tau proteins
DOI: 10.3233/JAD-240434
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
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. Pre-press, no. Pre-press, pp. 1-14, 2024
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