Pages 535-561
Review
Howard Chertkow, Natalie Phillips, Kenneth Rockwood, Nicole Anderson, Melissa K Andrew, Robert Bartha, Camille Beaudoin, Nathalie Bélanger, Pierre Bellec, Sylvie Belleville, Howard Bergman, Sarah Best, Jennifer Bethell, Louis Bherer, Sandra Black, Michael Borrie, Richard Camicioli, Julie Carrier, Neil Cashman, Senny Chan, Lynden Crowshoe, Claudio Cuello, Max Cynader, Thanh Dang-Vu, Samir Das, Roger A Dixon, Simon Ducharme, Gillian Einstein, Alan C Evans, Margaret Fahnestock, Howard Feldman, Guylaine Ferland, Elizabeth Finger, John D Fisk, Jennifer Fogarty, Edward Fon, Ziv Gan-Or, Serge Gauthier, Carol Greenwood, Charlie Henri-Bellemare, Nathan Herrmann, David B Hogan, Robin Hsiung, Inbal Itzhak, Kristen Jacklin, Krista Lanctôt, Andrew Lim, Ian MacKenzie, Mario Masellis, Colleen Maxwell, Carrie McAiney, Katherine McGilton, JoAnne McLaurin, Alex Mihailidis, Zia Mohades, Manuel Montero-Odasso, Debra Morgan, Gary Naglie, Haakon Nygaard, Megan O’Connell, Ron Petersen, Randi Pilon, Maria Natasha Rajah, Mark Rapoport, Pamela Roach, Julie M Robillard, Ekaterina Rogaeva, Pedro Rosa-Neto, Jane Rylett, Joel Sadavoy, Peter St. George-Hyslop, Dallas Seitz, Eric Smith, Bojana Stefanovic, Isabelle Vedel, Jennifer D Walker, Cheryl Wellington, Victor Whitehead, Walter Wittich
Impact of a national dementia research consortium: The Canadian Consortium on Neurodegeneration in Aging (CCNA)
Abstract: The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.
Pages 562-576
Review
Sarah B Scheinman, Hongxin Dong (Handling Associate Editor: Ornit Chiba-Falek)
The impact of sex on memory during aging and Alzheimer’s disease progression: epigenetic mechanisms
Abstract: Alzheimer’s disease (AD) is a leading cause of dementia, disability, and death in the elderly. While the etiology of AD is unknown, there are several established risk factors for the disease including, aging, female sex, and genetics. However, specific genetic mutations only account for a small percentage (1-5%) of AD cases and the much more common sporadic form of the disease has no causative genetic basis, although certain risk factor genes have been identified. While the genetic code remains static throughout the lifetime, the activation and expression levels of genes change dynamically over time via epigenetics. Recent evidence has emerged linking changes in epigenetics to the pathogenesis of AD, and epigenetic alterations also modulate cognitive changes during physiological aging. Aging is the greatest risk factor for the development of AD and two-thirds of all AD patients are women, who experience an increased rate of symptom progression compared to men of the same age. In humans and other mammalian species, males and females experience aging differently, raising the important question of whether sex differences in epigenetic regulation during aging could provide an explanation for sex differences in neurodegenerative diseases such as AD. This review explores distinct epigenetic changes that impact memory function during aging and AD, with a specific focus on sexually divergent epigenetic alterations (in particular, histone modifications) as a potential mechanistic explanation for sex differences in AD.
Pages 577-586
Review
Lauriina Soiniemi, Eino Solje, Anna Liisa Suominen, Katja M Kanninen, Arja M Kullaa
The association between oral diseases and neurodegenerative disorders
Abstract: Background: The association between cognitive neurodegenerative disease and oral diseases has been under great interest recently. Several studies have suggested a connection between periodontitis and Alzheimer’s disease (AD) or other neurodegenerative disorders. Objective: This study aimed to review the potential mechanisms between oral diseases and neurodegenerative diseases. Methods: The study was executed as a literature review of English-language publications from 2018-2022. The databases used for the search were PubMed, Cochrane, Scopus, and Web of Science. The search phrases used were "neurodegenerative diseases" AND "oral health" and "neurodegenerative diseases" AND "oral diseases." Results: The linkage between the two disease groups was observed in several distinct publications and several potential mechanisms were found. The link between periodontitis and AD proved to be the most significant. The effect was accentuated in elderly people where individuals possessed also other risk factors for neurodegenerative diseases and had generally worse oral health conditions. Conclusions: Oral diseases may be risks for neurodegenerative changes along many different pathways. Good oral health should be acknowledged as a potential preventative or risk-reducing act against neurodegenerative diseases.
Pages 587-596
Systematic Review
Marco Canevelli, Antonio Ancidoni, Martina Valletta, Marco Toccaceli Blasi, Alba Rosa Alfano, Simona Buscarnera, Martina Salzillo, Filippo Nuti, Francesca Zambri, Annachiara Di Nolfi, Eleonora Lacorte, Giulia Grande, Nicola Vanacore, Giuseppe Bruno (Handling Associate Editor: Carlo Abbate)
Reporting of comorbidities and health status of participants in clinical trials testing amyloid- and tau-targeting monoclonal antibodies for Alzheimer’s disease: A systematic review
Abstract: Background: Controversies exist around the external validity of clinical trials on disease-modifying treatments for Alzheimer’s disease (AD). Detailed information on the clinical characteristics of research participants is lacking, hampering the understanding of their representativeness. Objective: This study aimed to systematically review the baseline comorbidities and health status of patients with AD enrolled in clinical trials. Methods: A systematic review of scientific and gray literature was conducted. Randomized controlled trials, enrolling participants in the AD continuum, and testing amyloid- and tau-targeting monoclonal antibodies were selected. Data on the type of study and intervention and the baseline clinical characteristics of participants were extracted. The proportion of studies reporting information on comorbidities, integrative measures of health (e.g., number of chronic diseases and multimorbidity, frailty, and gait speed), and non-neurological concomitant therapies of participants was calculated. Results: Thirty-six articles, referring to 41 studies (21,952 participants) were included. None of the retained trials provided information on the comorbidities or other integrative measures reflecting the baseline health status of participants. Only three studies reported data on non-neurological concomitant therapies. Five documents providing relevant information were identified through gray literature searches covering the websites of regulatory agencies and pharmaceutical manufacturers. Conclusions: The health characteristics of patients with AD included in randomized controlled trials are poorly reported. Therefore, the external validity of the study findings cannot be fully appreciated.
Pages 597-616
Systematic Review
Ana Magdalena Vargas-Martínez
Economic evaluations of technology-based interventions used to provide care support for people with mild dementia or mild cognitive impairment and their caregivers: A systematic review
Abstract: Background: The cost-effectiveness of interventions is a key issue owing to the limited resources of healthcare services. Objective: To conduct a systematic review of economic evaluations of technology-based healthcare interventions in care support for people with dementia or mild cognitive impairment (MCI) and their caregivers, and of the tools used to assess effectiveness and costs. Methods: The following databases were used: PubMed, National Health Service Economic Evaluation Database, and Health Technology Assessment. A total of 207 articles from 2012 to 2024 were identified and then screened. Results: Seventeen studies were included, of which nine were study protocols. Almost half (n=8) the interventions were multicomponent. The most common components used in the interventions were cognitive stimulation, physical functioning and continuing support. Regarding the efficiency results of these interventions, only three studies provided a full economic evaluation. The most frequent tools in the economic evaluations used to measure effectiveness (measured in quality-adjusted life years) and costs were the European Quality of Life-5 Dimensions and Resource Utilization in Dementia instruments, respectively. Conclusions: Most of the interventions evaluated were cost-effective. However, these results should be interpreted with caution, given the scarcity of the literature, and further economic evaluations of technology-based healthcare interventions for people with mild dementia or MCI care support and their caregivers are therefore needed. Additionally, a meta-analysis could not be performed due to the heterogeneity of the data.
Pages 617-626
Hypothesis
Donald E. Moss, Ruth G. Perez
The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer’s disease: Anti-neurodegenerative benefits of acetylcholinesterase inhibitors
Abstract: A conundrum in Alzheimer’s disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein early on should be a high priority as a strategy to help reduce dementia and its widespread social and economic suffering.
Pages 627-632
Short Communication
Dror Shir, Tamara Shiner, Noa Bregman
Anti-amyloid treatments for Alzheimer’s disease: A study on physicians’ perspectives
Abstract: Advances in amyloid targeting therapies (ATT) for Alzheimer’s disease have introduced new options, necessitating an understanding of physicians’ perspectives as these therapies move from trials to practice. A survey of Israeli specialists found that 84% were familiar with new ATT, but 60% raised doubts about their ability to significantly impact disease progression. Neurologists were more likely to recommend these treatments, but concerns included treatment costs and limited real-world experience. The decision to refer patients was influenced by patient age, financial status, and diagnostic test availability. Strategies to enhance physician education and improve patient access to ATT are suggested.
Pages 633-638
Short Communication
Luca Tagliafico*, Bianca Drago*, Silvia Ottaviani, Alessio Nencioni, Fiammetta Monacelli *These authors contributed equally to this work.
Assessing palliative care needs in patients with dementia: A cross-sectional analysis of an predominantly oldest-old population from a geriatric memory clinic
Abstract: In this cross-sectional study, we assessed palliative care (PC) needs in older adults with dementia. Using the NECPAL CCOMS-ICO© 3.1 tool and comprehensive geriatric assessment, 16.25% of the 554 evaluated patients required PC, which had clinical frailty and a moderate stage of dementia. Advanced frailty was associated with the poorest prognosis, according to the PC-based stratification. Our findings support the use of PC assessment in dementia care, which focuses on a person-centered approach while minimizing unnecessary or ineffective treatments and meeting the real-world patient's needs. PC care may fulfill the multidimensional nature of dementia, shifting towards personalized palliative approaches.
Pages 639-641
Commentary
Pilar Andrés, Juan Francisco Flores-Vázquez, Stefanie Enriquez-Geppert
Associating faces with names and meals as a biomarker of early AD in cognitively healthy individuals
Abstract: The Learning and Associative Memory (LAM) test is a face-name associative memory test created to detect early Alzheimer’s disease (AD). In a recent study, it was administered to cognitively healthy individuals with different levels of amyloid-β (Aβ) and tau burden. The key findings for LAM were: 1) selective correlations with Aβ levels, 2) unique discriminatory power between A+ and A- individuals, 3) significantly higher areas under the curve in receiver operating curve analysis. Future research should focus on comparing performance on the LAM and face-name associative memory tests to determine the most effective method for detecting early signs of AD.
Pages 642-645
Commentary
Jeanne Gallée
A call for globally responsive screening materials to account for heterogeneity in dementia syndromes
Abstract: Effective screening for communicative ability in dementia is vital to drive theoretical understanding and optimize care responsiveness globally. Communication is central to the human experience; however, routine clinical screening for progressive communication change remains limited due to a variety of resource constraints. Other challenges include the subtlety of early communication-led symptoms, heterogeneous underlying pathologies, and a lack of culturally diverse research and tools. To address the scarcity of dedicated assessment resources, future initiatives must maximize responsiveness to and representation of our global population to appropriately respond to the rising, and vastly diverse, dementia crisis.
Pages 646-658
Shokufeh Bagheri, Masome Rashno, Iraj Salehi, Seyed Asaad Karimi, Safoura Raoufi, Alireza Komaki
Protective effects of geraniol in a male rat model of Alzheimer’s disease: A behavioral, biochemical, and histological study
Abstract: Background: Alzheimer's disease (AD) as a neurodegenerative disease can cause behavioral impairments due to oxidative stress. Aging and oxidative conditions are some AD risk factors. Objective: We assessed the influence of geraniol (GR), an acyclic monoterpene alcohol, on behavioral functions, hippocampal oxidative status, and histological alterations in AD rats induced by amyloid-β (Aβ). Methods: Male Wistar rats (n=70) were randomly allocated to the control, sham, AD, control-GR (100 mg/kg; per oral: P.O.), AD-GR (100 mg/kg; P.O.; treatment), GR-AD (100 mg/kg; P.O.; pretreatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment + treatment) groups. GR administration was done for four continuous weeks. After treatments, novel object recognition (NOR) and Morris water maze (MWM) tests assessed the animals’ behavior. Then, hippocampal specimens were collected for biochemical assessment. Finally, the number of intact neurons was identified in the hippocampus using hematoxylin and eosin staining. Results: Aβ microinjection increased learning and memory deficits in both NOR and MWM tests, oxidative stress status, and neuronal loss. Oral GR administration improved behavioral deficits and reduced oxidative stress status and neuronal loss in the Aβ-infused animals. Conclusions: GR ameliorates behavioral impairments through a decrease in neuronal degeneration and oxidative stress.
Pages 659-669
Jean M Lewis, Dorathy-Ann Harris, Janell Kosmatka, Emily Mikrut, Jack Evenson, Heath I Balcer, Harmeet Dhani, Juan Pablo Hinestrosa, Robert Rissman, and Paul R Billings
Single step capture and assessment of multiple plasma extracellular vesicle biomarkers in Alzheimer’s disease detection
Abstract: Background: Blood tests for Alzheimer’s disease (AD) that measure biomarkers related to neuropathology have demonstrated to be useful, minimally-invasive ways to identify patients for screening into clinical trials. While some AD biomarkers can be detected in plasma, greater sensitivity is needed to make plasma AD tests more effective. Extracellular vesicles (EVs) in plasma carry AD-related biomarkers from the brain and could offer a concentrated source of brain-related biomarkers, though the methodological complexities involved in isolating plasma EVs have hampered its validation for clinical use. Objective: To explore the feasibility and effectiveness of developing blood tests for AD utilizing extracellular vesicle-bound protein biomarkers. Methods: We developed a simplified method for isolating EVs directly from plasma using an alternating current electrokinetic (ACE) microchip. No sample pre-treatment steps were needed. Protein biomarkers on the EVs were detected by adding fluorescent antibodies to the plasma samples before capture by the chip. This allowed measurement of EV biomarker levels directly on the chip. Results: AD or non-AD control plasma was measured for ten different AD-related biomarkers. EV-associated NCAM1, pTau231, α-synuclein, and TDP-43 levels were able to distinguish a group of 10 AD, 10 mild cognitive impairment (MCI), and 10 non-AD subjects. pTau231 was different between AD and non-AD (p=0.0300) and α-synuclein differentiated AD from MCI (p=0.0148). Conclusions: This study shows how ACE microfluidic chip technology can help differentiate AD and MCI patients from non-AD controls with clinical relevance. This work also highlights the important diagnostic role of plasma EV biomarkers in neurodegenerative disease.
Pages 670-682
Shayan Nik Akhtar, Tuan D. Tran, Yan-Hua Chen, Qun Lu
Spatial and planar profiling of Rac1/Cdc42 signaling in Alzheimer’s disease brain
Abstract: Background: A neuropathogenic hallmark of Alzheimer’s disease (AD) is loss of neuronal synapses in selective brain regions. Small GTPases Rac1 and Cdc42, critical modulators of synaptic architecture and remodeling, are dysregulated in AD brains and are potential AD therapeutic targets. However, the exact contribution of their signaling to AD is still not clear. Objective: We intend to investigate the hypothesis that Rac1/Cdc42 activity changes in a spatial and planar dependent manner in relation to AD. Methods: We applied anti-pRac/Cdc42 (Serine 71 phosphorylation), which recognizes an inactive form of Rac1/Cdc42, and anti-pPAK (Threonine 423 phosphorylation), which detects the active PAK, a positive downstream effector of Rac1/Cdc42 signaling. For this study, triple transgenic mouse model (3xTg-AD) brain and human AD brain samples were used. Results: pRac/Cdc42 expression was decreased in 3xTg-AD mouse cortex while pPAK expression increased compared to wild-type mouse cortex. Immunostaining of mouse brain serial sections revealed increased pRac/Cdc42 expression in the rostral region, decreased expression in the caudal region, and pPAK showed an overall opposite trend of pRac/Cdc42. There was also a brain plane specific nuclear to cytoplasmic redistribution of pRac/Cdc42. Human non-dementia and AD cortex and cerebellum showed differential expressions for pRac/Cdc42, Rac1, and Cdc42. Mouse whole transcriptome analysis demonstrated spatial dependent expression of Rac1/Cdc42 signaling-associated genes in neuronal and non-neuronal (astrocyte) populations of 3xTg-AD hippocampi. Conclusions: Rac1/Cdc42 signaling is dysregulated in both 3xTg-AD mouse and AD human brain and Rac1/Cdc42 activity level changes along the spatial and planar dimensions.
Pages 683-702
Alice Oliver, Tim Wildschut, Edward S Redhead, Matthew O Parker, Saif Sharif, Antony P Wood, Constantine Sedikides, Richard Cheston (Handling Associate Editor: Juan C. Melendez)
Benefits of nostalgic landmarks for people living with Alzheimer’s disease
Abstract: Background: Emerging literature shows that nostalgia induced by autobiographical reflection and music confers psychological benefits to people living with dementia. Objective: Our objective was to test the potential benefits of nostalgic landmarks for people living with Alzheimer’s disease. Methods: We displayed the landmarks as wall-mounted pictures within a virtual environment. In Experiment 1, we developed the nostalgia manipulation by using pictures associated with the decade during which participants lived most of their childhood. To examine the effectiveness, tolerability, and safety of this pictorial nostalgia induction, we conducted the experiment with 172 healthy adults. In Experiment 2, we recruited 20 participants living with Alzheimer’s disease who experienced mild to moderate cognitive impairments. We further personalized the pictorial nostalgia induction by interviewing them about fond memories from their past and generating images corresponding to these events. We hypothesized that navigating a virtual environment with wall-mounted nostalgic (compared to control) pictures would confer psychological benefits. Results: The nostalgic (versus control) pictures evoked higher levels of momentary nostalgia; the manipulation was successful (Experiments 1 and 2). Compared to control pictures, nostalgic pictures significantly increased self-reported positive (but not negative) affect, self-esteem, self-continuity, social connectedness, and meaning in life (Experiments 1 and 2). Participants in the nostalgia condition (compared to controls) evinced better picture recognition, but not improved spatial memory (Experiment 2). Conclusions: Our findings demonstrate that nostalgic landmarks confer psychological benefits and enhance picture recognition among people living with Alzheimer’s disease. This work has real-world applications for dementia-friendly design and therapy-related practices.
Pages 703-719
Aazad*, Arunabh Choudhury*, Afzal Hussain, Mohamed F AlAjmi, Taj Mohammad, Sneh Prabha, Manoj Kumar Sharma, Anas Shamsi, Md. Imtaiyaz Hassan (Handling Associate Editor: Rekha Khandia) *These authors contributed equally to this work.
Exploring phytochemical inhibitors of protein kinase C alpha for therapeutic targeting of Alzheimer’s disease
Abstract: Background: Alzheimer's disease (AD) is characterized by neurodegeneration linked to amyloid-β (Aβ) plaques and tau protein tangles. Protein kinase C alpha (PKCα) plays a crucial role in modulating amyloid-β protein precursor (AβPP) processing, potentially mitigating AD progression. Consequently, PKCα stands out as a promising target for AD therapy. Objective: Despite the identification of numerous inhibitors, the pursuit of more effective and precisely targeted PKCα inhibitors remains crucial. Methods: In this study, we employed an integrated virtual screening approach of molecular docking and molecular dynamics (MD) simulations to identify phytochemical inhibitors of PKCα from the IMPPAT database. Results: Molecular docking screening via InstaDock identified compounds with strong binding affinities to PKCα. Subsequent ADMET and PASS analyses filtered out compounds with favorable pharmacokinetic profiles. Interaction analysis using Discovery Studio Visualizer and PyMOL further elucidated binding conformations of elucidated compounds with PKCα. Top hits underwent 200 ns MD simulations using GROMACS to validate stability and interactions. Finally, we propose two phytochemicals, kammogenin and imperialine, with appreciable drug-likeliness and binding potential with PKCα. Conclusions: Taken together, the findings suggest kammogenin and imperialine as potential PKCα inhibitors, highlighting their therapeutic promise for AD after further validation.
Pages 720-729
Michael Waller, Leon Flicker, Patrick Fitzgerald, Osvaldo P Almeida, Kaarin J Anstey, Annette J Dobson
Estimating the rates of dementia using administrative data linked to cohort studies
Abstract: Background: Current estimates of dementia and Alzheimer’s disease incidence and prevalence are required to understand the health needs of the elderly. Objective: We used two Australia cohort studies, administrative datasets, and data linkage techniques to estimate dementia rates in Australia. Methods: The study used Australian Longitudinal Study on Women’s Health and the Health in Men Cohort Study. Records of dementia were obtained from linked sources and incidence and prevalence estimates were produced. Capture-recapture methods were used to estimate numbers of dementia cases not identified through data linkage. Results: There were 3399 (28.5%) men with dementia identified from any source and 3767 (34.8%) women. Rates of dementia incidence and prevalence were similar between sexes but were raised in men once estimates of unidentified cases were included. Conclusions: Cohort studies and linked administrative data can be used together to produce current estimates of dementia prevalence and incidence comparable to other population estimates.
Pages 730-741
Hyehyun Kim, Bryan Le, Noah Goshi, Kan Zhu, Ana Cristina Grodzki, Pamela J Lein, Min Zhao, Erkin Seker (Handling Associate Editor: Marcel Verbeek)
Primary cortical cell tri-culture to study effects of amyloid-β on microglia function and neuroinflammatory response
Abstract: Background: Microglia play a critical role in neurodegenerative disorders, such as Alzheimer’s disease, where alterations in microglial function may result in pathogenic amyloid-β (Aβ) accumulation, chronic neuroinflammation, and deleterious effects on neuronal function. However, studying these complex factors in vivo, where numerous confounding processes exist, is challenging, and until recently, in vitro models have not allowed sustained culture of critical cell types in the same culture. Objective: We employed a rat primary tri-culture (neurons, astrocytes, and microglia) model and compared it to co-culture (neurons and astrocytes) and mono-culture (microglia) to study microglial function (i.e., motility and Aβ clearance) and proteomic response to exogenous Aβ. Methods: The cultures were exposed to fluorescently-labeled Aβ (FITC-Aβ) particles for varying durations. Epifluorescence microscopy images were analyzed to quantify the number of FITC-Aβ particles and assess cytomorphological features. Cytokine profiles from conditioned media were obtained. Live-cell imaging was employed to extract microglia motility parameters. Results: FITC-Aβ particles were more effectively cleared in the tri-culture compared to the co-culture. This was attributed to microglia engulfing FITC-Aβ particles, as confirmed via epifluorescence and confocal microscopy. FITC-Aβ treatment significantly increased microglia size, but had no significant effect on neuronal surface coverage or astrocyte size. Upon FITC-Aβ treatment, there was a significant increase in proinflammatory cytokines in tri-culture, but not co-culture. Aβ treatment altered microglia motility evident as a swarming-like motion. Conclusions: The results suggest that neuron-astrocyte-microglia interactions influence microglia function and highlight the utility of the tri-culture model for studies of neuroinflammation, neurodegeneration, and cell-cell communication.
Pages 742-744
Commentary
Aswathy Peethambaran Mallika
Tri-culture modeling of neuroinflammation, neurodegeneration, and neuroprotection
Abstract: The study of neurodegenerative diseases, such as Alzheimer's disease (AD), has long been a complex and challenging task. One of the major hurdles in understanding these diseases is the difficulty in recapitulating the complex interactions between neurons, astrocytes, and microglia in a laboratory setting. In recent years, researchers have made significant progress in developing triculture models that combine these three cell types, allowing for a more accurate representation of the cellular context of the human brain. This commentary discusses the recent advancements and importance of using tri-culture model systems in clarifying the pathophysiology of AD and discusses the recent article by Kim et al. (2024) published in the Journal of Alzheimer's Disease.
Pages 745-762
Adrián L Orjuela*, Marisín Pecchio*, Jessica Cruz-Mora, Lakshmi Sowmya Emani, Maria B Carreira, Oleg V Larionov, Muralidhar L Hegde, K S Jagannatha Rao, Jorge Alí-Torres, Johant Lakey-Beitia *These authors contributed equally to this work.
The role of carotenoids from red mamey fruit (Pouteria sapota) against amyloid-β monomers in Alzheimer’s disease: Computational analysis and ADMET prediction
Abstract: Background: Carotenoids, potent antioxidants in fruits and vegetables, have recently garnered attention for their potential therapeutic effects against neurodegenerative diseases. This study focuses on the interaction and anti-aggregation properties of conventional and unconventional carotenoids found in red mamey fruit, a nutraceutical fruit that is a rich source of these compounds. Objective: To assess computational the interaction between of amyloid-β (Aβ) peptide with a set of carotenoids and three carotenoids previously explored in experimental assays as well as to assess ADMET prediction of carotenoids selected by computational analysis results. Methods: We analyzed the interaction between these carotenoids and Aβ peptides using molecular docking, a key factor in Alzheimer’s disease (AD) pathology. Selected carotenoids were compared with the reference compounds cryptocapsin (1), zeaxanthin (2), lutein (3), and cryptocapsin-5,6-epoxide (24), which previously demonstrated significant anti-aggregation activity against Aβ. Using SwissADME and ADMET Predictor® software to determine the pharmaceutical analysis prediction. Results: Computational analysis identified (5R,8R)-sapotexanthin-5,8-epoxide (19) and (5S,8S)-cryptocapsin-5,8-epoxide (26) as the most promising candidates due to their strong binding affinity and potential anti-aggregation properties against Aβ. The pharmaceutical analysis identified compounds (5S,8S)-cryptocapsin-5,8-epoxide (26) and (5R,8R)-cryptocapsin-5,8-epoxide (28) as the most promising compounds. Our findings suggest that specific modifications in the carotenoid structure, particularly modifications in the type of epoxidation and stereochemistry, can significantly influence the biological activity of carotenoids and biopharmaceutical performance. Conclusions: These results provide valuable insights for future in vitro studies of most potential carotenoids (19 and 26) and the development of potential therapeutic agents for AD.
Pages 763-777
Ayse Uneri*, Colin J McArdle*, Zhiyong Deng, Samuel H Barth, C Dirk Keene, Suzanne Craft, Kimberly F Raab-Graham *These authors contributed equally to this manuscript.
DJ-1-mediated repression of the RNA-binding protein FMRP is predicted to impact known Alzheimer’s disease-related protein networks
Abstract: Background: RNA-binding proteins (RBPs) modulate the synaptic proteome and are instrumental in maintaining synaptic homeostasis. Moreover, aberrant expression of an RBP in a disease state would have deleterious downstream effects on synaptic function. While many underlying mechanisms of synaptic dysfunction in Alzheimer’s disease (AD) have been proposed, the contribution of RBPs has been relatively unexplored. Objective: To investigate alterations in RBP-messenger RNA (mRNA) interactions in AD, and its overall impact on the disease-related proteome. Methods: We first utilized RNA-immunoprecipitation to investigate interactions between RBP, DJ-1 (Parkinson’s Disease protein 7) and target mRNAs in controls and AD. Surface Sensing of Translation – Proximity Ligation Assay (SUnSET-PLA) and western blotting additionally quantified alterations in mRNA translation and protein expression of DJ-1 targets. Finally, we utilized an unbiased bioinformatic approach that connects AD-related pathways to two RBPs, DJ-1 and FMRP (Fragile X messenger ribonucleoprotein 1). Results: We find that oligomeric DJ-1 in AD donor synapses were less dynamic in their ability to bind and unbind mRNA compared to synapses from cognitively unimpaired, neuropathologically-verified controls. Furthermore, we find that DJ-1 associates with the mRNA coding for FMRP, Fmr1, leading to its reduced synaptic expression in AD. Through the construction of protein-protein interaction networks, aberrant expression of DJ-1 and FMRP are predicted to lead to the upregulation of key AD-related pathways, such as thyroid hormone stimulating pathway, autophagy, and ubiquitin mediated proteolysis. Conclusions: DJ-1 and FMRP are novel targets that may restore established neurobiological mechanisms underlying AD.
Pages 778-791
Cierra M Keith, Marc W Haut, Camila Vieira Ligo Teixeira, Rashi I. Mehta, Holly Phelps, Melanie Ward, Mark Miller, R Osvaldo Navia, Michelle M Coleman, Gary Marano, Xiaofei Wang, Stephanie Pockl, Nafiisah Rajabalee, David M Scarisbrick, William T McCuddy, Pierre-François D’Haese, Ali Rezai, Kirk Wilhelmsen
Memory consolidation, temporal and parietal atrophy, and metabolism in amyloid-β positive and negative mild cognitive impairment
Abstract: Background: Alzheimer’s disease (AD) is classically characterized by alterations in memory consolidation. With the advent of diagnostic biomarkers, some patients clinically diagnosed with AD display biomarkers inconsistent with the diagnosis. Objective: We aimed to explore differences in memory consolidation and neurodegeneration of the temporal and parietal lobes as a function of amyloid-β status in amnestic mild cognitive impairment (aMCI). Methods: We examined differences in memory consolidation and neurodegeneration between patients diagnosed with amyloid-β positive aMCI (Aβ+ N=78), amyloid-β negative aMCI (Aβ- N=48), and healthy participants (HP; N=41), within a well-characterized clinical cohort. Results: Aβ+ exhibited more pronounced consolidation impairments compared to Aβ-, while Aβ- faced more consolidation challenges than HP. Both Aβ+ and Aβ- were similar in hippocampal volume and entorhinal thickness, but Aβ+ had thinner inferior parietal cortex than Aβ-. Using 18F-fluoro-deoxyglucose-positron emission tomography, metabolism in both temporal and parietal regions was lower in Aβ+ relative to Aβ-. Conclusions: These findings suggest pathologies other than AD likely contribute to memory consolidation difficulties in aMCI, and neurodegeneration of the parietal cortex in combination with hypometabolism may contribute to more pronounced consolidation problems in Aβ+.
Pages 792-800
Julia-Sophia Scheuermann, Elmar Graessel, André Kratzer*, Petra Scheerbaum* *These authors share last authorship.
Mild behavioral impairment in people with mild cognitive impairment: Are the two conditions related?
Abstract: Background: Mild cognitive impairment (MCI) and mild behavioral impairment (MBI) are both considered potential prodromal stages of dementia, especially Alzheimer’s disease. Previous literature has lacked specific information about MBI in individuals with MCI and associations of several aspects of both, MBI and MCI. Objective: Our aim was to investigate whether associations exist between aspects of MBI and aspects of cognitive performance in certain dimensions of the Montreal Cognitive Assessment (MoCA). Methods: We used baseline data from the double-blind randomized controlled intervention MCI-CCT-study. Current cognitive performance of individuals with MCI was measured with the MoCA. MBI was assessed with the MBI Shortscale (MBI short), which was administered through a self-report interview. Associations were assessed with Pearson correlations. Sensitivity analyses were conducted for gender and cognition. Group differences were examined with independent samples t-tests or Welch test. Significant correlations were considered in binary logistic regressions under control of covariates. Results: There was no significant correlation between the current MoCA and MBI short scores in the total sample or in the gender-related analysis. Using dichotomized cognitive performance, significant correlations between MCI and MBI were revealed for individuals with lower MoCA scores. On the task level, several significant associations were identified between MoCA dimensions and MBI dimensions in the total sample and in the sensitivity analyses, also under control of covariates. Conclusions: Our findings support the hypothesis that with increasing cognitive decline, the association between MCI and MBI becomes stronger. Furthermore, a certain cut-off on the MoCA must be reached to identify a correlation.
Pages 801-814
Kai Shao, Xiao Chen, Xianfeng Yu, Jie Yang, Min Wei, Mingkai Zhang, Ruixian Li, Xuanqian Wang, Yongzhe Wei, for the SILCODE study group, Chaogan Yan, Ying Han (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Functional connectivity changes in two cortico-hippocampal networks of Alzheimer’s disease continuum and their correlations with cognition: A SILCODE study
Abstract: Background: The anterior-temporal (AT) and posterior-medial (PM) networks have been proposed to play pivotal roles in the memory processing associated with Alzheimer's disease (AD). Nevertheless, these two networks’ intrinsic functional coupling characteristics are still vague in different AD stages. Objective: To explore the functional connectivity (FC) alterations within and across the AT&PM networks in patients with dementia of the Alzheimer's type (DAT), mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal controls (NC). Methods: A total of 368 participants over 50 years old from the SILCODE study were recruited, including 99 NC, 134 SCD, 67 MCI, and 68 DAT patients. All the participants underwent a resting-state functional magnetic resonance imaging scan and a battery of neuropsychological tests. The 56 regions-of-interest of the AT&PM networks were defined broadly following existing literature. The FCs were calculated using DPABINet and compared among these four groups. Correlation analyses were performed on FCs and cognitive tests. Results: Analysis of variance of all four groups showed significant alteration, mainly in the PM networks. Compared to NC, globally decreased FCs regarding AT&PM networks were observed in DAT and MCI patients, while globally increased FCs regarding AT&PM networks were observed in SCD. The decreased FCs in DAT were significantly correlated with the neuropsychological test on the memory domain. Conclusions: The FC alteration showed different patterns across the AD continuum, especially in individuals with SCD. The elevated FCs in the AT&PM networks of SCD may implicate certain compensating processes in the early stage of AD.
Pages 815-829
Michael J Kleiman, James E Galvin
High frequency post-pause word choices and task-dependent speech behavior characterize connected speech in individuals with mild cognitive impairment
Abstract: Background: Alzheimer’s disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree. Objective: This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks. Methods: Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined. Results: Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs. Conclusions: Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.
Pages 830-840
Yanxin Zhang*, Chunxue Ji*, Yaping Meng, Yong He, Xiao Su, Wen Qin, Nan Zhang (Handling Associate Editor: Yi Tang) *These authors contributed equally to this work.
Altered neurovascular coupling in semantic variant primary progressive aphasia
Abstract: Background: Semantic variant primary progressive aphasia (svPPA) is one of the main clinical phenotypes of frontotemporal lobar degeneration. Changes in both neuronal activity and cerebral perfusion have been observed in svPPA, suggesting a possible breakdown of neurovascular coupling (NVC). Objective: To investigate alterations in NVC and their correlations with clinical manifestations in svPPA patients. Methods: In this study, a cohort consisting of 19 subjects diagnosed with svPPA and 36 cognitively unimpaired controls (CUCs) have been enrolled for analysis. All participants underwent multimodal magnetic resonance imaging (MRI) scans, resting-state functional MRI and arterial spin labelling, and neuropsychological assessments. The amplitude of low-frequency fluctuations (ALFF) and cerebral blood flow (CBF) were obtained to measure neural activity and perfusion, respectively. The calculation of voxel CBF-ALFF correlation and CBF/ALFF ratio enables the assessment of global NVC and regional NVC, respectively. Correlations between the CBF/ALFF ratios and cognitive scores of the svPPA patients were analyzed. The relationships between the CBF/ALFF ratios and the cognitive performance of the svPPA patients were investigated through correlational analyses. Results: Compared with CUCs, svPPA patients had decreased global CBF-ALFF correlation coefficients (p < 0.001) and lower CBF/ALFF ratios in bilateral inferior temporal gyrus, fusiform gyrus, left temporal pole and middle temporal gyrus (p < 0.05). In svPPA patients, the CBF/ALFF ratios in the left inferior and middle temporal gyrus correlated positively with naming ability and general cognition, respectively. Conclusions: The study indicate that NVC is disrupted in svPPA patients and is relevant to cognitive and language function.
Pages 841-854
Yu Fung Yau*, Irwin K Cheah*, Rathi Mahendran, Richard MY Tang, Ru Yuan Chua, Rachel E S Goh, Lei Feng, Jialiang Li, Ee Heok Kua, Christopher Chen, Barry Halliwell *These authors contributed equally to this work.
Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study
Abstract: Background: Dementia, particularly Alzheimer’s disease, is a major healthcare challenge in ageing societies. Objective: This study aimed to investigate the efficacy and safety of a dietary compound, ergothioneine, in delaying cognitive decline in older individuals. Methods: Nineteen subjects aged 60 or above with mild cognitive impairment were recruited for this double-blinded, randomized, and placebo-controlled study (ClinicalTrials.gov identifier: NCT03641404, registration date: 19/08/2018). Subjects received either ergothioneine (25 mg per capsule) or a placebo, taken 3 times a week for one year. The whole blood profile, markers of renal and liver functions, neurocognitive performance, plasma levels of ergothioneine and its metabolites, and plasma biomarkers related to neurodegeneration were measured across the study. Results: Ergothioneine intake did not alter clinical safety markers (blood counts, kidney and liver function) throughout the study, further validating its safety for human consumption. Subjects receiving ergothioneine demonstrated improved performance in assessment of learning ability and stabilized plasma levels of neurofilament light chain, compared with the placebo group, which saw no improvement in cognitive assessments and a significant increase in neurofilament light chain levels. Conclusions: Prolonged intake of ergothioneine showed no toxicity in older people. Enhanced Rey Auditory Verbal Learning Test performance and stabilized neurofilament light chain levels suggest improvements in memory and learning abilities and a deceleration of neuronal damage, respectively. Our results add to existing data that ergothioneine is safe for extended consumption and may hold the potential to delay cognitive decline in older adults.
Pages 855-865
Lan-Yang Wang*, Hao Hu*, Ze-Hu Sheng, He-Ying Hu, Zi-Hao Zhang, Lan Tan *These authors contributed equally to this work.
Associations among healthy lifestyle characteristics, neuroinflammation, and cerebrospinal fluid core biomarkers of Alzheimer’s disease in cognitively intact adults: The CABLE study
Abstract: Background: The occurrence of Alzheimer's disease (AD) can be partially prevented through healthy lifestyles, but the mechanisms associated with AD pathology are unclear. Objective: To explore associations among healthy lifestyle characteristics (HLCs), cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), and AD biomarkers. Methods: From the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, 924 cognitively normal participants were enrolled in this cross-sectional analysis. We defined the following 11 HLCs: appropriate frequencies of coffee and tea consumption, sufficient frequencies of fish and fruit intake, non-social isolation, adequate sleep, regular physical activity, no depression, never smoking, non-hazardous drinking, and well-maintained blood pressure. We categorized participants according to the number of HLCs reported by participants into favorable, intermediate, and unfavorable lifestyle groups. Multiple linear regression was used to investigate the relationship among HLCs, CSF sTREM2, and AD biomarkers. Mediation effects were tested using a causal mediation analysis having 10,000 bootstrap iterations. Results: Included subjects were with a mean age of 61.8 ± 10.2 years, of which 41.8% were female. Sufficient fish intake (β = −0.164, p = 0.017) and well-maintained blood pressure (β = −0.232, p = 0.006) were significantly correlated with lower CSF sTREM2 levels. A larger number of HLCs were associated with lower CSF T-tau (p = 0.001), P-tau (p = 0.012), and sTREM2 (p = 0.040) levels. CSF sTREM2 partially mediated the association between the number of HLCs and CSF tau pathology (mediating proportion T-tau: 22.4%; P-tau: 25.0%). Conclusions: HLCs might impact the pathological processes of AD by regulating neuroinflammation.
Pages 866-876
José María García-Alberca, Paz De La Guía, Esther Gris, Silvia Mendoza, María López De La Rica, José Antonio López-Trigo, Rosa López-Mongil, Teresa García-López, Raquel López-García, Teresa Rodríguez Del Rey, Javier Gay-Puente, Jesús García-Castro, Federico Casales, Xavier Morato, Mercè Boada, Gemma González-Velasco, José Manuel Marín-Carmona, Nora Inés Páez, María León, Rosario Carrillejo, Francisca Rius, Miguel Ángel Barbancho, José Pablo Lara, Encarnación Blanco-Reina
Real-world assessment of caregiver preference and compliance to treatment with twice-weekly versus daily rivastigmine patches in Alzheimer's disease
Abstract: Background: Adherence is critical in patients with Alzheimer’s disease (AD) in order to achieve optimal benefit from therapy. However, patient compliance with the treatment remains a challenge. Objective: To evaluate, in a real-world clinical setting, caregiver preference and treatment compliance with twice-weekly versus daily transdermal rivastigmine patch in mild-to-moderate AD. Methods: 92 patients who had been treated with daily rivastigmine patch for at least six months prior to switching to twice-weekly patch were evaluated. The change in therapeutic regimen was decided by the treating physician in accordance with standard practice. Caregivers’ satisfaction with daily rivastigmine patch was assessed at study entry. Caregiver’s preference and satisfaction with twice-weekly patch as well as patient compliance were evaluated at weeks 12 and 24 using the Alzheimer’s Disease Caregiver Preference Questionnaire. Results: A significantly higher proportion of caregivers expressed a preference for the twice-weekly patch over the daily patch (p<0.001), and this preference was found to be associated with ease of use (p<0.001), ease of following the schedule (p<0.001), and ease of compliance (p<0.001). Furthermore, caregivers were more satisfied with the twice-weekly patch (p<0.0001). At 24 weeks, patient compliance was significantly better with the twice-weekly patch than with the daily patch (p=0.002). Caregiver burden significantly improved at the end of the treatment (p=0.003). No serious adverse events were reported. Conclusions: The twice-weekly rivastigmine patch offers a convenient and straightforward dosing regimen for caregivers, with potential to enhance adherence with treatment in AD patients without causing serious adverse events.
Pages 877-884
Andrew M Kiselica, Kelly J Atkinas, S Duke Han, Unai Diaz-Orueta, Marissa A Gogniat, Alberto Blanco-Campal, Greta Hermann, Contributing Neuropsychologists, Kevin Duff
Reactions of clinical neuropsychologists to the Alzheimer’s Association workgroup’s draft diagnostic and staging criteria for Alzheimer’s disease
Abstract: Background: An Alzheimer’s Association (AA) workgroup published criteria for the diagnosis and staging of Alzheimer’s disease (AD). To date, there have not been empirical investigations of professionals’ opinions regarding the AA criteria for AD. Objective: Our goal was to survey clinical neuropsychologists with expertise in dementia about these criteria. Methods: Participants were recruited from a professional interest group of neuropsychologists focused on dementia. They rated their agreement with 15 statements about the AA draft criteria for AD prior to publication of the final version. The 15 statements were rated on a 4-point Likert scale ranging from 1=Strongly Disagree to 4=Strongly Agree. Results: Sixty-one respondents provided analyzable data. When all 15 statements were coded such that higher values suggested more concern about the recommendations, the mean rating was 3.12 (SD=0.36), suggesting that overall respondents had modest concerns about the recommendations. The statements that yielded the most concern focused on barriers to the implementation of the recommendations, including a lack of healthcare resources and costs of biomarker testing. Conversely, participants were equivocal about the criteria being a positive step forward and had mixed opinions about the applicability of these criteria to diverse groups. Conclusions: Opinions of neuropsychologists suggest the need for important revisions or additions to the AA criteria for AD, including a clearer statement of purpose and more guidance on practical implementation.