Review
Zhirong Liu*, BingShuang Hu*, Ju Tang*, XinLian Liu, BaoJing Cheng, Cui Jia, LuShun Zhang *These authors contributed equally to this work.
Frontiers and hotspots evolution between air pollution and Alzheimer’s disease: A bibliometric analysis from 2013 to 2023
Abstract: In recent years, the study of air pollution has received increasing attention from researchers, but a summary of Alzheimer’s disease (AD) and air pollution is missed. Through combing the documents in the core dataset of Web of Science, this study analyzes current research based on specific keywords. CiteSpace and VOSviewer perform statistical analysis of measurement metrics to visualize a network of relevant content elements. The research devotes discussion to the relationship between air pollution and AD. Keyword hotspots include AD, children, oxidative stress, and system inflammation. Overall, 304 documents on air pollution and AD from 2013 to 2023 were retrieved from Web of Science. One hundred twenty-two journals published relevant articles, and the number of articles has increased gradually since the past decade. Research and development in AD and air pollution are progressing rapidly, but there is still a need for more connections with multidisciplinary technologies to explore cutting-edge hotspots.
Review
Min Tang*, Jie-jie Guo*, Ron-gxia Guo*, Shu-jun Xu, Qiong Lou, Qiaoxia-Hu, Wan-yi Li, Jing-bo Yu, Qi Yao, Qinwen Wang (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Progress of research and application of non-pharmacologic intervention in Alzheimer's disease
Abstract: Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles formed by high phosphorylation of tau protein. At present, drug therapy is the main strategy of AD treatment, but its effects are limited to delaying or alleviating AD. Recently, non-pharmacologic intervention has attracted more attention, and more studies have confirmed that non-pharmacologic intervention in AD can improve the patient's cognitive function and quality of life. This paper summarizes the current non-pharmacologic intervention in AD, to provide useful supplementary means for AD intervention.
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.
Systematic Review
Xinyang Zhang, Renhua Lv, Yanqiu Sun, Timon Cheng-Yi Liu
The safety and effectiveness of 40 Hz γ-tACS in Alzheimer’s disease: A meta-analysis
Abstract: Background: The efficacy and safety of 40 Hz gamma transcranial alternating current stimulation (γ-tACS) in Alzheimer's disease (AD) are still uncertain. Objective: This meta-analysis was conducted to investigate the therapeutic potential and safety of 40 Hz γ-tACS for AD. Methods: The meta-analysis was conducted by systematically searching four databases from their start to 28 December 2023. Subgroup analyses were performed to identify the intervention effects of γ-tACS. Results: Of the 7 included studies, γ-tACS has a notable impact on improving overall cognition [standardized mean difference (SMD): 0.49, 95% CI: 0.09 to 0.89], memory (SMD: 0.79, 95% CI: 0.18 to 1.41), and cholinergic transmission (weighted mean difference: -0.40, 95% CI: -0.43 to -0.37). Furthermore, subgroup analysis revealed that γ-tACS treatment had a substantial impact on enhancing memory targeting the left angular gyrus in both home (SMD: 3.12, 95% CI: 1.54 to 4.70) and non-home settings (SMD: 0.53, 95% CI: 0.24 to 0.82). However, γ-tACS had a positive effect on overall cognition in non-home settings (SMD: 0.55, 95% CI 0.11 to 0.98), but not in home settings (SMD: 0.22, 95% CI -0.76 to 1.20). Additionally, targeting temporo-frontal or bitemporal γ-tACS treatment resulted in improvement in overall cognition (SMD: 0.61, 95% CI: 0.06 to 1.16), but not targeting the left angular gyrus (SMD: 0.22, 95% CI: -0.76 to 1.20). Conclusions: γ-tACS could be beneficial in enhancing cognition, memory and restoring cholinergic dysfunction in AD. The different selection of stimulation sites plays distinct roles. Meanwhile, AD patients are recommended to receive γ-tACS treatment at home.
Commentary
Ana-Maria Vranceanu, Claire Szapary
The partner paradox: How can we better understand shared cognitive decline in couples?
Abstract: Shared cognitive decline among spouses remains in the early stages of being understood. In this commentary, we discuss Meng et al.’s systematic review and meta-analysis, which synthesizes the evidence for concordance of cognitive decline in couples. The study’s methodology is robust and brings to light the challenges that persist within this field of research, namely the lack of specificity and standardization across outcomes and long-term follow-up. Here, we also situate the findings within the broader context of the many social influences on health and underscore the importance of dyadic preventive strategies and future longitudinal and mechanistic research.
Commentary
Guillaume Chapelet, Wendy Noble, Pascal Derkinderen
Microbiota and cognitive impairment: Current challenges and future perspectives
Abstract: Recent studies indicate that gut microbiota may play a crucial role in cognitive function. Individuals with cognitive impairment tend to have fewer beneficial gut bacteria and lower microbial diversity. Therefore, gut microbiota could be a potential biomarker for cognitive vulnerability. Further research is needed to understand the mechanisms and lifestyle factors affecting both microbiota composition and cognitive health. While the direct impact of microbiota and diet on cognitive impairment remains unconfirmed, this area holds promise for developing new preventive and treatment strategies.
Commentary
Stefania Gessi, Prisco Mirandola, Stefania Merighi
Keep neuroinflammation in mind when addressing Alzheimer’s disease: A microglia perspective
Abstract: This commentary offers a detailed examination of a newly published paper on the effects of small molecule decoys of amyloid-β (Aβ) aggregation on microglial activation. It was discovered that the NSC16224 decoy peptide inhibited proinflammatory cytokines TNF and IL6 release from microglia in response to Aβ40 and Aβ42 treatment. The research addresses the potential of blocking a sequence of events that lead to the progression of Alzheimer’s disease (AD). Here, we discuss the significance of these results in neuroinflammation, highlighting the greater implications for how decoy peptides would be interesting for the research and development of new drugs for AD therapy.
Editorial
Bilal Irfan, Abdallah Abu Shammala, Nour Alshaer, Elias Nasser, Muaaz Wajahath, Adam Hamawy, Mohammed Tahir, Haseeb Khawaja, Osaama Khan, Karim Fikry, Arshad Kaleem, Mosab Nasser, Khaled J. Saleh
There are dementia patients in Gaza too
Abstract: This editorial highlights the devastating impact of the ongoing Israeli military assault in Gaza on dementia patients, whose fragile care systems have collapsed, leaving them vulnerable and without essential medical support. Through harrowing stories of displacement, medication shortages, and tragic deaths, the piece underscores the profound moral failure in protecting Gaza's most vulnerable, calling for urgent global action to address the humanitarian crisis and ensure dignity and healthcare for all affected individuals.
Hainan Zhao, Hongxia Yuan, Ermin Wang (Handling Associate Editor: Guiyou Liu)
Causal effects of kidney function and chronic kidney disease on Alzheimer’s disease by analyzing large-scale genome-wide association study datasets
Abstract: Background: Alzheimer’s disease (AD) is the leading cause of dementia. Genetic components play an important role in AD and have been widely evaluated by genome-wide association studies (GWAS) and exome sequencing, and some common and rare genetic variants have been identified. In addition to genetic factors, environment factors have a role in AD. Growing evidence from observational studies linked impaired kidney function to cognitive impairment and AD; however, there are inconsistences in these findings. Objective: To determine the causal effects of impaired kidney function and chronic kidney disease (CKD) on AD. Methods: Mendelian randomization (MR) methods have been widely used to infer causal associations between exposure and outcome. Here, we conducted an MR study to investigate the causal effects of impaired kidney function and CKD on the risk of AD by analyzing large-scale GWAS datasets from FinnGen and CKD Genetics (CKDGen) Consortium. Results: We found no significant but a suggestive effect of CKD on decreased risk of AD using inverse-variance weighted (IVW) (p = 8.46E−02) and simple mode (p = 7.60E−02) methods. We identified a statistically significant effect of the estimated glomerular filtration rate (eGFR) on increased risk of AD using IVW (p = 1.11E−02), weighted median regression (p = 5.60E−03), and weighted mode (p = 2.45E−02) methods. Conclusions: Together, our findings indicate that high eGFR levels may increase the risk of AD. These findings need to be verified in future studies.
Marissa Ciesla*, Claudio Toro-Serey*, Ali Jannati, Russell E. Banks, Joyce Gomes-Osman, John Showalter, David Bates, Sean Tobyne, Alvaro Pascual-Leone *These authors contributed equally to this work.
Detecting functional impairment with the Digital Clock and Recall
Abstract: Background: Distinguishing between mild cognitive impairment (MCI) and early dementia requires both neuropsychological and functional assessment that often relies on caregivers' insights. Contacting a patient’s caregiver can be time-consuming in a physician’s already-filled workday. Objective: To assess the utility of a brief, machine learning (ML)-enabled digital cognitive assessment, the Digital Clock and Recall (DCR), for detecting functional dependence. Methods: We evaluated whether the DCR can help identify individuals at risk of functional deficits as measured by the informant-rated Functional Activities Questionnaire (FAQ) in older individuals including cognitively unimpaired, MCI, and dementia likely due to Alzheimer’s disease. Results: The DCR scaled well with FAQ scores, and ML classifiers trained on multimodal DCR features demonstrated strong performance in predicting functional impairment on a held-out test set. Differences in FAQ scores between DCR-predicted classes were comparable across key demographic groups. Conclusions: The DCR can streamline the clinical decision-making, triage, and intervention planning associated with functional impairment in primary care.
Lijun Zuo, Yang Hu, YanHong Dong, Raymond CS Seet, Zixiao Li, Yongjun Wang, Xingquan Zhao *These authors contributed equally to this work.
Pre-existing dementia is associated with 2-3 folds risk for in-hospital mortality and complications after intracerebral hemorrhage stroke
Abstract: Background: Pre-existing dementia was related to poor functional outcome after intracerebral hemorrhage (ICH), and its commonly underlying pathologies were considered as cerebral amyloid angiopathy. But the impact of pre-existing dementia on in-hospital mortality in Chinese ICH patients has not been well characterized. Objective: To investigate the association between pre-existing dementia and in-hospital mortality after ICH. Methods: Data were extracted from the China Stroke Center Alliance database. Information about the existence of prior to stroke dementia was obtained from next of kin informants and registered in clinical charts. Patients’ characteristics, in-hospital mortality, home discharge and complications were compared between ICH patients with and without pre-existing dementia. Results: Out of the 72,318 ICH patients, we identified 328 patients with pre-existing dementia. Patients with pre-existing dementia were more likely to experience greater stroke severity as measured by the National Institute of Health Stroke Scale and Glasgow Coma Scale. In the adjusted models, the presence of pre-existing dementia was associated with an increased risk of in-hospital mortality (OR 2.31, 95% CI 1.12-4.77), more frequent in-hospital complications of pulmonary embolism (OR 5.41, 95% CI 1.16-25.14), pneumonia (OR 1.58, 95% CI 1.08-2.33), urinary tract infection (OR 2.37, 95% CI 1.21-4.64), gastrointestinal bleeding (OR 2.39, 95% CI 1.27-4.49) and lower home discharge (OR 0.59, 95% CI 0.38~0.93). Conclusions: ICH patients with pre-existing dementia are more likely to suffer from greater stroke severity, poorer outcomes and lower home discharge. Future studies should evaluate the value of intensive risk factor control among individuals with pre-existing dementia for stroke prevention.
Chao Ren*, Wen-Qian Wang*, Hui-Hua Li*, Bing-Yu Li, Ke-Ning Shi, Li-Na Yang, Li-Na Guan, Min Kong, Mao-Wen Ba, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Valuing the importance of sex differences in prodromal Alzheimer’s disease based on structural magnetic resonance imaging
Abstract: Background: Alzheimer’s disease (AD) can be optimally managed from a healthcare point of view if detected at a prodromal stage. Amnestic mild cognitive impairment (MCI) is known as prodromal AD, has attracted extensive attention and research. Objective: To identify the differences in cognitive function and structural magnetic resonance imaging (MRI) features between men and women with MCI on the basis of A/T/N classification system ("A" means amyloid-β biomarker, "T" means tau biomarker, and "N" means neurodegeneration biomarker as determined by clinical imaging (e.g., positron emission tomography, magnetic resonance imaging (MRI)) or by the measurement of total tau protein (T-tau) in the cerebrospinal fluid (CSF)) and to further explore the correlation between them. Methods: 406 MCI subjects were selected from the Alzheimer’s Disease Neuroimaging Initiative database and divided into male and female MCI groups. Differences in demographic characteristics, biomarkers, cognitive assessment performance, and regions of interest (ROIs) of structural MRI were compared between the two groups. The correlations between brain structural changes quantified by MRI and cognitive abilities were investigated through linear regression models. Results: Compared with male MCI subjects, females had significantly higher T-tau concentration in CSF. There were significant differences in ROIs between the sex groups. In the male MCI group, the average cortical thicknesses of the right posterior cingulate, right anterior cingulate and right supramarginal gyrus were more closely correlated with cognitive function. In the female MCI group, the volume of the right rostral anterior cingulate, and the surface area and average cortical thickness of the right isthmus of the cingulate gyrus were more closely correlated with cognitive function. Conclusions: Based on A/T/N classification system, the structural MRI data analysis was closely correlated with the difference of cognitive function from patients with prodromal AD in a sex-dependent manner.
Lingling Zhou, Cui Zhang
Dietary protein intake interacts with weak handgrip strength and cognitive impairment
Abstract: Background: Handgrip strength correlates with cognitive function, but how gender and dietary protein interact with it is unclear. Objective: To investigate the relationship between handgrip strength and cognitive function among non-stroke elders, and potential interaction effects of gender and dietary protein. Methods: Non-stroke older adults with handgrip strength and cognitive tests available were included from National Health and Nutrition Examination Survey (NHANES) database. Multivariable linear regression analyses were used to explore the association between grip strength and cognitive performance. Multivariable logistic regression analyses were to investigate the effect of weak handgrip strength on cognitive impairment. Subgroup analyses were conducted to explore differences among sub-populations. Interaction effects of gender and protein intake were investigated by interaction analyses. Results: Larger handgrip strength was associated with preferable memory function in men (CERAD Word Learning sub-test: p=0.005; CERAD Delayed Recall: p=0.009), better verbal fluency (Animal Fluency test: p=0.005) and executive function in women (Digit Symbol Substitution Test: p=0.017). Weak handgrip strength was associated with cognitive impairment, especially in older, female, obese participants or elders with low protein consumption. Participants with weak grip strength, compared to normal strength, were twice as likely to perform poorly in complex cognition evaluations (odds ratio=2.01, p=0.028). Interaction effect of protein intake was observed (p-interaction=0.022). Compared to conditions of low protein intake, high protein intake significantly offset the impact of weak handgrip on cognitive impairment. Conclusions: The association between grip strength and cognitive performance varies by gender. Non-stroke elders with weak handgrip strength are vulnerable to cognitive impairment. Improving muscle strength and increasing protein intake may be effective to mitigate decline in executive function.
Hattapark Dejakaisaya, Runxuan Lin, Anna Harutyunyan, Jianxiong Chan, Patrick Kwan, Nigel C Jones (Handling Associate Editor: Ifrah Zawar)
Effect of ceftriaxone on the glutamate-glutamine cycle and seizure susceptibility of Tg2576 mouse model of Alzheimer’s disease
Abstract: Background: Individuals with Alzheimer’s disease (AD) have a heightened risk of epilepsy. However, the underlying mechanisms are not well-understood. Objective: We aimed to elucidate the role of the glutamate-glutamine cycle in this mechanism and test the effect of ceftriaxone, a glutamate transporter-1 (GLT-1) enhancer, on seizure susceptibility in the Tg2576 mouse model of AD. Methods: First, we assessed expression levels of key proteins in the glutamate-glutamine cycle in Tg2576 (n=7) and wild-type littermates (n=7), and subsequently in the kindling model of epilepsy (n=6) and sham (n=6). Then, kindling susceptibility was assessed in three groups: 200 mg/kg ceftriaxone-treated Tg2576 (Tg-Ceft, n=9); saline-treated Tg2576 (Tg-Sal, n=9); and saline-treated wild-type (WT-Sal, n=15). Mice were treated for seven days before kindling, and seizure susceptibility compared between groups. Results: Protein levels of GLT-1 (p=0.0093) and glutamine synthetase (p=0.0016) were reduced in cortex of Tg2576 mice, compared to WT. Kindling increased GLT-1 (cortex: p<0.0001, hippocampus: p=0.0075), and glutaminase (cortex: p=0.0044) protein levels, compared to sham. Both Tg-Ceft and WT-Sal displayed Class IV seizures in response to the first stimulation (p>0.99), while Tg-Sal displayed Class V seizure (p=0.0212 versus WT-Sal). Seizure susceptibility of Tg-Ceft was not different from Tg-Sal (p>0.05), and kindling rates did not differ between groups. Conclusions: Disruptions to key components of the glutamate-glutamine cycle are observed in models of AD and epilepsy. However, increasing GLT-1 through ceftriaxone treatment did not influence seizure susceptibility in Tg2576 mice, suggesting this is not an effective strategy to lower seizure susceptibility in AD, or a higher dosage is needed.
Aderonke Agboji, Shannon Freeman, Davina Banner, Joshua Armstrong, Melinda Martin-Khan (Handling Associate Editor: Carolyn Zhu)
The prevalence and risk factors of apathy among the Canadian long-term care residents with Alzheimer’s disease and related dementias
Abstract: Background: Apathy is a prevalent and debilitating neuropsychiatric symptom among persons living with Alzheimer's disease and related dementias, particularly those residing in long-term care facilities (LTCF). Despite its profound effects on the quality of life for both residents and their caregivers, apathy remains underrecognized and poorly understood in the context of dementia care. Objective: To investigate the prevalence and biopsychosocial characteristics of apathy among newly admitted residents with dementia in Canadian LTCF using an Apathy Index derived from the interRAI Minimum Data Set (MDS) 2.0. Methods: This cross-sectional study analyzed data from newly admitted residents with dementia from various LTCF (N=97,789) across seven Canadian provinces between 2015 and 2019. Logistic regression analysis was performed to determine the relationship between apathy and multiple variables including sociodemographic and clinical variables. The biopsychosocial model of health was used to guide analysis. Results: The prevalence rate of apathy among the Canadian long-term care residents with Alzheimer’s disease and related dementias was 13.1%. Apathy was associated with various variables including male sex, pain, use of psychotropics, high Activity of Daily Living Self-Performance Hierarchy Scale scores, depression, aggression, severe cognitive impairment, and insomnia. Preferences for certain activities such as card games, art and craft, reading, music and exercise were inversely related to apathy while gardening was not. Conclusions: By shedding light on this complex phenomenon within a Canadian context, we recommend that targeted interventions and improved care strategies to enhance the well-being of persons living with dementia should be prioritized in LTCF.
Ales Bartos, Sofie Diondet (Handling Associate Editor: Carlo Abbate)
Sensitive written hedgehog PICture Naming and Immediate Recall (PICNIR) as a valid and brief test of semantic and short-term episodic memory for very mild cognitive impairment
Abstract: Background: Semantic and short-term episodic memory are impaired in some brain disorders including Alzheimer’s disease. Objective: Development and validation of an almost self-administered, but cognitively demanding four-minute test identifying very mild cognitive impairment (vMCI). Methods: The innovative hedgehog PICture Naming and Immediate Recall (PICNIR) consists of two parts. The first task was to write down the names of 20 black-and-white pictures to evaluate long-term semantic memory and language. The second task involves immediate recall and writing the names of as many pictures as possible in one minute. The PICNIR is assessed using the number of naming errors (NE) and correctly recalled picture names (PICR). The PICNIR and a neuropsychological battery were administered to 190 elderly individuals living independently in the community. They were divided into those with vMCI (n=43 with Montreal Cognitive Assessment (MoCA) 24±3 points) and sociodemographically matched cognitively normal (CN) individuals (n=147 with MoCA 26±3). Both subgroups had predicted mean Mini-Mental State Examination scores of 28–29 points. Results: Compared to CN, vMCI participants made more NE (0.3±0.6 versus 0.6±0.9; p=0.02) and recalled fewer PICR (8.9±2.2 versus 6.8±2.2; p<0.000001). Discriminative validity was satisfactory using the area under the ROC curve (AUC): 0.76 for PICR, 0.74 for MoCA, 0.67 for MoCA-five-word recall, and 0.59 for NE. The AUCs of PICR and MoCA were comparable and larger than those of MoCA five-point recall or NE. Logical Memory scores, RAVLT scores, Digit symbol, and animal fluency correlated with PICR. Conclusions: The picture-based PICNIR is an ultra-brief, sensitive cognitive test valid for assessing very mild cognitive impairment. Its effectiveness should be validated for other languages and cultures.
Zachary T Goodman, Maria M Llabre, Sonya Kaur, Nikhil Banerjee, Katalina McInerney, Xiaoyan Sun, Anita Seixas Dias Saporta, Bonnie E Levin
Exploring heterogeneity in mild cognitive impairment
Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous diagnostic entity, without a clear prognosis, often accompanied by psychiatric symptomatology and physical frailty. Objective: Understanding the heterogeneity within MCI is a critical step in improving the early detection of cognitive decline and developing effective interventions. Methods: Cross-sectional multivariate latent mixture analyses of data from patients evaluated between 2015 and 2019, who were routinely entered into a multidisciplinary database for research purposes. A sample of 538 community-dwelling older adults drawn from a large academic medical center, referred from within the Department of Neurology (63.7% Female, Mage = 67.8, SDage = 10.6). Participants completed comprehensive neuropsychological assessments, psychiatric symptom measures, and frailty evaluations. Results: Latent profile analyses supported five profiles of cognitive impairment: At-Risk, Pre-MCI, Amnestic MCI, Multiple Domain MCI, and Major Cognitive Impairment. The inclusion of concomitant psychiatric symptoms and frailty criteria revealed two additional profiles: Psychiatric/Frail, without cognitive impairments, and Multiple Cognitive Domains/Psychiatric/Frail. Critically, 55% of those classified as Healthy based on cognitive data alone were reclassified. Significant profile-wise differences emerged across auxiliary variables of brief cognitive screening, sociodemographics, and medical and psychosocial risk. Conclusions: Results highlight heterogeneity represented by neurologic patients referred for cognitive evaluation that include key physical and emotional symptoms known to increase the risk of cognitive decline. Findings are in alignment with more recent research suggesting that the traditional paradigm cognitive impairment may need to be expanded to improve diagnostic accuracy and to develop more tailored, precision-driven interventions.
Jonathas Rodrigo dos Santos, Carlos Henrique Rocha Catalão, Anderson Vulczak, Ana Elisa Caleiro Seixas Azzolini, Luciane Carla Alberici
Voluntary wheel running decreases amyloidogenic pathway and rescues cognition and mitochondrial energy metabolism in middle-aged female 3xTg-AD mouse model of Alzheimer’s disease
Abstract: Background: Evidence supports the neuroprotective effects of physical activity, either in experimental animal models or humans. However, the biological mechanisms by which physical exercise modulates dementia and Alzheimer’s disease (AD) progression are still unclear. Objective: This study investigated whether long-term (6 months) of voluntary wheel running induces neuroprotective effects in the pathogenesis of AD in middle-aged (8 months) female mice, focusing on energy metabolism. Methods: A genetic mice model of AD (3xTg-AD) that performed wheel running presented changes in body metabolism and muscle oxidative profile, as well as restored discriminative and non-associative retention memories, evaluated by novel object recognition and open field tasks, respectively. Results: In the hippocampus, these mice exhibited reduced levels of amyloidogenic AβPPβ fragment, phospho-Tau protein and phospho-Akt (activated form), without changes in phospho-AMPK (activated form). In addition, hippocampal mitochondria presented a restored respiratory function, characterized by lower coupling degree and weak contribution from complex I found in 3xTg-AD mice. Conclusions: The results demonstrated that voluntary exercise improves cognitive parameters and biochemical hallmarks of AD, modulates Akt activation and enhances mitochondrial energy metabolism in hippocampus of middle-aged 3xTg-AD female mice, thereby reinforcing the neuroprotective role of physical exercise and the involvement of mitochondria in the etiology of the AD.
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.
Huifeng Chen*, Lijun Wang*, Feifan Chen, Wenhao Sun, Siqi Wang, Nan Zhang (Handling Associate Editor: Jia Liu) *These authors contributed equally to this work.
Performance of the Benton Judgment of Line Orientation test across patients with different types of dementia
Abstract: Background: The Benton Judgment of Line Orientation (JLO) test is one of the most frequently used tests for assessing visuospatial function. Objective: This study aimed to determine the diagnostic and differential performance of JLO for different types of dementia. Methods: A total of 258 participants, including 68 patients with Alzheimer’s disease (AD), 86 with subcortical ischemic vascular dementia (SIVD), 30 with frontotemporal lobar degeneration (FTLD), 22 with Lewy body dementia (LBD), and 52 cognitively unimpaired (CU) controls, were enrolled from a memory clinic. The total scores and error types in the JLO test were compared between groups. Receiver operating characteristic curve analyses were used to estimate the diagnostic and differential abilities of the JLO test for patients with different types of dementia. Results: We found that the JLO score was significantly lower in patients with AD, SIVD, FTLD, or LBD than in CU controls (12.90 ± 8.72 versus 17.06 ± 6.14 versus 15.47 ± 8.39 versus 9.23 ± 8.96 versus 21.69 ± 3.72, respectively; all p < 0.05). In particular, for patients with LBD, the JLO score was significantly lower than that for patients in the other groups (all p <0.05) and showed excellent performance in distinguishing LBD patients from CU controls, with an AUC of 0.888 (sensitivity 72.73% and specificity 94.23%) at a cutoff value of 16. Intraquadrant oblique error was the most common type of error in dementia patients. Conclusions: The JLO test is an effective tool for evaluating visuospatial function in patients with dementia, particularly for identifying LBD patients.
Claudia L Satizabal, Jayandra Jung Himali, Sarah C Conner, Alexa S Beiser, Pauline Maillard, Ramachandran S Vasan, Charles DeCarli, Sudha Seshadri (Handling Associate Editor: Melissa Lamar)
Circulating adipokines and MRI markers of brain aging in middle-aged adults from the community
Abstract : Background: Midlife obesity is related to late-onset dementia. Studying adipose tissue-secreted adipokines in the context of brain aging may help us understand this association. Objective: To investigate associations between adipokines and brain MRI markers in middle-aged adults from the Third-Generation cohort of the Framingham Heart Study. Methods: Serum adiponectin, retinol-binding protein 4 (RBP4), fetuin-A, and Fatty Acid-Binding Protein 4 (FABP4) concentrations were measured by enzymatic immunoassays. MRI measures included total brain, cortical gray matter, hippocampal (total and anterior), lateral ventricular, and white matter hyperintensity volumes. We used linear regression models to separately relate adipokine concentrations to MRI measures, adjusting for potential confounders. Results: We included 1882 participants (mean age of 48±8 years, 54% women). Higher RBP4 concentrations were related to markers of brain atrophy, including smaller total (Beta ± standard error, -0.05±0.02; p=0.014) and cortical gray brain volumes (-0.06±0.02; p=0.004), and larger lateral ventricular volumes (0.06±0.02; p=0.006). Additionally, higher RBP4 (-0.06±0.03; p=0.042), Fetuin-A (-0.06±0.03; p=0.039), and FABP4 (-0.09±0.03; p=0.008) concentrations were associated with smaller anterior hippocampal volumes. Most associations remained after additional adjustment for vascular risk factors. In exploratory analyses, higher FABP4 was related to larger total brain in non-obese participants, and to smaller anterior hippocampal volumes in obese participants. Finally, higher adiponectin concentrations were related to smaller cortical gray, only in non-obese participants. Conclusions: Our results suggest that adipokines are associated with markers of brain atrophy during midlife. Further studies are needed to replicate these findings and elucidate any potential mechanisms contributing to abnormal brain aging.
Shu-Ping Chao, Wei-Che Lin, Cheng-Hsien Lu, Hsiu-Chuan Wu, Hsing-Cheng Liu, Chaur-Jong Hu
Changes in plasma biomarkers differentiate clinical stages of Alzheimer’s disease using immunomagnetic reduction assays
Abstract: Background: Many groups have been using immunomagnetic reduction (IMR) for assaying plasma amyloid-β 1-40 (Aβ1-40) peptide, Aβ1-42 peptide and total tau protein (T-Tau) in cognitively normal controls (NC), patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease dementia (ADD). Tremendous results have been independently reported. Objective: We used traditional knowledge databases (e.g., PubMed, Embase), papers published at international conferences, and private communications to obtain data involving the use of IMR assay for plasma biomarkers of plasma Aβ1-40, Aβ1-42, and T-Tau in NC, aMCI, and ADD. Methods: Results of thirty studies were analyzed, including twenty-five studies published in papers, two studies presented at conferences and three unpublished studies. Results: Among the thirty studies, there were 1189 subjects of NC, 544 aMCI patients and 853 ADD patients. The average value of plasma Aβ1-40 in subjects significantly decreased from NC (59.72 pg/ml) to aMCI (45.92 pg/ml, p < 0.0001), which was no significant different from ADD (48.34 pg/ml, p > 0.05). The average level of plasma Aβ1-42 significantly increased from NC (15.72 pg/ml) to aMCI (17.66 pg/ml, p < 0.0001), which was not significantly different from ADD (19.39 pg/ml, p > 0.05). However, the average level of plasma T-Tau significantly increased from NC (17.92 pg/ml) to aMCI (28.26 pg/ml, p < 0.0001), further significantly increased to AD (35.51 pg/ml, p < 0.001). Conclusions: Plasma Aβ1-40, Aβ1-42, and T-Tau levels are able to discriminate NC from patients with aMCI and ADD. Plasma T-Tau levels are disease-severity dependent.
Minmin Pan, Dongbing Lai, Frederick Unverzagt, Liana Apostolova, Hugh C Hendrie, Andrew Saykin, Tatiana Foroud, Sujuan Gao
Genetic variants for Alzheimer’s disease and comorbid conditions
Abstract: Background: Alzheimer’s disease and related dementias (ADRD) frequently co-occur with comorbidities such as diabetes and cardiovascular diseases in elderly populations. Objective: Utilize a life-course approach to identify genetic variants that are associated with the co-occurrence of ADRD and another comorbid condition. Methods: Research data from African American participants of the Indianapolis-Ibadan Dementia Project (IIDP) linked with electronic medical record (EMR) data and genome-wide association study (GWAS) data were utilized. The age of onset for ADRD was obtained from longitudinal follow-up of the IIDP study. Age of onset for comorbid conditions was obtained from EMR. The analysis included 1,177 African Americans, among whom 174 were diagnosed with ADRD. A semi-parametric marginal bivariate survival model was used to examine the influence of single nucleotide polymorphisms (SNPs) on dual time-to-event outcomes while adjusting for sex, years of education, and the first principal component of GWAS data. Results: Targeted analysis of 20 SNPs that were reported to be associated with ADRD revealed that six were significantly associated with dual-disease outcomes, specifically congestive heart failure and cancer. In addition, eight novel SNPs were identified for associations with both ADRD and a comorbid condition. Conclusions: Using a bivariate survival model approach, we identified genetic variants associated not only with ADRD, but also with comorbid conditions. Our utilization of dual-disease models represents a novel analytic strategy for uncovering shared genetic variants for multiple disease phenotypes.
Noah Cook, Ira Driscoll, Julian M Gaitán, Matthew Glittenberg, Tobey J Betthauser, Cynthia M Carlsson4, Sterling C Johnson, Sanjay Asthana, Henrik Zetterberg, Kaj Blennow, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Dena B Dubal, Ozioma C Okonkwo
Amyloid-β positivity is less prevalent in cognitively unimpaired KLOTHO KL-VS heterozygotes
Abstract: Background: Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VSHET) is hypothesized to be protective against the accumulation of Alzheimer’s disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau). Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A+T-), tau (A-T+), both (A+T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk. Methods: The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; MeanAge(SD)=64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; MeanAge(SD)=66.8(7.4). Covariate-adjusted logistic regression examined whether A+ or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status. Results: A+ prevalence was lower in KL-VSHET (p=0.05), with no differences in T+ prevalence (p=0.52). KL-VSHET also had marginally lower odds of being A+T- (p=0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps≥0.40). Conclusions: KL-VSHET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD.
Caleigh A Findley, Samuel A McFadden, Tiarra Hill, Mackenzie R Peck, Kathleen Quinn, Kevin N Hascup, Erin R Hascup
Sexual dimorphism, altered hippocampal glutamatergic neurotransmission, and cognitive impairment in APP knock-in mice
Abstract: Background: It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer’s disease (AD) progression, contributing to negative cognitive outcomes. Objective: In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F). Methods: At 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Results: Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. Conclusions: These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.
Krista M Schroeder, Ana Sofia Afonso, Huabo Wang, Sarah Grace, Adam Phipps, John R Sims
Demographics, comorbidities, and comedications in newly diagnosed patients with Alzheimer’s disease and related dementias: Findings from United States Medicare claims data
Abstract: Background: Medicare claims data enables broad characterization of United States (US) patients with Alzheimer’s disease and related dementias (ADRD). Resulting insights can be used as a reference to describe this population and as a benchmark for generalizability of patients with ADRD enrolled in clinical trials. Objective: To characterize demographics, comorbidities, comedications, and healthcare resource utilization in US patients with newly diagnosed ADRD, focusing on differences across Medicare fee-for-service (FFS) and Medicare Advantage enrollees. Methods: This observational cohort study used complete (100%) Medicare claims data inclusive of both FFS and Medicare Advantage insurance types. Study patients were ≥65-years-old with ≥12 months of continuous pre-index enrollment and Medicare Part D coverage. Two cohorts of patients were selected in calendar year 2019; those newly diagnosed with ADRD and those with a new acetylcholinesterase inhibitor (AChEI) claim. Results: The newly diagnosed ADRD and new AChEI users cohorts included 861,727 and 395,319 patients, respectively. Demographics and comedications were generally similar across the two cohorts, supporting internal validity of the study results. Circulatory system-related comorbidities and mood disorders were common in both cohorts. Differences in race and inpatient and long-term care claims were observed between insurance types. Conclusions: The study results provide a reference for describing the ADRD population in the US and emphasize the importance of evaluating new Alzheimer’s disease drugs in broad patient populations with comorbidities and concomitant medication use.
Saloni Behl, Mary Slomkowski, Dalei Chen, Denise Chang, Nanco Hefting, Daniel Lee, Alpesh Shah, Alvin Estilo, Uwa Kalu, Mary Hobart
Brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer’s disease: A 12-week, active-treatment, extension trial
Abstract: Background: A 12-week randomized controlled trial demonstrated that brexpiprazole is efficacious for treating agitation in patients with Alzheimer’s disease. Objective: To assess the long-term safety and tolerability of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer’s disease. Methods: This 12-week, active-treatment (oral brexpiprazole 2 or 3 mg/day) extension trial ran from October 2018–September 2022 at 66 sites in Europe/US. Patients with agitation in Alzheimer’s disease in a care facility/community-based setting who completed the randomized trial were eligible (N=259 enrolled/analyzed for safety; 88.4% completed). Stable Alzheimer’s disease medications were permitted. The primary safety endpoint was the frequency and severity of treatment-emergent adverse events (TEAEs). Change in Cohen-Mansfield Agitation Inventory (CMAI) total score was an exploratory efficacy endpoint. Results: Mean (SD) age was 74.3 (7.6) years, 145 patients (56.0%) were female, and 248 (95.8%) were White. TEAEs were reported by 67 patients (25.9%), most commonly headache (3.5%) and fall (2.3%). Most TEAEs were mild or moderate in severity; 5 patients (1.9%) reported a severe TEAE, including 3 severe falls attributed to tripping, misjudging sitting, or dehydration. Twelve patients (4.6%) discontinued due to TEAEs. No patients died. Mean CMAI total score improved by 9.1 points over 12 weeks. Conclusions: Considering the randomized and extension trials together, brexpiprazole 2 or 3 mg was generally well tolerated for up to 24 weeks in elderly patients with agitation associated with dementia due to Alzheimer’s disease. Patients showed continued improvement in agitation.
