Review
Yuhan Nong, Jung Soo Kim, Litian Jia, Ottavio Arancio, Qi Wang (Handling Associate Editor: Subodh Kumar)
The interaction between neurotransmitter receptor activity and amyloid-β pathology in Alzheimer’s disease
Abstract: The accumulation of amyloid-β (Aβ) peptides is a hallmark of Alzheimer’s disease (AD). Central to AD pathology is the production of Aβ peptides through the amyloidogenic processing of amyloid-β protein precursor (AβPP) by β-secretase (BACE-1) and γ-secretase. Recent studies have shifted focus from Aβ plaque deposits to the more toxic soluble Aβ oligomers. One significant way in which Aβ peptides impair neuronal information processing is by influencing neurotransmitter receptor function. These receptors, including adrenergic, acetylcholine, dopamine, 5-HT, glutamate, and gamma-aminobutyric acid (GABA) receptors, play a crucial role in regulating synaptic transmission, which underlies perceptual and cognitive functions. This review explores how Aβ interacts with these key neurotransmitter receptors and how these interactions contribute to neural dysfunction in AD. Moreover, we examine how agonists and antagonists of these receptors influence Aβ pathology, offering new perspectives on potential therapeutic strategies to curb AD progression effectively and improve patients' quality of life.
Review
Xiaoyuan Meng, Yong Gong, Fengxin Xiao, Zhao Cao, Zheyu Zhuang, Xinan Yi, Juan Wang, Renjun Feng, Chunmei Gong, Panli Ni
Curcumin’s multi-target mechanisms in the treatment of Alzheimer’s disease and creative modification techniques
Abstract: Alzheimer's disease (AD) is a well-established neurodegenerative disorder characterized by memory impairment, cognitive dysfunction, and behavioral disturbances. With the global population aging, the prevalence of AD continues to rise, presenting significant challenges to both society and healthcare systems. Curcumin, a polyphenolic compound derived from turmeric rhizomes, has demonstrated considerable potential in AD treatment due to its anti-inflammatory, antioxidant, and neuroprotective properties. However, its clinical application remains constrained by chemical instability, poor water solubility, rapid metabolism, and accelerated elimination. To overcome these limitations, various curcumin derivatives have been synthesized, and combination therapy strategies have been explored. This review examines the potential mechanisms through which curcumin may exert therapeutic effects in AD, including the inhibition of neuroinflammation, regulation of tau protein hyperphosphorylation, modulation of amyloid-β peptides, and provision of antioxidant benefits. Additionally, the advantages of curcumin derivatives and combination therapy approaches are discussed, offering novel perspectives and promising strategies for AD treatment. It is anticipated that advancements in drug design and therapeutic approaches will contribute to the development of more effective treatment options for AD.
Review
Luca Tagliafico, Elena Bogliacino, Stefano Raffa, Nicola Girtler, Andrea Brugnolo, Pietro Mattioli, Dario Arnaldi, Valentina Marozzi, Gabriele Giacomini, Alessio Nencioni, Gianluca Serafini, Paolo Nozza, Fabio Gotta, Paola Mandich, Stefano Pretta, Ilaria Gandoglia, Massimo Del Sette, Luca Sofia, Mehrnaz Hamedani, Luca Roccatagliata, Mattia Losa, Gabriella Biffa, Lucia Argenti, Paola Castellini, Lorenzo Lombardo, Luigi Lorenzini, Carlo Serrati, Martina Pulze, Gianmario Sambuceti, Giulia Bozzo, Silvia Daniela Morbelli, Angelo Schenone, Federico Massa, Virginia Pelagotti, Wendy Kreshpa, Fiammetta Monacelli, Beatrice Orso#, Matteo Pardini#, Disease Management Team on Dementia of the IRCCS Ospedale Policlinico San Martino #These authors contributed equally to this work.
How can we define a brain health chart? A narrative review and a proposal
Abstract: In recent years, there has been a significant change in the type of patients referred to memory clinics, characterized by an increase in mildly symptomatic individuals and potentially even healthy people at risk of cognitive decline due to Alzheimer's disease and other neurodegenerative diseases in this context. Additionally, there is growing interest in developing health services focused on brain health throughout the lifespan, particularly within a primary prevention framework. This effort has led to proposing dedicated “brain health services” for dementia risk reduction. However, in the context of cognitive disorders, distinguishing between primary and secondary prevention poses significant challenges, particularly in identifying individuals within the general population who may exhibit subtle cognitive decline or early-stage neurodegeneration. We propose seven key dimensions for assessing “brain health”: cognitive reserve along with social and functional status, cognitive decline, mood and sleep disorders, general dementia risk factors, geriatric syndromes in older adults, structural brain damage, and neurodegenerative proteinopathies. Together, these dimensions form a comprehensive "brain health chart”. We review the known evidence for each dimension's role in assessing brain health, emphasizing approaches that can be applied in a community setting. We believe that by identifying broadly applicable assessment methods for these dimensions, the development of personalized strategies for maintaining brain health could be facilitated.
Systematic Review
Pinya Lu#, Mingfeng Chen#, Lili Chen, Fan Lin, Hongqin Yang, Yuhua Wang, Xuemei Ding (Handling Associate Editor: Yasunori Yamada) #These authors contributed equally to this work.
Translational computerized clinical decision support systems for Alzheimer’s disease: A systematic review
Abstract: Background: Alzheimer's disease (AD), marked by progressive memory loss and cognitive decline, poses diagnostic challenges due to its multifactorial nature. Therefore, researchers are increasingly leveraging artificial intelligence and data-driven approaches to develop computerized clinical decision support systems (CCDSS), aiming to enhance early detection, improve treatment, and slow disease progression. Objective: This study seeks to conduct a systematic review of the most recently developed AD-CCDSS, delving into their progress and the challenges to guide future development and implementation of CCDSS for AD-related decision-making and intervention strategies. Methods: We follow the PRISMA 2020 guideline to search for articles published within the past seven years across PubMed, ScienceDirect, IEEE Xplore Digital Library, Web of Science, and Scopus, with Google Scholar as a supplementary source. Key components are then extracted from the selected studies for qualitative analysis, including data modalities, computational modeling approaches, system explainability and interpretability, research priorities, and graphical user interfaces designed for non-technical stakeholders. Results: After searching and removing duplicates, we meticulously selected 55 studies. After reviewing key components of CCDSS, we highlight advancements and potential clinical applications, demonstrating their promise in enhancing decision support. However, despite growing attention to explainability in AD-CCDSS, its clinical applicability remains limited. Moreover, challenges such as multi-center system interoperability and data security remain underexplored, hindering real-world implementation. Conclusions: This study analyzes recent translational AD-CCDSS, identifying key challenges in advancing CCDSS for clinical applications. It offers insights for researchers to enhance CCDSS development and facilitate their integration into clinical practice.
Systematic Review
Clément Rimlawi, Abdoul Razak Sawadogo, Gilles Kehoua, Caroline Gayot, Achille Tchalla
Health economic assessment of technologies for preventing cognitive impairment in elderly people living at home: The case of the digital tablet combined with human support
Abstract: Background: The study addresses the challenges of cognitive impairment in an aging population, focusing on the health economic assessment of technologies used by community-dwelling older adults to support cognitive function. Objective: To conduct a systematic review of economic evaluations of digital tablets combined with human support in preventing cognitive impairment in elderly people living at home. Methods: The following databases were used: PubMed, Scopus, Science Direct, Cochrane library. A total of 45 articles from 2000 to 2024 were identified and screened following the PRISMA guidelines. Results: One protocol study and one randomized control trial were included. Conclusions: The economic evaluation of tablet-based digital intervention for older adults with cognitive impairments is underexplored, necessitating broader research on technology use in this area.
Systematic Review
Giulia Perini, Matteo Cotta Ramusino, Marco Vergani, Alberto Gatti, Camillo Imbimbo, Silvia Leone, Elena Ballante, Nicola Allegri, Fabrizia D’Antonio, Marta Zuffi, Simone Pomati, Elisabetta Farina, Lucio Tremolizzo, Alfredo Costa, for the SINdem BPSD Study Group (Handling Associate Editor: Teruyuki Matsuoka)
BIOmarkers in NEuropsychiatric SYmptoms (BIONESY): A multicenter nation survey and a systematic review
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) have poorly understood pathological/morphological correlates. Objective: We aimed to 1) investigate the perception of the utility of different biomarkers in the assessment of BPSD among Italian Memory Clinics and 2) review current literature in this regard. Methods: A multicenter, national survey was launched by the BPSD Study Group of the Italian Neurological Society for Dementia (SINdem). Participants completed a semi-structured questionnaire on their perception of possible associations between the occurrence/severity of different BPSD and different biomarkers, based on their individual knowledge and clinical experience, regarding any type and severity of cognitive impairment. Then, we performed a systematic review according to PRISMA guidelines. Only papers reporting biomarkers correlates of BPSD in neurocognitive disorders were included. Results: Among the 53 responders, 94%, 68%, 68%, and 45% perceived neuropsychological testing, MRI, FDG-PET, and EEG, respectively, associated with the total amount of BPSD. EEG alterations were perceived selectively associated with nighttime behavior disturbances and psychosis cluster (p<0.01). Hallucinations, apathy and delusions were perceived as more correlated with biomarkers. Years of experience using biomarkers for diagnosis were associated with a more selective use of topographical biomarkers (p<0.01). 91% of participants consider useful increasing the use of biomarkers to predict the occurrence/severity of BPSD. The literature review identified 99 eligible studies. Brain MRI (60 articles) and FDG-PET (12 studies) alterations are the most associated with BPSD. Conclusions: In clinical practice, topographical biomarkers related to regional consequences of the pathology are perceived as potentially informative in the BPSD’s assessment.
Short Communication
Paolo Salvioni Chiabotti, Mirco Nasuti, Olivier Rouaud, Gilles Allali
Posterior cortical atrophy in the age of anti-amyloid treatments: An 11-year retrospective study of eligible patients from the Leenaards Memory Center
Abstract: At the era of the anti-amyloid treatments (AAT), it is striking to note posterior cortical atrophy (PCA) cases, the most predictive phenotype of Alzheimer’s disease neuropathology, have not been explicitly included or excluded from clinical trials. In a retrospective analysis of the Lausanne Memory Center registry, we identified 41 PCA cases and, applying the recent appropriate use recommendations for lecanemab, estimate a high (20%) eligibility rate, that doubles in pure PCA phenotypes with biomarker work-up available (40%). This high proportion of PCA patients eligible for AAT should prompt a timely exploration to assess inclusion/exclusion criteria for these novel therapies.
Short Communication
Daiki Ishimaru, Yuto Satake, Hideki Kanemoto, Daiki Taomoto, Maki Hotta, Yuma Nagata, Kunihiko Katsuki, Manabu Ikeda
Thieves in the delusions of theft in patients with Alzheimer’s disease living alone: A case series
Abstract: This study explored the phenomenology of theft delusions in four female patients with Alzheimer’s disease (AD) living alone, aiming to understand its psychological relevance. Caregivers participated in semi-structured interviews to assess delusion phenomenology, while patients were evaluated on their aging perceptions and life values. In three cases, the primary persecutor was a family member involved in managing finances, whereas the persecutor in the fourth patient who managed finances independently was a specific neighbor. Thieves in the delusion of theft in patients with AD living alone were likely to be persons who helped in the management of money or property.
Short Communication
Janardan P Pandey, Christine Kimball, Paul J Nietert
Epistatic effects of immunoglobulin KM (κ Marker) allotypes and APOE ε4 allele on the risk of Alzheimer’s disease
Abstract: We investigated whether immunoglobulin KM (κ marker) allotypes were associated with Alzheimer’s disease (AD) individually and/or epistatically with APOE ε4, the strongest known genetic susceptibility factor for the disease. Results showed a significant (p=0.01) interaction between KM and APOE ε4. In KM 3/3 homozygotes, APOE ε4 was strongly associated with AD (OR = 8.3); however, in non-KM 3/3 subjects, the association between APOE ε4 and AD was markedly lower (OR = 0.9) and non-significant. If confirmed, these results may identify a subgroup of the population with a markedly higher risk of developing AD, who might require a different preventive/treatment strategy.
Short Communication
Nathan HM Friedman, Sophie Hallot, Inbal Itzhak, Richard Camicioli, Alex Henri-Bhargava, Jacqueline A Pettersen, Linda Lee, John D Fisk, Paula McLaughlin, Vladimir Khanassov, Zahinoor Ismail, Morris Freedman, Howard Chertkow, Philippe Desmarais, Megan E O’Connell, Maiya R Geddes
Red flags for remote cognitive diagnostic assessment: A Delphi expert consensus study by the Canadian Consortium on Neurodegeneration in Aging
Abstract: Despite the potential benefits of remote cognitive assessment for dementia, it is not appropriate for all clinical encounters. Our aim was to develop guidance on determining a patient’s suitability for comprehensive remote cognitive diagnostic assessment for dementia. A multidisciplinary expert workgroup was convened under the auspices of the Canadian Consortium on Neurodegeneration in Aging. We applied the Delphi method to determine ‘red flags’ for remote cognitive assessment of dementia. This resulted in 14 red flags that met the predetermined consensus criteria. We then developed a novel clinical decision-making infographic that integrated these findings to support multidisciplinary clinicians in determining a patient’s readiness to undergo comprehensive remote cognitive assessment.
Commentary
Sim K Singhrao
Porphyromonas gingivalis-lipopolysaccharide and amyloid-β: A dangerous liaison for impairing memory?
Abstract: Alzheimer’s disease is characterized by declining memory and the presence of insoluble amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. Gui et al.1 studied the effects of low levels of Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) and soluble Aβ on synaptic proteins, synapsin1 (SYN1) and post-synaptic density protein-95 (PSD-95). Their study revealed increased proinflammatory cytokine production in microglial cells (MG6) treated with P. gingivalis-LPS and Aβ, while neuronal cells, N2a, exposed to MG6-conditioned medium showed SYN1 and PSD-95 loss. This suggests that excessive neuroinflammation may contribute to synaptic protein and memory loss, offering mechanistic insights into P. gingivalis-LPS-mediated inflammatory pathways in periodontitis.
Ethics Response
Bilal Irfan, Elijah Wiseman, J Wesley Boyd, Jonathan Reader, Annalise Rahman-Filipiak
Toward a person-centered return of research results of dementia risk: A pluralistic, constructive expansion
Abstract: Graham et al.’s article offers a thoughtful account of why disclosing modifiable dementia risk factors to cognitively unimpaired research participants may be ethically defensible. In this Ethics Response, we seek to engage constructively with their arguments, affirming value in a person-centered approach, while also expanding on how cultural, communal, and religious contexts can further illuminate the ethics of returning individual research results. Drawing on emerging ethical issues and examples from diverse settings, this response highlights how stigmatization, religious worldviews, family care traditions, and broader socioeconomic factors may influence the perceived meaning and impact of dementia risk communication.
Kevin M Knox, Stephanie Davidson, Leanne M Lehmann, Erica Skinner, Alexandria Lo, Suman Jayadev, Melissa Barker-Haliski
Alzheimer’s disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine efficacy in aged mice
Abstract: Background: Alzheimer’s disease (AD) patients are at greater risk of focal seizures than similarly aged adults, which may accelerate cognitive decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled model of chronic seizures allows for precisely timed drug administration studies to expediently screen for efficacy and tolerability of investigational treatments in AD-associated mouse models. Objective: We hypothesized that mechanistically distinct ASMs would differentially control seizures of aged AD mice (9-14 months), thereby informing rational ASM selection for AD. Methods: PSEN2-N141I and APPswe/PS1dE9 mice underwent corneal kindling at 9-14 months old to quantify latency to kindled criterion versus matched wild-type mice. Dose-related response to commonly prescribed ASMs for older adults with epilepsy (valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin) was then assessed. Results: Sex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more kindling stimulations to reach criterion (χ2=5.521; p<0.05). Male APP/PS1 mice were no different in kindling rate versus controls, but did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive to valproic acid and lamotrigine. Conclusions: AD genotypes may differentially impact ASMs activity in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD to slow cognitive decline.
Yue Shi, Ying Tang, Ya Wang, Xiao Fei, Xiaoyan Xu, Yi Zhang (Handling Associate Editor: Joshua Ehrlich)
Investigating the relationship between visual impairment and cognitive impairment in the older adults using the novel Vision Screening Assessment (VISA) Tool
Abstract: Background: Early identification and multimodal treatment of dementia, especially Alzheimer's disease, is a common goal of global efforts. Objective: This study aims to investigate the relationship between visual impairment (VI) and cognitive impairment in older adults using the Vision Screening Assessment (VISA) tool. Methods: A total of 94 healthy older adults from community settings in Changzhou were recruited for the study. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Clock Drawing Test (CDT). The VISA tool was employed to evaluate participants' visual acuity, ocular motility, visual fields, and visual attention. Results: This study examined 94 participants, identifying 80 with VI, 26 with abnormal visual attention, 58 with cognitive impairment, and 11 with visuospatial dysfunction. Analyses showed: 1) Visual acuity negatively correlated with MMSE and CDT scores; 2) Groups with near vision impairment or visual attention abnormalities had significantly lower MMSE and CDT scores, while cognitively normal participants showed better visual acuity; 3) Logistic regression revealed MMSE scores were primarily influenced by left-eye near vision and visual attention, whereas CDT scores were additionally affected by education level; 4) Mediation analysis indicated left-eye near vision and visual attention may impact cognitive function via visuospatial function. Conclusions: VI is closely associated with cognitive impairment, with left-eye near vision and visual attention potentially affecting cognition through their impact on visuospatial function. The application of the VISA tool may provide scientific evidence for optimizing dementia prevention and control strategies in China.
Keiko Ide, Shunsaku Mizushima, Kyoko Saito, Hiroko Suzuki, Yuhei Chiba, Kie Abe, Asuka Yoshimi, Akitoyo Hishimoto, Taro Yamanaka, Takashi Sakurai, Hidenori Arai, Masataka Taguri, Shoko Suzuki, Toshinari Odawara (Handling Associate Editor: Kenjiro Ono)
Japan-Multimodal Intervention Trial for the Prevention of Dementia in older people with lifestyle-related diseases: A community-based, 18-month, randomized controlled trial
Abstract: Background: The prevalence of Alzheimer’s disease is increasing in Japan, highlighting the need to establish evidence-based strategies for its prevention. Objective: We aimed to evaluate the effectiveness of a multimodal community-based intervention for Japanese older people with lifestyle-related diseases and to identify challenges in implementing such interventions to prevent dementia in local communities. Methods: An 18-month randomized controlled trial was conducted among individuals aged 65–85 years with lifestyle-related diseases (hypertension, hyperlipidemia, diabetes, overweight/underweight, smoking), residing in a single apartment complex. Participants were randomly assigned to a multimodal intervention group (group-based physical exercise, nutritional guidance, management of lifestyle-related diseases, and cognitive training) or a control group. The primary outcome was the change in the composite score derived from seven neuropsychological tests. The trial was registered (UMIN000041887: September 24, 2020). Results: Of 224 screened individuals, 198 were randomized (99 in each group), and 175 (88.4%) completed the 18-month assessment. There was no significant difference between the intervention and control groups in the primary outcome (change in composite test score: 0.25; 95% confidence interval 0.16 to 0.33 versus 0.29; 95% confidence interval 0.20 to 0.38, respectively; p = 0.463). However, a subgroup analysis of participants with mild cognitive impairment showed a significant intervention effect on changes in logical memory, for both immediate (p = 0.041) and delayed recall tasks (p = 0.043). Conclusions: This multimodal intervention program demonstrated no effectiveness in mitigating cognitive decline. Further research is needed to develop more effective strategies and to better define target populations.
Yorito Hattori, Yoshinori Kakino, Yuriko Nakaoku, Soshiro Ogata, Takeshi Yoshimoto, Kunihiro Nishimura, Hidehiro Iida, Masafumi Ihara
Cerebral hemodynamic severity of asymptomatic carotid artery stenosis/occlusion estimated by neurocognitive domains
Abstract: Background: The severity of cerebral hemodynamic impairment in patients with carotid artery stenosis or occlusion (CASO) is not always correlated with the severity of stenosis or occlusion. There are no established noninvasive indicators of cerebral hemodynamic impairment in CASO. Objective: The study aimed to identify impaired neurocognitive domains as promising noninvasive severity markers. Methods: In a retrospective study of 142 patients with asymptomatic CASO, we assessed associations of Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog) with 15O-gas positron emission tomography. Results: In patients with right CASO (n = 45), worse delayed recall on MoCA was significantly associated with decreased CBF (adjusted β for cerebral blood flow [CBF] 1.70, 95% confidence interval [CI] 0.21–3.28, p = 0.027), with the cutoff value of 1/2 for CBF of 52.9% (specificity 96.4%). In patients with bilateral CASO (n = 37), worse executive function on MoCA score was significantly associated with decreased CBF (adjusted β for CBF 2.70, 95% CI 0.29–5.13, p = 0.030), with the cutoff value of 2/3 for CBF of <35.0 mL/100g/min (sensitivity 83.3%). Conclusions: Neuropsychological examinations could be useful for noninvasively estimating the severity of cerebral hemodynamic impairment in patients with CASO.
Zhixuan He#, Yu Nie#, Weijie Zhang#, Yue Liu, Yaping Liu, Huachen Xue, Sizhi Ai, Hongliang Feng, Yujing Zhou, Jihui Zhang, Yannis Yan Liang, Yuping Ning #These authors contributed equally to this work.
Social isolation, loneliness, genetic risk, and incident dementia in people with type 2 diabetes mellitus: A population-based cohort study
Abstract: Background: Social isolation and loneliness, two independent constructs of social disengagement, are becoming increasingly recognized factors for dementia risk. Objective: We aimed to investigate whether these two constructs also associate with dementia risk in individuals with type 2 diabetes mellitus (T2DM), which is becoming more prevalent. Methods: The longitudinal study included 24,986 participants (mean age: 60.0 ± 6.9 years, median follow-up: 12.0 years) with T2DM at baseline from the UK Biobank. Social isolation and loneliness were assessed using self-reported questionnaires. Genetic risk factors for dementia including polygenic risk score (PRS) and APOE genotype were extracted. We identified incident dementia cases by linking hospital records and death registries. Results: Social isolation (most versus least: hazard ratio, HR: 1.46 [95% confidence intervals, CI: 1.22-1.75]) and loneliness (yes versus no: 1.56 [1.25-1.95]) were associated with an increased risk of incident dementia after adjusting for demographic factors; however, such associations attenuated when further adjusting for health behaviors, psychological factors, or diabetes-related characteristics. The social isolation-dementia association was predominantly attributable to health behaviors (48% for the most social isolation), while the loneliness-dementia association was largely explained by psychological factors (46%). Significant modification effects of dementia genetic risk were observed on these associations. Conclusions: Social isolation and loneliness were associated with a greater risk for incident dementia among T2DM individuals, with differential explanatory factors. The genetic risk for dementia modified these associations. The findings underscore the importance of strengthening social connections to mitigate diabetes-related dementia risk.
Yuanyuan Lu#, Jie Chang#, Yiwei Zhao, Peiyang Gao, Yi Tang (Handling Associate Editor: Kay Deckers) #These authors contributed equally to this work.
Association of healthy lifestyle with excess risk of dementia in individuals with hypertension
Abstract: Background: The extent to which hypertension-related excess risk of dementia can be mitigated or eradicated through lifestyle factor modification remains unclear. Objective: To explore the association between lifestyle behaviors and hypertension-related excess risk of dementia. Methods: In this prospective cohort study using data from the UK Biobank, participants were enrolled from 2006 to 2010 and followed up until December 2022. A healthy lifestyle score was constructed by assigning one point for each of the seven selected healthy lifestyle factors. The association of dementia risk in individuals with hypertension according to the healthy lifestyle score was compared to individuals without hypertension. Results: This study included 337,378 individuals. During a median follow-up of 13.6 years, 5390 participants developed dementia. A higher healthy lifestyle score was associated with a gradual decrease in the excess risk of dementia for individuals with hypertension compared to individuals without hypertension. Excess dementia risk was not detected among individuals with hypertension who adopted at least six healthy lifestyle factors (hazard ratio (HR) = 1.05 (95% confidence interval (CI): 0.96–1.14)) for six scores; HR = 0.93 (95% CI: 0.82–1.06 for seven scores). The protective association between adhering to all seven healthy lifestyle factors and dementia was significantly stronger for individuals < 60 years old than for individuals ≥60 years old. Conclusions: For individuals with hypertension who adopted at least six healthy lifestyle factors had no hypertension-related excess risk of dementia.
Shota Suzumura, Junpei Sugioka, Keita Sakurai, Aiko Osawa, Taisei Matsubayashi, Masaki Kamiya, Yuko Sano, Akihiko Kandori, Tomohiko Mizuguchi, Yoshiharu Uchida, Hitoshi Kagaya, Izumi Kondo
Finger motor skills and related brain regions in patients with cognitive disorder
Abstract: Background: Motor impairment precede cognitive impairment and may be early biomarkers for dementia. We have previously reported an association between finger tapping and cognitive function; however, the link between finger motor movements and associated brain regions is unclear. Objective: In this study, finger tapping movements were used to identify brain regions strongly associated with finger motor dexterity in individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Methods: This exploratory, cross-sectional study included individuals with AD or MCI who underwent finger motor movement measurements and 3D magnetic resonance imaging (MRI). Voxel-based morphometry analysis was conducted using Statistical Parametric Mapping 12 and Computational Anatomy Toolbox 12 to assess gray matter volume. Correlations between MRI and finger motor parameters were analyzed using intracranial volume, Mini-Mental State Examination score, age, and sex as covariates. Results: We included 136 individuals (AD, 71; MCI, 65). The number of taps and the number of freezing calculated from acceleration significantly correlated with gray matter volume in motor and sensory regions, including the primary motor (BA4) and primary somatosensory (BA3, 1, 2) cortices. Many correlations with the left hemisphere were found in both left- and right-handed bimanual alternating tapping tasks. Conclusions: Finger motor dexterity in individuals with cognitive impairment is associated with gray matter volume in specific brain regions, with a pronounced correlation in the left hemisphere. These findings suggest that finger motor skills may be linked to structural brain changes.
Rui Wu, Jing Guo, Yang Liu, Sirou Huang, Pingping Wu, Weiping Liu
Angiogenesis promotion of the transplantation of human amniotic mesenchymal stem cells via the Ang-1/Tie-2 signaling pathways in Alzheimer’s disease model
Abstract: Background: Alzheimer's disease (AD) is a progressive degenerative disease of the central nervous system, leading to cognitive decline, mental symptoms, and behavioral disorders. The comorbidity of cerebrovascular disease in AD patients will accelerate the development of cognitive impairment and dementia. Since the dysfunction of the cerebral vasculature is closely related to neuropathology in AD patients, the protection of cerebral microvascular function and the improvement of cerebral microcirculation may bring a potential path for AD treatment. Human amniotic mesenchymal cells (hAMSCs) as a more advantageous cellular therapy for AD are proven to improve AD model mice's learning and memory abilities significantly, but fewer studies on angiogenesis and blood-brain barrier recovery have been found. Objective: The study aimed to analyze the changes in angiogenesis-related factors of hAMSCs transplantation in the AD model and explore the underlying molecular mechanism. Methods: hAMSCs were injected into APP/PS1 and wild type (WT) mice via tail vein, and the hAMSCs distribution in the cerebral tissue and angiogenesis in the hippocampal tissues were observed. Results: hAMSCs were found in the cortex and hippocampal areas of APP/PS1 and WT mice. hAMSCs transplantation significantly increased CD31 and Tie-2 expression in AD mice compared with the control group. Conclusions: The study indicates that hAMSCs can cross the blood-brain barrier and enter the cerebral tissue of the mouse, transplantation of hAMSCs may promote angiogenesis in the AD model. The Ang-1/Tie-2 signaling pathway may be a therapeutically attractive target for the hAMSCs treatment of AD.
Seda Sacu, Catherine F Slattery, Karl J Friston, Ross W Paterson, Alexander JM Foulkes, Keir Yong, Sebastian Crutch, Jonathan M Schott, Adeel Razi (Handling Associate Editor: Yaakov Stern)
Neural mechanisms of disease pathology and cognition in young-onset Alzheimer's disease variants
Abstract: Background: Late-onset Alzheimer’s disease is consistently associated with alterations in the default-mode network (DMN)—a large-scale brain network associated with self-related processing and memory. However, the functional organization of DMN is far less clear in young-onset Alzheimer’s disease (YOAD). Objective: The current study aimed to identify effective connectivity changes in the core DMN nodes between YOAD variants and healthy controls. Methods: We assessed resting-state DMN effective connectivity in two common YOAD variants (i.e., amnestic variant (n=26) and posterior cortical atrophy (n=13) and healthy participants (n=24) to identify disease- and variant-specific connectivity differences using spectral dynamic causal modelling. Results: Patients with the amnestic variant showed increased connectivity from prefrontal cortex to posterior DMN nodes relative to healthy controls, whereas patients with posterior cortical atrophy exhibited decreased posterior DMN connectivity. Right hippocampus connectivity differentiated the two patient groups. Furthermore, disease-related connectivity alterations were also predictive of group membership and cognitive performance. Conclusions: These findings suggest that resting-state DMN effective connectivity provides a new understanding of neural mechanisms underlying the disease pathology and cognition in YOAD.
Serena Low, Angela Moh, Bhuvaneswari Pandian, Huili Zheng, Sharon Pek, Jian-Jun Liu, Keven Ang, Tsz Kiu Kwan, Wern Ee Tang, Ziliang Lim, Tavintharan Subramaniam, Chee Fang Sum, Su Chi Lim
Double product is longitudinally associated with reduced cognitive function in type 2 diabetes with insights from cross-lagged panel analysis and mediation by leucine-rich α-2-glycoprotein 1
Abstract: Background: Elevated systolic blood pressure (SBP) and resting heart rate (RHR) contribute to pathogenesis of diabetic complications. They increase inflammation which can upregulate leucine-rich α-2-glycoprotein 1 (LRG1), an emerging biomarker of cognitive decline. Objective: To examine association between double product (DP, derived from multiplying SBP and RHR) and cognitive function in type 2 diabetes (T2D), with possible mediation by plasma LRG1. Methods: In this prospective cohort of 1319 patients (mean age 62.5±7.3), plasma LRG1 was measured with enzyme-linked immunosorbent assay. Cognitive function was assessed using Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Cross-lagged panel analysis was done to examine temporal relationship between DP and cognitive function. Results: Baseline DP was associated with lower baseline RBANS total score (adjusted coefficient= -2.43; 95%CI -4.76, -0.10; p=0.041). 586 patients were followed up to 8.6 years. Baseline DP was associated with follow-up RBANS total score (adjusted coefficient= -3.80; 95%CI -6.51,-1.10; p=0.006). It was also associated with lower follow-up RBANS scores in immediate memory and delayed memory with adjusted coefficients -4.38 (95%CI -8.49,-0.28; p=0.036) and -5.12 (95%CI -9.88,-0.35; p=0.035) respectively. In cross-lagged panel analysis, standardized effect size of baseline DP on follow-up RBANS total score (β=-0.08; p=0.002) was larger than that of baseline RBANS total score on follow-up DP (β=-0.04; p=0.266). LRG1 accounted for 14.7% of the association in mediation analysis (p=0.035). Conclusions: DP was independently associated with cognitive function with possible mediation by LRG1. DP preceded decline in cognitive function. DP may be potential intervention and monitoring target for prevention of cognitive impairment and possibly Alzheimer’s disease in T2D.
Edmarie Guzmán-Vélez, David Aguillón, Angelys Rivera-Hernández, Ana Y Baena, Natalia Londoño-Sotomayor, Glen Picard, Arthur F Kramer, Steven E Arnold, Domingo I Caraballo-Gracia, J Andrew Taylor, Yakeel T Quiroz
Association among cardiorespiratory fitness, plasma biomarkers of pathology and astrocyte reactivity, and cognition in autosomal-dominant Alzheimer’s disease
Abstract: Background: High cardiorespiratory fitness has been associated with greater neuroplasticity and slower neurodegeneration, and cognitive decline in healthy adults. Yet, less is known about whether low-to-intermediate cardiorespiratory fitness is associated with lower markers of disease progression in the preclinical stage of Alzheimer’s disease (AD). Objective: We investigated whether cardiorespiratory fitness was associated with plasma biomarkers for AD-related pathology, neural injury, and astrocyte reactivity, and episodic memory in Presenilin-1 E280A carriers without dementia from the world’s largest kindred with autosomal-dominant AD. Methods: Twenty-seven mutation carriers (25 cognitively unimpaired, 2 with mild cognitive impairment; ages: μ=30.22 years, SD=5.24; 74% female) participated in the study. Participants underwent a graded aerobic fitness test to assess cardiorespiratory fitness, measured in maximum metabolic equivalent of task (MET). Plasma biomarkers included amyloid 42/40, phosphorylated tau-181, neurofilament light chain, and glial fibrillary acidic protein. Participants completed the Consortium to Establish a Registry for AD word list learning and delayed recall. We conducted multiple linear regressions controlling for age and sex, and years of education. Results: Fourteen participants’ MET values were indicative of low cardiorespiratory fitness (<9 MET), and 13 participants’ MET values of intermediate cardiorespiratory fitness (9-14 MET). METs were not associated with age, biomarkers, or episodic memory. Conclusions: Our findings suggest that low-to-intermediate cardiorespiratory fitness may not be associated with biomarkers for AD-related pathology, neural injury, and astrocyte reactivity, or memory in people at genetic risk for dementia. Longitudinal studies and randomized-controlled trials are needed to understand better the relationships among cardiorespiratory fitness and AD progression.
Da-wei Wang#, Xue-ting Qin#, Gang Wang, Juan Liu, Yu-ping Xu, Yuan Tian, Bin Liu #These authors contributed equally to this work.
Effect of comprehensive geriatric assessment intervention on serum S100β levels and clinical outcomes in patients with Alzheimer's disease
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that significantly impairs cognitive function, emotional health, and daily living activities. Comprehensive Geriatric Assessment (CGA) is a multidisciplinary approach designed to optimize health outcomes in older adults, but its effectiveness in managing AD remains to be fully elucidated. Objective: To evaluate the impact of CGA intervention on serum S100β levels and clinical outcomes in patients with AD. Methods: In this prospective study, 120 patients diagnosed with AD were randomly assigned to either a Control group or an Intervention group. The Control group received standard treatment and routine care, while the Intervention group received individualized care plans based on CGA in addition to standard management. Primary outcomes included serum S100β levels, Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Neuropsychiatric Inventory–Questionnaire (NPI-Q), Geriatric Depression Scale (GDS) scores, Mini-Nutritional Assessment (MNA) scores, Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), and Parkinson’s Disease Questionnaire (PDQ-39) scores, assessed at baseline and during follow-up. Results: Serum S100β levels remained stable in the Control group but significantly decreased in the Intervention group at 6 months. ADLs and IADLs scores were consistently higher in the Intervention group. Although ADAS-Cog and NPI-Q scores improved in both groups, the Intervention group demonstrated significantly lower NPI-Q scores at 6 months. Conclusions: CGA intervention effectively enhances cognitive function, emotional well-being, mobility, and social interaction in patients with AD.
Kefu Yu#, Ruiqi Jiang#, Dabiao Zhou, Zhigang Zhao #These authors contributed equally to this work.
Therapeutic targets for Alzheimer's disease: Proteome-wide Mendelian randomization and colocalization analyses
Abstract: Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with limited treatment options. Objective: This study aimed to identify novel therapeutic targets for AD using proteome-wide Mendelian randomization (MR) and colocalization analyses. Methods: We conducted a large-scale, proteome-wide MR analysis using data from two extensive genome-wide association studies (GWASs) of plasma proteins: the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study. We extracted genetic instruments for plasma proteins from these studies and utilized AD summary statistics from European Bioinformatics Institute GWAS Catalog. Colocalization analysis assessed whether identified associations were due to shared causal variants. Phenome-wide association studies and drug repurposing analyses were performed to assess potential side effects and identify existing drugs targeting the identified proteins. Results: Our MR analysis identified significant associations between genetically predicted levels of 9 proteins in the deCODE dataset and 17 proteins in the UKB-PPP dataset with AD risk after Bonferroni correction. Four proteins (BCAM, CD55, CR1, and GRN) showed consistent associations across both datasets. Colocalization analysis provided strong evidence for shared causal variants between GRN, CR1, and AD. PheWAS revealed minimal potential side effects for CR1 but suggested possible pleiotropic effects for GRN. Drug repurposing analysis identified several FDA-approved drugs targeting CR1 and GRN with potential for AD treatment. Conclusions: This study identifies GRN and CR1 as promising therapeutic targets for AD. These findings provide new directions for AD drug development, but further research and clinical trials are warranted to validate the therapeutic potential of these targets.
Junhua Liang, Qianqian Wang, Jiahao Wang, Yuxuan Shao, Shuxiang Zhu, Nianshuang Wu, Xiaolin Huo, Guanghao Zhang, Hua Lin
Individual electric field in cortical white matter is correlated with cognitive improvement in patients with mild cognitive impairment due to Alzheimer’s disease after repetitive transcranial magnetic stimulation treatment
Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) may be effective for Alzheimer’s disease (AD) and mild cognitive impairment (MCI); however, the therapeutic efficacy varies significantly, highlighting the need for reliable biomarkers to predict treatment response. While rTMS may activates cortical white matter, the relationship between induced electric field (E-field) in this region and clinical outcomes remains unclear. Objective: This study characterized the E-field in cortical gray matter (EFgm), cortical white matter (EFwm), and region-of-interest (EFROI) in the left dorsolateral prefrontal cortex (DLPFC), and explored their correlations with treatment efficacy in patients with MCI due to AD. Methods: Thirty patients with MCI due to AD received 2-week rTMS treatment, with efficacy measured by Auditory Verbal Learning Test (AVLT) and a comprehensive neuropsychological battery. Responders were defined as those with >25% improvement in AVLT-immediate memory. Correlations between regional brain volumes and E-field magnitudes, and the correlations between E-field magnitudes and cognitive improvement, were analyzed. Predictive performance of E-fields for responder classification was evaluated. Results: Pronounced inter-individual variability in magnitudes of EFgm, EFwm and EFROI was observed, partially explained by differences in regional brain volumes of DLPFC targeted area. Treatment responders exhibited significantly higher EFwm magnitude. EFwm positively correlated with AVLT-immediate memory improvement (R² = 0.37) and predicted responder groups, achieving an area under the curve (AUC) of 0.76. Conclusions: E-field within cortical white matter in the DLPFC correlates with rTMS efficacy and predicts therapeutic response in MCI due to AD. Personalized stimulation protocols incorporating EFwm modeling may optimize treatment parameters.
Juan C Lopez-Alvarenga, Isabel Omaña-Guzmán, Oscar Rosas-Carrasco, Jose Cavazos, Michael Mahaney, Gladys Maestre
Vitamin D and cognition: Demographic disparities in memory recall and word intrusion in a multiethnic cohort
Abstract: Background: Vitamin D3 is essential for calcium metabolism and exerts pleiotropic effects, including neuroprotective activities in cognition. Its insufficiency has been linked to dementia, Alzheimer's disease, and cognitive impairments. The association between vitamin D3 and particular cognitive functions, including memory recall and word intrusion, remains imprecise, particularly among diverse ethnic and socioeconomic groups. Objective: To examine the relationship between vitamin D3 levels with memory recall and word intrusion in individuals aged 60 and above, emphasizing demographic differences. Methods: Data was collected from 2,759 individuals in the NHANES 2011-2014 surveys. Cognitive performance was evaluated with the CERAD Word Learning, Animal Fluency, and Digit Symbol Substitution assessments. Factor analysis was employed to identify two cognitive domains: F1 'Memory Recall' and F2 'Word Intrusion'. Linear and quantile regression models, controlled for demographic variables, were performed to assess the association between vitamin D3 levels and cognitive domains. Bootstrap techniques were used for standard error estimation, and nonparametric regression was applied to identify non-linear correlations. Results: Vitamin D3 levels positively correlated in linear models and quantile regression with F1 'Memory Recall' at diminished cognitive function levels. F2 was not associated with vitamin D3. Socioeconomic factors influenced these correlations, revealing inequalities among ethnic and income groups. Conclusions: Elevated vitamin D3 levels correlate with improved memory recall, especially in individuals with lower cognitive percentiles. These findings suggest the potential of vitamin D3 to alleviate cognitive decline, including Alzheimer’s disease, highlighting the need for focused interventions, particularly in underrepresented demographic groups.
Ha Na Kim#, Won Hee Jang#, Nam Sook Kang, Sungsub Kim, Kwang-Eun Choi, Anand Balupuri, Seong Su Hong, YunHyeok Choi, Eun-jae Lee, Lynkyung Choi, Jae-Young Koh, Gil Hong Park (Handling Associate Editor: Colin Combs) #These authors contributed equally to this work.
Pterosin D-activated protein kinase A mitigates Alzheimer’s disease in 5xFAD mice
Abstract: Background: Protein kinase A (PKA) is a key activator of cAMP response element-binding protein signaling; it plays a pivotal role in cognition, memory, and adult neurogenesis. Phosphodiesterase (PDE) inhibitors that indirectly activate PKA through cAMP are promising candidates for Alzheimer’s disease (AD) therapeutics. Objective: We examined whether pterosins bind directly to PKA as activators and enhance cognition and memory. Methods: We investigated PKA phosphorylation and performed in silico docking analysis using the cAMP-binding domains (CBD1, CBD2) of bovine PKA. Our focus was on exploring the effects of oral pterosin D on learning and memory in a 5xFAD mouse model of AD. Results: We demonstrated that C3-hydroxylated pterosins directly activated PKA in neuronal cells but not in astrocytes and did not affect intracellular cAMP levels or inhibit PDE. In silico modeling implied that C3-hydroxylated pterosins fitted the CBD of PKA. Pterosins enhanced long-term potentiation mossy fiber-CA1 in the mouse hippocampus without affecting normal synaptic transmission. Pterosins more potently accelerate neuronal proliferation and neurite outgrowth in primary mouse cortical neurons than dibutyryl-cAMP does. Pterosin D significantly restored cognition and memory in 5xFAD mice on the Morris water maze. Conclusions: C3-hydroxylated pterosins, as activators of PKA, have substantial potential as disease-modifying/-slowing therapeutic agent for AD.
Farshad Alishahi, Christopher R Beam, Margaret Gatz, Lon S Schneider, Daniel A Nation, Hussein N Yassine, Hillard Kaplan, Suchita Ganesan, Ioannis Pappas, Deborah Winders Davis, Ebrahim Zandi (Handling Associate Editor: Joao Duraes)
High precision and cost-effective multiplex quantification of amyloid-β40, amyloid-β42, p181Tau, p217Tau, neurofilament light chain, and glial fibrillary acidic protein from plasma and serum
Abstract: Background: Current methods to quantify blood biomarkers for Alzheimer’s disease (AD) are expensive and are not widely available. Objective: To develop a low-cost, sensitive, and accurate multiplex assay to quantify amyloid-β (Aβ)40, Aβ42, p181Tau), p217Tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) biomarkers in plasma and serum based on a widely available technology. Methods: We used commercial antibodies to Aβ40, Aβ42, p181Tau, p217Tau, NfL, and GFAP, and xMAP Luminex technology, and developed the multiplex 5ADCSI to quantify these biomarkers from plasma and serum. The utility of 5ADCSI was tested in matched cerebrospinal fluid (CSF) and plasma or serum of a cohort of cognitively normal (CN: n = 35), with mild cognitive impairment (MCI: n = 17), and with AD (n = 11) individuals. Results: The 5ADCSI demonstrated high specificity and sensitivity, with excellent precision. In clinical samples, moderate to strong correlation is observed between CSF and plasma or serum for Aβ42/40 (r = 0.78), p181Tau/Aβ42 (r = 0.57), p217Tau/Aβ42 (r = 0.72), p181Tau (r = 0.59), p217Tau (r = 0.75), and GFAP (r = 0.59). The AUC of receiver-operator characteristic curve for differentiating CN from AD for plasma/serum and CSF are 0.75, and 0.80 for Aβ42/40, 0.95, 0.91 for p217Tau, 0.76, 0.81 for p181Tau, and 0.73 and 0.78for GFAP, respectively. Conclusions: The 5ADCSI assay is highly specific, sensitive, and accurate. The wide availability of the base technology of 5ADCSI is an advantage over other similar methods and would allow cost-effective large-scale studies for validation of blood biomarkers for early diagnosis of AD.
Mark Rapoport, Patrick A Byrne, Kim Pho, Gary Naglie
Drivers with dementia: Forecasting the future
Abstract: Background: A decline in driving skills is well documented in people with dementia. Objective: To provide a current estimate and future forecast of drivers with dementia in Ontario, Canada, taking into account sex differences and longitudinal estimates of driving cessation in dementia. Methods: We used historical provincial licensing data, population estimates and projections, as well as estimates of diagnosable dementia from the Landmark study of the Alzheimer’s Society of Canada to create current estimates and forecasts of drivers with dementia in the province of Ontario, the most populous province of Canada, from 2024 to 2046. Sensitivity analyses were used to determine the impact of sex and assumptions regarding the rate of driving cessation. Results: Assuming that an estimated 35% of people with diagnosable dementia stop driving very shortly after symptom onset followed by a more gradual decline over time, and that females stop driving twice as fast as men, we forecast approximately 154,000 drivers with dementia in the province of Ontario in 2046. Conclusions: As dementia prevalence increases, our study provides a novel set of projections for drivers with dementia over the coming two decades, estimating a 221% to 226% increase. This work adds to the myriad of concerns about health and public services that will be needed to treat and support this population effectively, to detect early signs of dangerous driving among the cognitively impaired, and to provide alternative transportation options, once driving is no longer viable.
Yichen Li#, Yu-Lin Yao#, Yong Wu #These authors contribute equally to this work.
Causal relationships between plasma proteins and Alzheimer’s disease using bidirectional Mendelian randomization
Abstract: Background: Alzheimer’s disease (AD) is influenced by a complex interplay of genetic, immune, and metabolic factors. Identifying plasma proteins causally linked to AD could help clarify these pathways and uncover potential therapeutic targets. Objective: This study aims to investigate the causal relationship between AD and plasma proteins. Methods: We conducted a two-stage, two-sample Mendelian randomization (MR) analysis to explore the causal relationships between plasma protein levels and AD risk. In both stages, we used non-overlapping genome-wide association study datasets for exposure (plasma protein levels) and outcome (AD) to ensure robust and independent analyses. We examined both forward (from plasma proteins to AD risk) and reverse (from AD to plasma protein expression) causal effects to elucidate potential bidirectional relationships. Results: Our MR analysis identified 25 plasma proteins with causal associations to AD, with many implicated in immune and lipid metabolic pathways. These findings reinforce the roles of inflammation and lipid metabolism in AD pathogenesis and offer novel insights into specific proteins that may serve as biomarkers or therapeutic targets. Conclusions: This study provides further support for the relationship between immune and lipid metabolic dysregulation and AD, advancing our understanding of the molecular mechanisms underlying disease progression and highlighting key proteins for future research and therapeutic development.
Lorenzo Loffredo#, Alba Rosa Alfano#, Evaristo Ettorre, Giovambattista Desideri, Roberto Carnevale, Maurizio Forte, Vittorio Maglione, Simona Bartimoccia, Valentina Castellani, Chiara Maria Totè, Pasquale Pignatelli, Francesco Violi, Neurodegenerative Disease study group #These authors contributed equally to this work.
Effect of the probiotic Escherichia coli Nissle 1917 on serum levels of NADPH oxidase-2 and lipopolysaccharide in patients with Alzheimer’s disease
Abstract: Background: Intestinal bacteria-derived molecules, such as lipopolysaccharide (LPS) produced by Gram-negative bacteria, can translocate into the bloodstream through the gut wall, contributing to inflammation and neurodegeneration via oxidative stress mechanisms. NADPH oxidase-2 activation and superoxide anion production play a key role in this process, particularly in conditions like Alzheimer’s disease (AD), where gut permeability is often altered. This study hypothesized that modulating gut microbiota with the probiotic Escherichia coli Nissle 1917 (ECN) could mitigate LPS translocation and its associated inflammatory effects. Objective: To evaluate the effect of daily ECN administration on serum LPS levels in elderly AD patients. Methods: A randomized, double-blind, placebo-controlled trial was conducted with 40 mild AD patients, with 39 completing the study (20 ECN, 19 placebo). Participants received ECN (2.5–25 × 10^9 CFU/capsule) or placebo for six weeks. The serum activity of soluble NOX2-dp (sNOX2-dp), H2O2 production, tumor necrosis factor (TNF)-α levels and LPS was evaluated, while serum zonulin levels were measured to assess gut permeability Results: The ECN group showed significant reductions in sNOX2-dp (−21%), H₂O₂ (−27%), TNF-α (−18%), LPS (−15%), and zonulin (−35%), along with improved MMSE scores. No significant changes were seen in the placebo group. Mixed ANOVA showed significant time-by-treatment interactions for zonulin (p=0.04) and MMSE (p<0.001). Changes in LPS correlated with changes in zonulin (Rs=0.408, p=0.011). Conclusions: ECN may strengthen gut barrier function, reduce endotoxemia, and attenuate inflammation in AD, though larger studies are needed to confirm these findings.
Wiesław J Cubała, Ana Berrio, Katherine Chi-Burris, Gustavo Alva, Lambros Chrones, Sanjeev Pathak
Pimavanserin safety in adult and elderly patients with neuropsychiatric symptoms related to neurodegenerative disease: An open-label extension study
Abstract: Background: An 8-week, phase 3b, randomized placebo-controlled trial demonstrated that pimavanserin, a selective 5HT2A inverse agonist, is generally well tolerated in elderly patients with neuropsychiatric symptoms related to neurodegenerative disease (NDD). Objective: This open-label extension (OLE) study assessed the long-term safety and tolerability of pimavanserin. Methods: Patients from the antecedent double-blind (DB) trial who were treated with oral pimavanserin (34 mg/day) or placebo were enrolled. The safety analysis population included all patients who received ≥1 dose of pimavanserin. The primary endpoint was treatment-emergent adverse events (TEAEs). Exploratory endpoints included change from baseline in Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS A), Mini-Mental State Examination (MMSE), Clinical Global Impression-Severity (CGI-S), EuroQoL 5-Dimension 5-Level (EQ-5D-5L), and Sleep Disorders Inventory (SDI) scores. Results: Patients (N=595; mean age 72.2 years) received pimavanserin treatment (mean exposure 312.4 days). Most patients (95.3%) had dementia (68.7% of whom had Alzheimer's disease), and 70.6% were concomitantly treated with anti-dementia drugs. TEAEs occurred in 238 (40.0%) patients, and 37 (6.2%) had a serious TEAE; 1 (0.2%) was pimavanserin-related. TEAEs resulted in treatment discontinuation in 39 (6.6%) patients. Fatal TEAEs occurred in 11 (1.8%) patients (none considered related to pimavanserin). The mean (standard error) change from DB baseline to OLE Week 52 in MMSE, ESRS-A, CGI-S, EQ-5D-5L, and SDI scores was +0.9 (0.21), –0.3 (0.22), –1.0 (0.05), +10.7 (0.87), and –0.9 (0.07), respectively. No patients reported suicidal behavior. Conclusions: Pimavanserin was generally well tolerated in frail older adults and elderly patients with neuropsychiatric symptoms related to NDD for up to 52 weeks of treatment.
