Journals
2025 EN
Yamada Shinnosuke · Farsad Huifangjie L. · Feng Wei
+8 more
Abstract Background Neuropathology of Lewy bodies is reported in Parkinson disease (PD), Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLBD), and the latter two disorders comprise Lewy body dementias (LBDs). LBDs and Alzheimer's disease (AD) are the most common neurodegenerative dementias with the commonality of protein deposition but distinct pathological and clinical characteristics. Method We performed snRNA‐seq on the substantia nigra (SN) tissues obtained from 45 subjects with AD, PD, PDD, or DLBD, and cognitively normal controls. We compared our data with three published snRNA‐seq data of SN derived from subjects with PD or PDD and cognitively normal controls by Wang et al., 2022, Kamath et al. 2022, and Martirosyan et al. 2024 through uniform data analysis using the same analysis approaches and parameters. We performed MERFISH spatial transcriptomics and immunohistochemical staining to investigate spatial distribution of neuronal populations and their selective vulnerability. Result We identified 9 neuronal subpopulations in our data including two Dopamine (DA) neuron populations: SOX6+ vs. SOX6‐ DA neurons. SOX6+ DA neurons, RORB+, and FAT2+ neurons were shared by all four datasets whereas the SOX6‐ DA neurons were shared only by the Martirosyan et al. data. Additionally, other neuronal populations were shared by some but not all datasets and each dataset had their own unique neuronal population suggesting the regional differences among the four datasets. Differentially expressed gene (DEG) analysis in each disease condition revealed that DEGs of DA neurons in AD overlapped significantly with those of PD and LBDs. However, ALDH1A1 expression was oppositely regulated in AD versus in PD and LBDs, which may contribute to selective vulnerability of DA neurons in PD and LBDs. We demonstrated that SOX6‐ DA neurons were more vulnerable than the SOX6+ DA neurons and they had distinct spatial distributions in human SN with SOX6‐ DA neurons located at ventral SN. Pathway analysis revealed vast differences in gene dysregulation in the corresponding neuronal populations among the four datasets. Conclusion We report spatial heterogeneity of both cell composition and gene dysregulation in PD and LBDs, unveiling molecular mechanisms underlying selective neuronal and regional vulnerability in the human SN.
Journals
2025 EN
Saliu Ibrahim Olabayode · Feng Wei · Yamada Shinnosuke
+4 more
Abstract Background snRNA‐seq has advanced our understanding of astrocyte heterogeneity. However, studies vary in biological factors (disease conditions and brain regions), technical approaches, and analytical methods, making it challenging to distinguish whether observed astrocyte heterogeneity reflects true biological differences or technical variations. Currently, the number of astrocyte subpopulations in different brain regions, the similarities and differences of astrocyte and their responses to diseases remain poorly understood. Method We conducted uniform analysis of eight human snRNA‐seq datasets using the same analytical approaches and parameters. The datasets were derived from seven brain regions and six neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, Parkinson disease dementia, dementia with Lewy bodies, Huntington disease, and Nasu‐Hakola disease. We compared astrocyte heterogeneity, transcriptional regulation, and disease‐associated transcriptomic changes. Result We identified three astrocyte subpopulations: Ast‐0 and Ast‐2 were present across all eight datasets, while Ast‐1 was found in six datasets. This identification of homologous populations enabled comparative analysis of astrocyte reactivity, disease response, and transcriptional control across diseases and brain regions. We defined core conserved marker genes and pathways shared across all conditions for each astrocyte subpopulation. Notably, Ast‐1 across all datasets showed unique enrichment for amyloid‐beta binding and ND‐related pathways suggesting a specific role of Ast‐1 in neurodegeneration. Differentially expressed genes (DEGs) in disease conditions were largely shared among astrocyte subpopulations within each disease and brain region, indicating coordinated responses to disease pathology. Importantly, both canonical and non‐canonical Wnt signaling pathways along with their downstream targets, and endolysosomal pathways were concordantly dysregulated across all disease conditions and brain regions. This suggests these pathways may represent a common mechanism underlying ND pathogenesis. By ranking disease DEGs based on their frequency of dysregulation across datasets, we identified both known disease risk genes and novel candidates. We defined consensus transcription regulatory networks controlling astrocyte subpopulation identities. Functional validation through astrocyte‐specific knockdown of PBX1 and SOX2 resulted in endocytosis defects in primary mouse astrocytes and motor defects in flies, confirming their astrocyte‐specific functions. Conclusion Our analysis revealed astrocyte‐specific molecular changes shared across six NDs and seven brain regions. These findings illuminate the common mechanism underlying different dementias and provide potential novel therapeutic targets.
Journals
2025 EN
Kayıklık Zeynep Didar · Çakır Bilal · Gülseren İbrahim
+1 more
Abstract Background Alzheimer's disease is associated with dementia and occurs due to the misfolding and extracellular accumulation of amyloid‐beta (Aβ) protein in the brain. Aβ 25‐35 peptide is a toxic form of Aβ commonly used in in vitro models. Although no definitive cure exists, several FDA‐approved drugs help patients maintain mental function. Bioactive peptides are specific protein fragments and are distinguished by their ability to promote positive effects on different neurodegenerative diseases. Bioactive peptides derived from hazelnuts ( Corylus avellana L.) hold promise for neuroprotective effects against Alzheimer's disease. Method Alzheimer's disease model was established using PC‐12 cell line treated with Aβ 25‐35 . Toxic doses for the disease model were determined using resazurin‐based cell viability assays. Subsequently, bioactive peptide derived from hazelnuts were applied to the Alzheimer's disease model, and the neuroprotective effect doses were identified through cell viability assays. Colony forming unit assay was performed to analyze the growth inhibition on Alzheimer's disease model. Cell cycle and Annexin V/PI assay was evaluated using flow cytometry. 2′,7′‐dichlorofluorescin diacetate (DCF‐DA) reagent was used to detect intracellular ROS production by fluorescent microscopy. Result OC1 bioactive peptide from hazelnut ameliorated the cell viability of in vitro Alzheimer's model. OC1 peptide was further evaluated for their neuroprotective effects at the molecular level. Cell cycle analysis revealed that Alzheimer's model group (Aβ 25‐35 treated) showed G2/M phase arrest in cell cycle assay when compared to control. Conversely OC1 peptide treatment improved the G2/M arrest caused by Aβ 25‐35. Annexin V/PI results demonstrate that Aβ 25‐35 treated group induced late apoptosis, while OC1 peptide treatment reversed this effect. OC1 peptide exerted neuroprotective effect by reducing intracellular ROS formation compared to Aβ 25‐35 treated alone. Conclusion Our findings indicate that the newly synthesized bioactive peptide OC1 is promising as potential neuroprotective agents for neurodegenerative diseases and may offer encouraging results for the prevention of Alzheimer's disease. This study was supported by Türkiye Sağlık Enstitüleri Başkanlığı, grant number: 22740 TÜSEB. Attendance at this conference was supported by an AAIC 2025 Conference Fellowship.
Journals
2025 EN
Walid Mohammad · ElAlfy Haneen Beshr · Ibrahim Rahma Mohammed
+2 more
Abstract Background Early‐onset Alzheimer's disease (EOAD) arises from genetic and environmental factors; however, therapies targeting presumed pathogenic processes remain ineffective. This gap highlights the need to reassess traditional pathogenesis models and investigate alternative mechanisms. Method A comprehensive review of MEDLINE, PsycINFO, and Cochrane Central Register through January 2025 was conducted, supplemented by analyses of genetic/protein databases and molecular studies using human‐induced neural stem cells (hiNSCs). Result Neuroimmune dysregulation emerges as central to Alzheimer's pathogenesis, surpassing amyloid‐beta (Aβ) and tau's roles. Traumatic brain injury (TBI) and neurotropic pathogens (HSV‐1, VZV) activate innate immunity via pattern recognition receptors (PRRs), inducing Aβ/tau pathology in hiNSC models. These stimuli engage pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs), triggering self‐sustaining inflammation. Astrocyte‐derived interleukin‐1β (IL‐1β) stimulates neuronal Aβ production and activates glycogen synthase kinase‐3β (GSK‐3β) via Toll‐ like receptor (TLR) signaling, promoting tau hyperphosphorylation and impairing PI3K/Akt survival pathways. Critically, GSK‐3β facilitates HSV‐1 reactivation in models with latent HSV‐1 exacerbated by TBI, perpetuating TLR/IL‐1β feedforward cycles and increasing the amyloid burden in secondary analysis of hiNSCs studies. Aβ also functions as an antimicrobial peptide which reinforces the physiological role of Aβ but overproduced during immune hyperactivation which leads to the pathology of AD. Additionally, the protective gene LRRTM4, which regulates innate immunity via TLR4 and NF‐ kB pathways, has been implicated in modulating this immune response, suggesting that immune dysregulation may play a central role in AD pathogenesis. EOAD‐associated mutations (PSEN1, APP, APOE4) amplify astrocytic immune responses, triggering neuronal cytokine release and microglial activation, positioning Aβ as a downstream effector. Conversely, late‐onset AD (LOAD) stems from aging‐related immunosenescence, impairing microglial phagocytosis and Aβ/tau clearance. Hippocampal vulnerability in LOAD reflects metabolic‐oxidative stress interactions, while EOAD exhibits diffuse pathology from neuroinflammatory priming. Conclusion Alzheimer's disease (AD) heterogeneity reflects distinct etiologies: EOAD is characterized by a hyperimmune state driven by astrocytic immune hyperactivity due to genetic susceptibility and environmental triggers, while LOAD arises from an aging‐related immunosenescence process. Both pathways ultimately converge on Aβ/tau deposition as secondary outcomes. This paradigm shift highlights the central role of innate immunity in AD pathogenesis, providing novel therapeutic targets to disrupt pathological cycles via immune modulation.
Journals
2025 EN
Dahroug Nada · Eltayeb Esra Ahmed Ibrahim · Alamin Amal
+4 more
Abstract Background Alzheimer's disease is marked by progressive cognitive decline, including impairments in spatial awareness and short‐term memory. With the global prevalence of dementia, including Alzheimer's disease, expected to rise from 57 million cases in 2019 to nearly 153 million by 2050, innovative solutions are urgently needed. This systematic review aims to explore the role of wearable technology in improving the daily lives of Alzheimer's patients by evaluating its effectiveness. Method Utilizing the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, we conducted a systematic review on the efficacy of wearable technology in enhancing the quality of life for Alzheimer's patients. A comprehensive search of PubMed, Google Scholar, Cochrane, and Scopus was performed using keywords such as “assistive technology,” “wearable device,” and “Alzheimer's.” We included peer‐reviewed studies, published in English between 2015 and 2025, involving human participants diagnosed with Alzheimer's that assessed the impact of wearable devices on quality of life. Data extraction was independently conducted by three reviewers, and quality assessment was completed using the Critical Appraisal Skills Programme (CASP). Result Out of 13,077 studies, five met the inclusion criteria, with the majority excluded due to lack of relevant outcomes. Qualitative analysis revealed that three studies using SenseCam, a wearable camera employed as a memory aid, demonstrated consistently significant improvements in autobiographical, episodic, and semantic memory over both short‐ and long‐term follow‐ups, along with short‐term reductions in depressive symptoms and enhancements in activities of daily living. A study with a Bluetooth earpiece that provided task reminders, instructions, and encouragement showed task initiation and completion rates increasing from below 35% to over 90%, indicating improved independence. On the other hand, the Microsoft HoloLens, an augmented reality headset, showed no significant improvements in task performance. Conclusion This review identified wearable devices as promising tools for enhancing cognitive function, emotional well‐being, and daily activities in Alzheimer's care. While some devices significantly improved patients' quality of life, others require further refinement. These findings highlight the transformative potential of wearable technology and emphasize the need for continued research and user‐centered design to overcome implementation challenges and optimize integration in both clinical and home settings.
Journals
2025 EN
Brown Hannah · Giannakopoulou Georgia · Teoh Sandra
+5 more
Abstract Background Early recognition of Alzheimer's Disease (AD) symptoms is crucial for timely diagnosis. Yet, limited public awareness of symptoms may hinder early detection. In order to assess the need for more widespread education, this study evaluated which symptoms are likely to prompt individuals to visit a doctor and whether they feel adequately informed about AD. Method An online survey was conducted in August 2024 with 804 adults aged 18 years or older from the US ( n = 106), EU4+UK (France, Germany, Italy, Spain, UK, n = 517), Japan ( n = 106), and China ( n = 75). Respondents were screened to ensure some understanding of, but not currently suffering from, AD. Without indicating that the list comprised common mild cognitive impairment (MCI) symptoms, participants were asked to select up to three symptoms that would prompt them to seek medical help. They were also asked whether they believe enough information is shared about AD. Results “Memory loss that disrupts day‐to‐day life” was the most commonly cited symptom triggering an individual to seek medical help (60% overall), highest in the US (63%) and lowest in Japan (47%). Other symptoms were notably selected less frequently. “Decreased or poor judgment” was among the least commonly chosen (15%), but was selected more often in Japan (37%) and China (36%) than in the US (10%) or EU4+UK (9%). Respondents aged 70+ ( n = 109) were more likely to be prompted by “Forgetting the word you wanted to use” (35%) than those aged 18–35 (18%, n = 212). 66% of all respondents believed not enough information is shared about AD, with this perception strongest in EU4+UK (72%) versus US (54%) and China (45%). Conclusions In this study cohort, memory loss was most likely to prompt medical consultation. However, other common symptoms of MCI were less frequently cited, indicating potential gaps in awareness of the broader spectrum of symptoms associated with AD. Furthermore, the majority perception that insufficient information about AD is shared underscores the need for enhanced public education initiatives. Improving awareness of diverse symptoms could facilitate earlier AD diagnosis and better patient outcomes.
Journals
2025 EN
Brown Hannah · Gabriele Simone · Giannakopoulou Georgia
+5 more
Abstract Background Blood‐based biomarker tests for Alzheimer's Disease (AD) are showing promise in clinical trials and are expected to improve the accuracy of diagnosis. By facilitating earlier detection, these tests could enable more individuals to qualify for recently approved disease‐modifying therapies (DMTs). This study assessed public willingness to undergo such blood tests. Method An online survey was conducted in August 2024 with 804 adults aged 18 years or older from the US ( n = 106), EU4+UK (France, Germany, Italy, Spain, UK; n = 517), Japan ( n = 106), and China ( n = 75). Respondents were screened to ensure some understanding of, but not currently diagnosed with, AD. Participants were presented with a hypothetical scenario in which they were experiencing symptoms of mild cognitive impairment (MCI). They rated their willingness to take a blood test to confirm whether these symptoms were due to AD on a 7‐point scale (1 = Not at all willing, 7 = Very willing). Ratings of 6 or 7 were considered “very willing” (Top 2 Box, T2B). Results Overall, 53% of respondents indicated high willingness (T2B) to take the blood test. Willingness was highest in the US (66%) and lowest in Japan (27%) ( p < 0.05). Lower willingness reported in Japan may be influenced by a cultural tendency to avoid extreme responses in surveys. Significant factors associated with higher willingness included better understanding of the disease, personal experience with AD, greater concern about developing AD, and closer proximity to support networks. A significant association was also observed between willingness to undergo a blood test and subsequent willingness to take treatment if MCI were confirmed but symptoms were not yet impacting day‐to‐day life. Among the 427 individuals willing to take a test, 77% were very willing (T2B) to take treatment, compared to 39% among the 125 individuals not willing to take a test. Conclusions In this study cohort, variations exist in willingness to undergo blood testing for AD confirmation among different subgroups. These findings suggest that personal experience and knowledge of AD play crucial roles in shaping attitudes toward diagnosis. Consequently, educational initiatives may need to be differentiated for certain subgroups.
Journals
2025 EN
Ponvel Pavapriya · Shahar Suzana · Singh Devinder Kaur Ajit
+15 more
Abstract Background Cognitive frailty (CF) in older adults is linked to increased dementia risk, but is a potentially reversible syndrome that may benefit from lifestyle‐based multidomain interventions. The AGELESS randomized controlled trial (RCT) assessed the effect of a 2‐year multidomain intervention on cognitive, physical, vascular, dietary, and psychosocial outcomes, and its cost‐effectiveness, in a Low‐Middle‐Income Country (LMIC), Malaysia. Method 106 community‐dwellers from Klang‐Valley, Malaysia, aged 60+ years and meeting criteria for (pre)‐CF (≥ 1 Fried's criteria and Clinical Dementia Rating scale=0.5) were randomized 1:1 to a culturally adapted multidomain intervention ‐ physical activity, cognitive training, nutritional and psychological counselling, cardiovascular care – or to an educational module. Primary outcomes, assessed at baseline, 12 and 24 months, included the modified Neuropsychological Tests Battery (mNTB) and physical performance. Intervention costs were calculated to determine Incremental Cost‐Effectiveness Ratios (ICERs). An intention‐to‐treat analysis was conducted. Result The trial occurred during the COVID‐19 pandemic, with a 50% drop‐out rate over 2‐years. Yet, adherence among participants was over 50% for all intervention components (range 53%‐91%). Significant intervention effects were observed in mNTB primary outcomes including verbal memory (verbal paired associates), visual memory (visual paired associates), attention and working memory (digit span test), lower body flexibility (chair sit and reach), walking speed (6 meter walk test), cardiovascular endurance (2‐minute step test) (for all measures p <0.05 for interaction time*group in repeat‐measures ANOVA). Changes in (pre)‐CF status were not significantly different between intervention and control. Total cost of the AGELESS intervention for 2‐years was 356USD per subject (intervention arm) and 109USD in the control arm. The ICER computation showed that 2‐minute step test was the most cost effective (34USD), followed by chair sit and reach (63USD) and verbal paired associates delayed recall (113USD). Conclusion Multidomain lifestyle‐based interventions can be cost‐effective, sustainable preventive approaches to promote healthy aging and reduce dementia risk. AGELESS is part of the Worl‐Wide‐FINGERS global network of multidomain interventions for dementia risk reduction, and offers a successful model to develop preventive interventions in LMICs, where there is a larger prevention potential due to prevalent lifestyle‐related risk factors.
Journals
2025 EN
Danso Samuel O. · Alqatawneh Ibrahim · Owo Adewale Samuel
+3 more
Abstract Background While recent development of Artificial Intelligence (AI)‐based approaches have demonstrated to be effective in predicting risk of ADRD, these have mostly focused on AD subtype, aged and homogenous populations (Grueso et al, 2022; Rahim et al., 2023), thereby limiting their applicability to other types of ADRD and younger populations. Inspired by earlier work (Danso et al 2021), we propose an AI‐based deep‐learning framework for early detection of ADRD based on heterogeneous and diverse population from midlife (Figure 1). Method We obtained two datasets from the European Prevention of Alzheimer's Dementia‐ EPAD ( n = 2096) and PREVENT Dementia Programme ( n = 700) available online (AD workbench, 2020). Following procedures described in Danso et al (2018) a harmonised cohort was curated containing individuals with no diagnosis of dementia. We then created three risk groups (High risk = ApoE4 allele and family history of AD; Medium risk = ApoE4 allele but no family history of AD; Low risk = no ApoE4 allele and no family history of AD) following the risk definition by Ritchie & Ritchie (2012). Convolutional Neural Network (CNN) and Long‐ Short Term Memory (LSTM) models were developed using 5‐fold cross validation and then applied optimisation procedures to obtain optimal parameters for the trained models. Result The harmonisation resulted in a cohort ( n = 2796; mean age =62; range = 40 – 89years; female =57.5%, Caucasian = 95%), containing medical history, physiological, lifestyle, neuroimaging, and sociodemographic features. Overall, CNN outperformed LSTM by 7% points for accuracy and f1‐score (Table 1), with mean AUROC scores of 97% and 94% respectively (Figure 2), and mean validation loss scores (CNN = 0.36; LSTM =0.46). Conclusion The superior performance of CNN is consistent with the literature and the relatively low validation loss demonstrates its generalisability. While this model is currently optimised for AD with limited features, a Transfer Learning paradigm is being employed to further train the CNN model to predict risk of other AD sub‐types after including BioHermes dataset into pipeline. Future work will also explore modifications of the CNN architecture for multimodal features with explainability capabilities.
Journals
2025 EN
Aye Sandar · Åhrberg Signe · Wallén Sara
+7 more
Abstract Background Early and accurate diagnosis of Alzheimer’s disease (AD) is crucial for early intervention using disease‐modifying therapies. Primary healthcare centers (PHCs) play a key role in recognizing individuals at‐risk, as they are the first contact for memory complaints. Targeted screening for those with cognitive symptoms and dementia risk factors could be a realistic strategy to increase detection of early AD. For this purpose, blood‐based biomarkers (BBMs) combined with digital cognitive tests would be highly informative. Method This longitudinal prospective study aims to establish an efficient workflow to identify individuals at risk for AD in a primary care setting. Participants are recruited from PHCs in the Stockholm region and are subjected to screening questions, a digital cognitive test battery and BBM analysis. The cognitive tests and BBM analysis will be repeated after two years. Participants are stratified into three profiles: a) ≥65 years b) ≥65 years with hypertension, and c) ≥65 years with type 2 diabetes with or without hypertension. 400 participants per stratum will be recruited. Result A pilot study has been conducted to assess the feasibility of the study design. 547 potential participants were identified from electronic medical records. After manual review, 306 were invited to participate, and 40 (13%), all of which experienced subjective cognitive complaints (SCD), were included. Of these, 55% preferred to do digital cognitive testing at home, but only 25% completed it, and only 15% completed the tests without assistance. The mean age was 72 years, 58% were female, and nearly half had a family history of dementia. 82% were not worried about memory symptoms, and 62% reported no worsening over time. Conclusion The main study is ongoing. The pilot study shows feasibility in recruiting patients with dementia risk factors and using digital cognitive tests. The limited technical capability among some participants showed a need to establish digital test equipment at the PHCs. The high attrition is due to the low proportion of SCD cases and gives an estimate on the number of participants that can be expected in an AD screening program. Results will inform the clinical applicability and economic benefits of targeted screening.