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Bibliography on: Alzheimer Disease — Current Literature

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 15 Oct 2025 at 01:35 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: 2023:2025[dp] AND ( alzheimer*[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2025-10-14
CmpDate: 2025-10-14

Mountadem S, Oliet SHR, A Panatier (2025)

D-Serine's Journey Between Stars and Synapses.

Neurochemical research, 50(5):327.

Astrocytes play a pivotal role in regulating synaptic transmission, with D-serine emerging as a key gliotransmitter shaping NMDA receptor-dependent functions. This review is focusing on the multifaceted role of astrocytic D-serine from synaptic transmission to cognitive processes. While this review includes the work of other groups, it is mainly based on the findings obtained in our laboratory. Drawing from two decades of research spanning from the hypothalamus to the hippocampus, we here highlight how astrocyte-derived D-serine regulates NMDAR activity, long-term synaptic plasticity, and associated memory. Our findings have revealed the dynamic control exerted by astrocytic processes onto D-serine availability within the synaptic cleft, including the impact of the astrocytic morphological plasticity, the key role played by intracellular Ca[2+] as well as the involvement of CB1 and EphB3 receptors. We also discuss how an impairment in astrocytic D-serine synthesis can affect the co-agonist availability and consequently impact cognitive functions in neurodegenerative disorders such as Alzheimer's Disease. To conclude, this review highlights the role of astrocytic D-serine in astrocyte-neuron communication and higher-order brain functions.

RevDate: 2025-10-14

Jessen F, K Broich (2025)

Dementia: changes from ICD-10 to ICD-11.

Der Nervenarzt [Epub ahead of print].

The International Statistical Classification of Diseases and Related Health Problems version 11 (ICD-11) represents a conceptual advance over ICD-10 in the classification of dementias. Although the syndromic classification in the chapter "Neurocognitive disorders" remains in principle unchanged, the introduction of severity levels and the central positioning of mental and behavioral symptoms enables a more precise coding of the clinical diagnoses. Furthermore, the introduction of mild neurocognitive disorder as a prodromal state of dementia is new. The clinical criteria developed by international experts, e.g., for frontotemporal dementia or Lewy body disease, are not yet sufficiently included in ICD-11. Biomarkers for the etiological diagnostics of dementia are also not mentioned, so that it is unclear which role they play in the disease classification in ICD-11. Due to the rapid development in the field of neurodegenerative diseases, regular updates would be desirable.

RevDate: 2025-10-14

Chander R, Sharma R, VK Agnihotri (2025)

Natural β-citronellol derivatives as potential dual enzyme inhibitors for the treatment of type 2 diabetes and Alzheimer's diseases.

Natural product research [Epub ahead of print].

Effective strategies for treating type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) involve inhibition of α-amylase, α-glucosidase for T2DM and block acetylcholinesterase (AChE) enzymes for treating AD. To explore this potential natural β-citronellol, isolated from Dracocephalum heterophyllum Benth essential oil, was derivatized to yield three derivatives (Compounds 2-4), analysed using NMR and GC-MS techniques. The results showed that compounds 2 and 4 had the most significant α-glucosidase and AChE inhibition. Parent compound 1, along with 3 and 4, displayed the highest α-amylase inhibition. Network pharmacology identified CXCR4 (score: 14) and PIK3CA (score: 12) as top-ranked targets. These findings suggest that PIK3CA, which regulates glucose metabolism, insulin signalling, and cell survival, while CXCR4 suggests potential for neuroprotective and anti-inflammatory roles. Structure-activity relationship indicated that alkoxy group functionalization at β-carbon of β-citronellol is essential for activity. It highlights, a single β-citronellol derivative can manage dual T2DM and AD diseases.

RevDate: 2025-10-14

Mathai A, Kannoth S, Nambiar V, et al (2025)

Immune system modifications in atypical parkinsonism related to autoimmunity - a case control study.

Neurodegenerative disease management [Epub ahead of print].

BACKGROUND: Inflammation is known in atypical parkinsonism (AP), but the role of autoimmunity is unclear. This study evaluates immune system modifications suggesting autoimmunity in AP.

METHODS: Included patients with AP diagnosed at Amrita Institute of Medical Sciences, Kochi (December 2018-May 2019), and age- and sex-matched controls. Fifteen immune parameters, including T regulatory cells, RORγt, and cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IL-23, TNF, IFN-γ, GM-CSF, NF-κB, TGF-β), were assessed in peripheral blood (flow cytometry and ELISA).

RESULTS: Twenty-six cases (mean age 67.8 ± 7.5 years; 16 males) and 15 controls (mean age 68.1 ± 3.5 years; 10 males) studied. Diagnoses included progressive supranuclear palsy (n = 15), multiple system atrophy (n = 1), frontotemporal dementia with parkinsonism (n = 2), and unspecified AP (n = 8). AP cases had significantly higher RORγt (p = 0.041), IL-6 (p = 0.004), TNF (p = 0.020), IL-10 (p = 0.027), and IL-4 (p = 0.048).

CONCLUSIONS: Elevated RORγt and cytokines suggest immune dysregulation and possible autoimmune mechanisms in AP, warranting further investigation.

RevDate: 2025-10-14

Chua WY, Wang JDJ, Chan CKM, et al (2025)

Hospitalization with infections and risk of Dementia: a systematic review and meta-analysis.

Aging, 17: pii:206329 [Epub ahead of print].

BACKGROUND: Dementia affects more than 50 million people worldwide, with 10 million new diagnosis each year. The link between hospitalization with infections and risk of Dementia is unclear. We conducted a meta-analysis on the association between hospitalization with infection and risk of Dementia.

METHODS: We searched MEDLINE and Embase from inception to March 31, 2025 to identify cohort studies comparing the frequency of Dementia in patients hospitalized with infections with those without. We computed hazard ratios (HR) for each study and pooled the results using a random-effects meta-analysis.

RESULTS: Out of 1900 studies that were screened initially, 16 studies comprising 4,266,276 patients were included for analysis. Hospitalization with infection was associated with an increased risk of all-cause Dementia (HR: 1.83, 95% CI: 1.58-2.13, p < 0.0001), Alzheimer's Disease (AD) (HR: 1.60, 95% CI: 1.23-2.08, p < 0.001) and Vascular Dementia (HR: 3.68, 95% CI: 2.16-6.27, p < 0.001). Among the infections, having Sepsis (HR: 1.78, 95% CI: 1.53-2.08) was associated with the highest risk of all-cause Dementia, followed by Pneumonia, Urinary Tract Infections, Skin and Soft Tissue infections.

CONCLUSIONS: Our meta-analysis showed that hospitalization with infection was associated with increased risk of Dementia. Sepsis carried the highest risk, followed by Pneumonia, Urinary Tract Infections, Skin and Soft Tissue infections.

RevDate: 2025-10-14

Zhang S, Wu Z, Zhang S, et al (2025)

The intricate microbial-gut-brain axis in Alzheimer's disease: a review of microbiota-targeted strategies.

Food & function [Epub ahead of print].

The microbiome-gut-brain axis (MGBA) has emerged as a potential focus for the enhancement of cognitive abilities and the improvement of Alzheimer's disease (AD). Probiotics and prebiotics can improve the imbalance of gut microbiota to alleviate AD symptoms. Current research on probiotics/prebiotics and brain function mainly focuses on metabolic pathways such as those involving microbial metabolites like lipopolysaccharides and short-chain fatty acids, as well as immune pathways that regulate inflammation in the gut and brain. However, the roles played by endocrine and neural pathways remain less explored and warrant further attention. This review explores the intricate mechanisms of gut-brain communication within the MGBA, and especially systematically elaborates on the specific mechanisms of the endocrine pathway (impact of gut-derived and exogenous hormones on brain function) and the neural pathway (regulation of brain function by the sympathetic and parasympathetic systems). It also emphasizes the specific changes in gut microbiota noted in individuals with AD. Additionally, it examines the beneficial effects of probiotics, prebiotics, synbiotics, and postbiotics for cognitive function, reviewing their advancements in preclinical research, clinical trials, and commercial applications. Furthermore, this review delves into novel gut microbiota-related strategies to promote brain health, including antibiotics, certain gut-targeted inhibitors or agonists, fecal microbiota transplantation, whole microbiome transplantation, viral microbiota transplantation, genetically engineered bacteria, and bacteriophage-based in situ intestinal microbiome engineering. Ultimately, this review aims to advance the therapeutic application of gut microbiota-targeted strategies in AD.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Maghami-Mehr A, Torabi H, Nadeb H, et al (2025)

Nonparametric Inference for the Covariate-Adjusted Youden Index and Associated Cut-Off Points for Three Ordinal Diagnostic Groups.

Pharmaceutical statistics, 24(6):e70043.

In this paper, we propose point estimators and confidence intervals for the Youden index and optimal cut-off points in the context of three ordinal diagnostic groups, accounting for the presence of covariates. Using heteroscedastic regression models, we introduce two point estimators based on different assumptions and examine their asymptotic properties. Additionally, we present confidence intervals for the covariate-adjusted Youden index and its corresponding optimal cut-off points. The performance of the proposed estimators and confidence intervals is evaluated through a Monte Carlo simulation study. Finally, we demonstrate the applicability of our methods to an Alzheimer's disease dataset.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Naftali J, Glik A, Eliahou R, et al (2025)

Impact of cerebral small vessel disease on cognitive outcomes in early age at onset MCI and dementia: Findings from the DIASPORA study.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70773.

BACKGROUND: This study assessed the impact of cerebral small vessel disease (CSVD) on cognition in individuals with early-onset (EO; <65 years) and late-onset (LO; ≥65 years) cognitive complaints.

METHODS: Participants underwent prospective evaluations including cognitive testing, hyperphosphorylated tau-217 (p-tau217) and neurofilament-light-chain (NfL), and magnetic resonance imaging (MRI). Each CSVD marker was modeled for interaction with group age on results on cognitive outcomes: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory Questionnaire (NPI-Q), and Clinical Dementia Rating (CDR) scale plus National Alzheimer's Coordinating Center-Frontotemporal Lobar Degeneration module (NACC-FTLD).

RESULTS: Altogether, 168 patients (91 EO) were included. white matter hyperintensity (WMH) volume was associated with worse CDR+NACC-FTLD in EO (β = 17.8, p = 0.013), remaining significant after adjusting for p-tau217 and NfL, but not gray matter atrophy. Lacunes were associated with worse CDR plus NACC-FTLD in EO (β = 4.3, p = 0.011), with age-dependent associations with MoCA, MMSE, CDR + NACC-FTLD, and NPI-Q (p  <  0.01).

DISCUSSION: CSVD markers, although less prevalent in EO, had greater clinical impact. These findings highlight an increased vulnerability to vascular pathology in EO patients and the importance of early detection.

HIGHLIGHTS: Cerebral small vessel disease (CSVD) markers were more impactful in early-onset than late-onset dementia. White matter hyperintensity (WMH) volume predicted functional decline in early onset, independent of neurodegeneration. Lacunes showed age-dependent effects on multiple cognitive outcomes. Findings support early detection of CSVD in younger individuals with dementia.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Vromen EM, Lageman SB, Gobom J, et al (2025)

Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70738.

BACKGROUND: The apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome.

METHODS: Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A-T-), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways.

RESULTS: Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood-brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.

DISCUSSION: Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.

HIGHLIGHTS: Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD). Combining cohorts enabled analysis of rare APOE ε2-associated protection in AD. The rare ε2 genotype may confer protection through improved neuronal plasticity. APOE ε4 carriers show increased blood-brain barrier dysfunction and glucose metabolism. These findings offer new insights into genotype-specific mechanisms in early AD.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Santos A, Almeida FC, Gauthreaux K, et al (2025)

White matter microstructure is differentially impacted by cerebral amyloid angiopathy, neurofibrillary tangles, and neuritic plaque co-pathology.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70637.

INTRODUCTION: White matter (WM) is affected by and serves as a pathway to neurofibrillary tangle (NFT) propagation in Alzheimer's disease (AD). Cerebral amyloid angiopathy (CAA) associates with neuritic plaques (NPs) to exacerbate NFT accumulation. We aim to study how these co-pathologies affect WM integrity.

METHODS: We performed a cross-sectional study of ante mortem diffusion tensor imaging (DTI) data according to participants' post mortem NFT, NP, and CAA neuropathology, from the National Alzheimer's Coordinating Center dataset.

RESULTS: We found asymmetric DTI changes in several WM regions between Braak NFT stages II and IV and V/VI, and across CAA pathological burden, with increased mean, radial, and axial diffusivities. CAA-NFT co-pathology effects were observed mainly in the splenium of the corpus callosum. DTI metrics were associated with cognitive function and hippocampal volumes.

DISCUSSION: Our results suggest that WM integrity is differentially impacted by AD neuropathology, with CAA and NFTs influencing each other's effects on WM microstructure.

HIGHLIGHTS: Diffusion tensor imaging (DTI) changes were observed in several white matter (WM) regions between advanced Braak stages and across cerebral amyloid angiopathy (CAA). CAA demonstrated a greater WM impact on the right hemisphere, while neurofibrillary tangles (NFTs) had greater impact on the left. CAA-NFT concurrent effects were mainly noticed in the splenium of the corpus callosum. WM DTI metrics were associated with cognition and hippocampal volumes.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Greer RA, Tuckey RA, Dean HB, et al (2025)

TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70729.

INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2-apoE3 interactions and effects of AD-associated variants on TREM2-apoE3 interactions are not fully understood.

METHODS: We used consensus protein-protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2-apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects.

RESULTS: Our experimentally consistent TREM2-apoE3 complex structure identified new potential TREM2-apoE3 interactions alongside the known interactions. TREM2-apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4  variants altered TREM2-apoE binding mode and conformational stability.

DISCUSSION: This study determined an experimentally consistent TREM2-apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2-apoE3 binding mode. Understanding TREM2-apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants.

HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD). An experimentally consistent TREM2-apoE3 complex structure was determined. New potential interaction interfaces between TREM2 and apoE3 were identified. TREM2-apoE3 interactions altered TREM2 and apoE3 conformation. AD-associated TREM2  R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2-apoE complexes.

RevDate: 2025-10-14

Losa M, Ramusino MC, Cama I, et al (2025)

Cerebrospinal Fluid Biomarkers Profiling in Cerebral Amyloid Angiopathy and Relationship With Disease Phenotypes.

Journal of the American Heart Association [Epub ahead of print].

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a heterogeneous small vessel disease that can occur independently or alongside Alzheimer disease (AD). CAA is diagnosed using the Boston Criteria 2.0, integrating clinical and neuroimaging features, whereas the Cerebrospinal Fluid (CSF) role in clinical practice remains under investigation. This study explores whether CSF biomarkers can identify distinct disease phenotypes, supporting hemorrhagic risk stratification.

METHODS: We enrolled probable patients with CAA retrospectively (Boston Criteria 2.0) from 2 institutions, collecting clinical, neuroimaging, and follow-up data alongside core CSF biomarkers (Aβ40 [amyloid β 1-40], Aβ42 [amyloid β 1-42], p-Tau181 [phosphorylated Tau], total-Tau). Patients with CAA were stratified applying the Amyloid Tau Neurodegeneration (ATN) research framework, according to the presence of CSF amyloidosis (A[+]CAA versus A[-]CAA) and tauopathy (A[+]T[+]CAA versus A[+]T[-]CAA), and using unsupervised clustering, which defined CAA subgroups based on CSF biomarker levels only. Kaplan-Meier and Cox regression analyses assessed the predictive value of CSF-based subgroups for symptomatic hemorrhages during follow-up.

RESULTS: Seventy-one probable CAA patients (aged 71.77±8.45 years, 66% men, median follow-up 1.15 years [0.50-2.44]) were enrolled. A[+]CAA showed a higher prevalence of cortical superficial siderosis than A[-]CAA (67% versus 25%, P=0.016). A[+]T[-]CAA had a greater hemorrhagic risk than A[+]T[+]CAA during follow-up (29 versus 7 events per 100 patient-years, P=0.010; log-rank test: P=0.013). Unsupervised clustering identified 2 subgroups, which we defined as pure CAA and CAA-ADA, with pure CAA presenting more symptomatic hemorrhages during follow-up (22 versus 0 events per 100 patient-years, P=0.017; log-rank test, P=0.011).

CONCLUSIONS: CSF-based profiling effectively stratifies CAA phenotypes, offering a promising prognostic tool alongside neuroimaging markers. Further validation is needed to confirm its role in identifying patients with CAA with different natural histories.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Ismail Z, Sivananthan S, Main S, et al (2025)

Culturally sensitive CLEAR guidelines on disclosing and communicating a diagnosis of dementia.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70744.

Providing a dementia diagnosis is challenging, especially in primary care and considering diverse patient backgrounds. The Alzheimer Society of Canada (ASC), the College of Family Physicians of Canada, and the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) guideline group partnered with patients, care partners, and clinicians to generate contemporaneous guidance for primary care practitioners. While relevant to all communities, Black and Chinese Canadians were formally represented in working groups. A literature review identified needs areas. Informed by Guidelines International Network (GIN) principles and through iterative group meetings with all partners, these needs were explored and incorporated into guidance. The Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR) offers recommendations on: holistic engagement, fostering hope, acknowledging care partners, identifying disclosing clinicians, appointment structure and environment, person-centered communication, specific discussion topics, and emotional supports, all through a cultural competence lens. These guidelines address communication challenges in disclosing a dementia diagnosis and enhancing care and support for persons living with dementia and their care partners. HIGHLIGHTS: Healthcare practitioners (HCPs) struggle with disclosing and communicating dementia diagnoses. Guidance is limited in primary care and different patient ethnocultural groups. We developed culturally sensitive guidelines with scripts and practical materials. Appropriate communication techniques and terminology are recommended in Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR). Patient-centered and holistic approaches for the patient and care partner are emphasized.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Fischer DL, Grinberg LT, Ahrendsen JT, et al (2025)

Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70734.

Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical-pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease-modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. HIGHLIGHTS: We celebrate 40 years of NIA-funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease-modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Zhu CW, Flournoy C, Raman R, et al (2025)

Employment, volunteering, and health-related resource use in pre-symptomatic AD: Results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70641.

INTRODUCTION: Little is known about productive time use and health-related resource use during "pre-symptomatic" AD, defined by the presence of brain amyloid in the absence of cognitive symptoms. We compared changes in resource use and participation in paid employment and/or volunteering in cognitively unimpaired older adults with amyloid accumulation (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease [A4] study, N = 1165) to otherwise matched participants without amyloid accumulation (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study, N = 507).

METHODS: Health-related resource use was self-reported using the Resource Use Inventory (RUI). Longitudinal analyses examined effect on RUI from study (A4 vs LEARN), time, and their interaction, controlling for Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) and the Clinical Dementia Rating (CDR) scale, and their change scores from baseline.

RESULTS: Over time, paid employment and volunteering decreased, and unpaid help and hospitalization increased. Results showed clear associations between ADCS-PACC and CDR with RUI.

DISCUSSION: Little detectable impact of amyloid levels on RUI was found in pre-symptomatic AD that has been identified as an ideal stage to target for dementia prevention.

HIGHLIGHTS: Using data from a cohort of cognitively unimpaired older adults with evidence of amyloid accumulation enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and otherwise matched participants who did not meet subthreshold levels of amyloid accumulation enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study, this study showed clear associations between clinical variables and resource use and participation in paid employment and volunteering but suggested little detectable impact of amyloid levels on rate of change during the preclinical stage. Our results suggest that economic benefits from currently available treatment that effectively removes amyloid may not be immediately or concurrently observed during the short timeline of clinical trials. It is critical that our examination of economic consequence of treatment include broad ranges of items on resource use and productivity loss, longer time horizon, and that we balance between cost of detection, treatment, and burden and benefit.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Lorenzini L, Tranfa M, Pieperhoff L, et al (2025)

Cortical thickness subtypes in cognitively unimpaired individuals: Differential network and transcriptomic vulnerability to cortical thinning.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70762.

INTRODUCTION: The emergence, stability, and contributing factors of Alzheimer's disease (AD) gray matter subtypes remain unclear.

METHODS: We analyzed data from 1323 individuals without a diagnosis of dementia (CDR < 1) with T1w-MRI and amyloid-PET, including 622 with longitudinal data (3.66 ± 1.78 years). Cortical thickness subtypes were identified using a non-negative matrix factorization (NMF) clustering algorithm. We examined clinical and demographic differences, subtype stability, and longitudinal thinning patterns using brain network models and imaging-transcriptomic analysis. Replication was performed with an alternative clustering approach and a validation cohort.

RESULTS: Two stable subtypes emerged: limbic-predominant and hippocampal-sparing. Limbic-predominant participants were older, had higher amyloid burden, and faster memory decline, while hippocampal-sparing individuals showed greater attention and executive function decline. Distinct thinning patterns were linked to specific network properties and gene expression profiles.

DISCUSSION: These MRI-based subtypes reflect underlying pathophysiological mechanisms and may aid in prognostication and clinical trial stratification.

HIGHLIGHTS: Two gray matter thickness subtypes can already be identified in preclinical stages, exhibiting distinct clinical characteristics and progression patterns. Individual subtype assignment remains stable over time. Longitudinal cortical thinning patterns follow distinct network- and transcriptomic-based mechanisms within each subtype.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Bauer A, Rabe C, Schiffman C, et al (2025)

Blood-based pre-screening in the SKYLINE secondary prevention Ph3 gantenerumab study.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70676.

INTRODUCTION: SKYLINE was a secondary prevention study that used blood-based biomarker (BBBM) pre-screening to screen out participants with a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing.

METHODS: This retrospective analysis used data from SKYLINE (ClinicalTrials.gov: NCT05256134; terminated prematurely) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to compare predicted and actual clinical performance characteristics of various biomarker combinations using prototype Elecsys[®] plasma immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland).

RESULTS: In >3500 participants screened in SKYLINE, tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein (ApoE4p) was the highest-performing BBBM combination. Actual clinical performance of the BBBM pre-screening in SKYLINE was similar to predictions based on A4 in terms of screen-out rate, positive predictive value, and 1-negative predictive value.

DISCUSSION: BBBM pre-screening in SKYLINE using prototype plasma pTau181 and ApoE4p immunoassays effectively alleviated participant burden by avoiding unnecessary PET or CSF testing.

HIGHLIGHTS: We compared blood-based biomarker (BBBM) performance in SKYLINE and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4). Pre-screening improved amyloid positivity (defined by positron emission tomography/cerebrospinal fluid) screen failure rate. Tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein was the highest-performing combination among BBBMs tested. Pre-screening eased participant burden by reducing subsequent screening procedures.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Li X, Fernandes BS, Liu A, et al (2025)

GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70779.

INTRODUCTION: Polygenic risk score (PRS) assesses genetic risk for diseases, yet some high-risk individuals avoid illness while low-risk individuals develop it. We hypothesize that unknown counterfactors may reverse PRS predictions, offering insights into disease mechanisms and interventions.

METHODS: We developed a novel framework to identify genetically-regulated pathways (GRPas) using PRS-based stratification in Alzheimer's disease (AD) and schizophrenia (SCZ) cohorts. We calculated PRS models, stratified individuals by risk and diagnosis, and analyzed differential GRPas. For AD, analyses were further conducted with and without apolipoprotein E (APOE) effects, and across APOE haplotype.

RESULTS: In AD, we identified several well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and resilience-related calcium signaling pathway, and divalent inorganic cation homeostasis.

DISCUSSION: Our method offers flexibility for exploring GRPas among PRS-stratified subgroups using summary statistics or individual-level data. Fewer GRPas identified in the no-APOE AD model and SCZ suggest a more polygenic architecture, necessitating larger samples to detect significant GRPas.

HIGHLIGHTS: Characterize genetically-regulated expression (GReX) among groups stratified by polygenic risk score (PRS) Leverage GReX and PRS to explore the resilience and susceptibility at the pathway level Highlight calcium signaling and cation homeostasis functions linked to resilience Enable personalized prevention by reinforcing the different resilience factors present or absent in each individual Our genetically-regulated pathway (GRPa) -PRS framework can be further expanded to other complex polygenic traits.

RevDate: 2025-10-14

Abdeljawaad KAA, Arynbek Y, Mamatkulov K, et al (2025)

pH modulates amyloid-β42 conformation in lipid membranes: evidence from circular dichroism, Raman spectroscopy, and molecular dynamics simulations.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Alzheimer's disease (AD) progression is strongly linked to conformational changes of amyloid-β42 (Aβ42) in neuronal membranes. This study examined the influence of pH on Aβ42 conformation in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) membranes using Raman spectroscopy, circular dichroism (CD), and molecular dynamics (MD) simulations. At acidic pH (5.5), Aβ42 predominantly adopted α-helical structures (∼75-80%), whereas neutral (pH 7.4) and alkaline conditions (pH 9.5) reduced α-helical content to ∼48-58% and ∼44-47%, respectively, with a corresponding rise in random-coil structures (∼20-36%). Across all pH conditions, β-sheet content remained minimal, although MD trajectories indicated transient β-bridge contacts suggestive of early aggregation. MD analyses revealed modest pH-dependent perturbations in bilayer thickness and lipid order. Consistency across experimental and computational methods highlights pH as a critical modulator of Aβ42 structural dynamics in membranes, providing mechanistic insight into its neurotoxic potential and informing future therapeutic strategies.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Kolouei A, M Barati (2025)

Molecular interactions of diabetes medications with alzheimer's related targets by molecular docking.

Journal of diabetes and metabolic disorders, 24(2):220.

Diabetes, a prevalent chronic disease known for its complications such as cardiovascular issues, eye damage, and neuropathy, has increasingly been linked to an elevated risk of Alzheimer's disease and cognitive impairment. Individuals with diabetes are approximately twice as likely to experience cognitive dysfunction compared to the general population. This heightened risk is potentially mediated by factors such as hypoglycemic episodes, which can negatively impact brain function, particularly the hippocampus, a key region for memory. Furthermore, shared molecular and cellular characteristics between diabetes and Alzheimer's, such as the role of insulin in amyloid plaque formation, suggest a direct link between insulin resistance in the brain and the development of Alzheimer's-related pathology. This study investigates the potential of two commonly prescribed diabetes medications, Ertugliflozin and Sitagliptin, to impact Alzheimer's disease-related factors. Ertugliflozin, an SGLT2 inhibitor, lowers blood glucose by increasing glucose excretion via the kidneys, while Sitagliptin, a DPP-4 inhibitor, enhances insulin secretion and reduces glucagon secretion by preventing the breakdown of incretin hormones. Molecular docking was performed to assess the interaction of these drugs with five key targets implicated in Alzheimer's disease: amyloid-β, β-secretase (BACE1), γ-secretase, and acetylcholinesterase (AChE). The aim was to determine whether Ertugliflozin and Sitagliptin exhibit inhibitory effects on these Alzheimer's-related targets, suggesting a potential dual role beyond their established glucose-regulating mechanisms in diabetes. In this study, Metformin was utilized as the positive control ligand. Docking analysis revealed that Ertugliflozin and Sitagliptin exhibited the highest molecular affinity for γ-secretase (PDB code: 6iyc), followed by favorable interactions with β-secretase (PDB code: 1fkn) and amyloid-β (PDB code: 1iyt). Notably, Ertugliflozin showed notable interactions with acetylcholinesterase (PDB code: 1eve), whereas Sitagliptin showed no significant interaction with acetylcholinesterase. These findings suggest that Ertugliflozin and Sitagliptin, commonly used for diabetes management, may also influence factors implicated in Alzheimer's disease. By potentially inhibiting these factors, the drugs could exhibit a dual action, benefiting both diabetes and Alzheimer's. Further in vivo and clinical studies are needed to confirm these observations.

RevDate: 2025-10-14

Atkins KJ, Evered L, Silbert B, et al (2025)

Feasibility of the Modified Telephone Interview for Cognitive Status (M-TICS) in the peri-operative environment.

Anaesthesia [Epub ahead of print].

INTRODUCTION: Peri-operative neurocognitive disorders are common among older adults presenting for surgery and anaesthesia. Cognitive screening is recommended to identify patients at risk for adverse neurocognitive outcomes, though the most appropriate peri-operative tool remains debated. Remote assessment methods may be advantageous, but they need robust validation. We aimed to examine the feasibility and validity of the Modified Telephone Interview for Cognitive Status (TICS-M) among older adults and provide recommended TICS-M scores to identify those most at risk of poor postoperative cognitive outcomes.

METHODS: As part of a prospective longitudinal study with 215 older adults living in the community or scheduled for elective surgery, we conducted the modified, 22-item, 50-point version of the TICS remotely, followed by in-person assessments using two common cognitive screening tools: the Mini-Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale Cognition Subscale (ADAS-Cog); and a comprehensive neuropsychological and functional assessment.

RESULTS: The TICS-M was feasible and acceptable, with a completion rate of 86%. TICS-M scores correlated with scores on the MMSE (r = 0.61, p < 0.001) and ADAS-Cog (r = -0.55, p < 0.001) at baseline, and associations remained consistent at 12- and 24-month follow-up. After controlling for age, sex and education, baseline performance on the TICS-M was independently associated with subsequent cognitive impairment at 12 months (OR 0.84, 95% CI 0.77-0.92, p < 0.001) and 24 months (OR 0.84, 95% CI 0.76-0.94, p = 0.001). A TICS-M score of 32.5 was the optimal threshold to identify people with cognitive impairment (0.76, 95% CI 0.70-0.82, p < 0.001).

DISCUSSION: The TICS-M is a feasible, valid and reliable remotely administered tool that shows utility in the peri-operative environment. We recommend its implementation into routine clinical practice for remote pre-operative assessment in patients aged ≥ 65 y scheduled for surgery and anaesthesia.

RevDate: 2025-10-14

Lee A, Al-Dahwi S, Angell T, et al (2025)

A systematic review of brain health in adults with chronic pain.

Anaesthesia [Epub ahead of print].

INTRODUCTION: Recent research has linked chronic pain with an increased risk of clinical dementia diagnosis. Yet structural and functional brain changes associated with chronic pain and their potential role in accelerating brain ageing have not been characterised comprehensively. Understanding these effects is crucial to developing targeted prevention and management strategies.

METHODS: We conducted a systematic review of all English language articles in MEDLINE and Embase. Studies were eligible if they compared neuroimaging, clinical, biological, cognitive or mental health outcomes in adults with chronic pain to healthy controls. Following screening, data were extracted and the risk of bias was assessed.

RESULTS: Of 5805 identified studies, 365 met the inclusion criteria. Most were cross-sectional studies with small sample sizes; conducted in middle-aged populations in China or the USA; had moderate to high risk of bias; and represented > 30 distinct pain phenotypes. Magnetic resonance imaging was the most common method for assessing brain health. Key findings in patients with chronic pain included: lower grey matter volumes and reduced fractional anisotropy; evidence of accelerated brain ageing including older brain age and higher white matter hyperintensities; mixed results in resting state functional connectivity; increased power densities and connectivity on electroencephalography; and higher levels of serum brain-derived neurotrophic factor. The most consistently affected brain regions across magnetic resonance imaging studies were the insula; anterior and posterior cingulate; thalamus; hippocampus; primary motor cortex; and cerebellum.

DISCUSSION: Adults with chronic pain exhibit widespread alterations in brain health compared with healthy controls. Several observed features overlap with biomarkers of Alzheimer's disease and other forms of neurodegeneration. These findings highlight the need for larger, well-designed studies incorporating clearly defined pain phenotypes, multimodal imaging and causal inference methods to clarify the role of chronic pain in brain ageing and dementia risk.

RevDate: 2025-10-14

Raabe AC, Correa RAS, Rodrigues CCPR, et al (2025)

History, Challenges, and Perspectives of CNS-Targeted Transdermal Formulations.

Current pharmaceutical design pii:CPD-EPUB-150979 [Epub ahead of print].

Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (Sch) present significant challenges for healthcare systems, both in terms of prevalence and the complexity of pharmacological treatment. While current therapies offer symptomatic relief, there is a high rate of failure in addressing the full spectrum of clinical symptoms and patient adherence issues, especially in long-term care. Since ancient times, various civilizations, including the Chinese, Egyptians, and indigenous South African cultures, have investigated and utilized the transdermal route for therapeutic and medicinal applications. Recent advances in transdermal drug delivery systems (TDS) offer a promising alternative to traditional routes of administration, enhancing drug absorption and minimizing side effects, such as gastrointestinal distress. This review explores the potential of TDS for improving the pharmacotherapy of AD, PD, and Sch. We also highlight the ongoing challenges in optimizing TDS formulations, such as drug absorption through the skin, skin irritation, and maintaining therapeutic efficacy. Furthermore, the review discusses the progress in prodrug design strategies aimed at enhancing skin permeation and bioavailability, particularly in the context of CNS-targeted drugs. The need for continued research into TDS technology is emphasized, as it holds promise for improving treatment adherence, patient quality of life, and caregiver burden, thereby advancing therapeutic options for CNS disorders.

RevDate: 2025-10-14

Schiavoni V, Alia S, Pompei V, et al (2025)

Resveratrol Supplementation Modulates Endothelial Dysfunction in Alzheimer's Disease (AD): In Vitro Effects on Human Aortic Endothelial Cells Exposed to AD Plasma.

Current neuropharmacology pii:CN-EPUB-150967 [Epub ahead of print].

INTRODUCTION: Increasing evidence indicates a connection between Alzheimer's disease (AD) and endothelial dysfunction. Given the lack of a definitive cure for AD, the purpose of this research was to explore the impact of a short incubation with plasma samples obtained from 30 patients with sporadic AD and 21 age- and sex-matched control subjects on cultured human aortic endothelial cells (HAECs), as well as to assess the effects of resveratrol (RSV) supplementation to the plasma.

METHODS: Specifically, the study analyzed: the production of nitric oxide (NO) and peroxynitrite; the activities of superoxide dismutase (SOD) and Na+/K+-ATPase; membrane fluidity; and levels of thiobarbituric acid-reactive substances (TBARS).

RESULTS: When incubated with AD plasma, cells showed a decrease in NO levels, enzymatic activities, and membrane fluidity, as well as an increase in peroxynitrite and TBARS production, compared to those exposed to plasma from healthy controls. In contrast, supplementation with RSVenriched plasma, reduced reactive oxygen species (ROS) levels, and enhanced SOD activity. RSV also improved endothelial function, by increasing membrane fluidity, Na+/K+-ATPase activity, and enhancing NO production and bioavailability, potentially benefiting cerebral perfusion.

DISCUSSION: Though preliminary, our findings highlight the critical role played by vascular health in Alzheimer's disease, and the potential impact of resveratrol in maintaining the endothelial integrity, thus mitigating the progression of AD .

CONCLUSION: In conclusion, our study supports the use of dietary natural compounds to reduce oxidative stress and prevent or reverse vascular endothelial dysfunction associated with AD.

RevDate: 2025-10-14

Tamaddon-Abibigloo Y, Dastmalchi S, Mahdipanah F, et al (2025)

Isatin Derivatives as Emerging Promising Anti-Alzheimer Agents: Focusing on Their Chemical Structure and Biological Targets.

Current topics in medicinal chemistry pii:CTMC-EPUB-150957 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder with a complex pathology. Until now, there is no generally effective treatment for AD. Isatin is a natural alkaloid whose derivatives have shown a wide spectrum of biological activities. This molecule is also the basic scaffold for several compounds with useful biological properties against AD. In this review, for the first time, we focus on the anti-AD properties of isatin derivatives. We tried to present comprehensive data about their structure and mechanism of action. Results showed that indirubins, isatin Schiff Bases, and spiro derivatives of isatin were the most studied molecules. The most studied targets were the glycogen synthase kinase-3, cholinesterases, and amyloid beta aggregation. It was concluded that isatin could be considered an important scaffold for the development of new anti-AD compounds.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Amniouel S, Suh J, Zheng W, et al (2025)

Beyond amyloid: nanobody-mediated neuroinflammatory therapy for Alzheimer's disease.

Translational neurodegeneration, 14(1):51.

Alzheimer's disease (AD) is one of the most common and devastating neurodegenerative diseases, characterized by accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles of tau protein, and persistence of neuroinflammation, leading to progressive cognitive decline, loss of independence, emotional and financial strain on families, and significant societal costs. Current anti-amyloid treatments are partly successful in removing Aβ amyloid, but often lead to increased inflammation. This leads to limited therapeutic efficacy and causes side effects such as amyloid-related imaging abnormalities. In addition, they do not address neuroinflammation in AD patients. In this review, we discuss a new therapeutic strategy that combines single-domain antibodies (sdAbs, nanobodies) against Aβ fibrils and anti-inflammatory drugs and applies them to the regions of neuroinflammation associated with the plaques in AD patients. This strategy aims to control the function of activated microglia and astrocytes, thereby avoiding unnecessary immunosuppression. We also discuss the unique features of sdAbs, including small size, good tissue penetration, and lack of Fc-mediated immune reactions, as well as relevant payloads (i.e., small molecules, biologics, and nanoparticles) and delivery systems. This immunomodulatory therapy targets the plaques specifically and therefore represents a promising opportunity to improve amyloid clearance and target the inflammatory components of AD, potentially improving the therapeutic efficacy of the disease.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Kirsebom BE, Nilsson J, Vromen E, et al (2025)

Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways.

Molecular neurodegeneration, 20(1):107.

BACKGROUND: Synapse loss is linked to cognitive symptoms in Alzheimer's Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets.

METHODS: We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins.

RESULTS: In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts.

CONCLUSIONS: Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.

RevDate: 2025-10-14

Springer MV, Chang W, Heeringa SG, et al (2025)

Population Attributable Fraction for Cognitive Impairment in Mexican American Older Adults.

Journal of racial and ethnic health disparities [Epub ahead of print].

BACKGROUND: The contribution of modifiable risk factors to cases of mild cognitive impairment (MCI) and Alzheimer's disease and related dementias (AD/ADRD) among Hispanic/Latin (a,o,x) adults is unclear.

OBJECTIVE: To determine the population attributable fraction (PAF), the proportion of MCI and AD/ADRD cases that would be eliminated with elimination of modifiable risk factors.

METHODS: This was a cross-sectional analysis nested within a prospective cohort study (2018 - 2023) of Mexican American older adults. Logistic regression estimated the odds of probable MCI or AD/ADRD (defined by education-specific cutoff scores on the Montreal Cognitive Assessment) associated with age, sex, education, medical comorbidities, cigarette smoking, and alcohol consumption. We calculated the PAF for MCI and AD/ADRD associated with individual and combined risk factors.

RESULTS: Among 1,272 participants, the prevalence of MCI was 48% and of AD/ADRD was 23%. Having no more than a high school education was associated with a PAF for MCI of 17% (95% CI, 10 - 24%) and a PAF for AD/ADRD of 52% (95% CI, 40 - 64%). Heart disease and diabetes were each associated with a PAF for MCI of 5% (95% CI, 3 - 7% and 95% CI, 1 - 10% respectively). A history of stroke was associated with a PAF for AD/ADRD of 7% (95% CI, 3 - 11%). The elimination of all modifiable risk factors was associated with 28% of MCI and 55% of AD/ADRD cases.

DISCUSSION: Low educational attainment and cardiovascular comorbidities greatly contribute to cases of MCI and AD/ADRD among Mexican American adults.

RevDate: 2025-10-14
CmpDate: 2025-10-14

Huang XT, Huang LY, Tan CC, et al (2025)

The role of APOE ε4 in modulating the relationship between non-genetic risk factors and dementia: a system review and meta-analysis.

Journal of neurology, 272(10):690.

BACKGROUND: The ε4 allele of the apolipoprotein E gene (APOE ε4) is the strongest genetic risk factor for dementia. However, it remains unclear whether APOE ε4 status modulates the associations of non-genetic risk factors and dementia risk. This study aims to comprehensively evaluate this potential modulating role.

METHODS: A systematic search of electronic databases was conducted up to June 2023. Population-based longitudinal studies were included if they reported associations of risk factors with all-cause dementia (ACD) or Alzheimer's disease (AD) stratified by APOE ε4 status. Subgroup and meta-regression analyses were performed to test stratification effects by APOE ε4.

RESULT: A total of 170 studies (173 factors) were included, with 48 factors for meta-analyses. Meta-regression confirmed significant modification effect by APOE ε4 status for nine risk factors. Stronger associations in APOE ε4 carriers were found for nonsteroidal anti-inflammatory drugs, statins, frequent drinking, and high systolic blood pressure; in noncarriers, stronger associations were observed for light-to-moderate alcohol consumption, female sex, physical activity, diabetes, and loneliness. Diabetes specifically increased AD risk only in APOE ε4 noncarriers. Additionally, the subgroup analyses stratified by APOE ε4 status indicated that nine other factors may influence risk differentially between carriers and noncarriers, though the associations were not significant in meta-regression (vitamin E intake, heart failure, serum neurofilament light chain, serum testosterone, agitation, air NO2 concentration, ever smoker, current smoker, and head injury).

CONCLUSION: Evidence from the current investigation suggests that APOE ε4 defines distinct etiological pathways for dementia, underscoring the promise of genotype-tailored prevention strategies.

RevDate: 2025-10-13

Fieldhouse R (2025)

Men's brains shrink faster than women's: what that means for Alzheimer's.

RevDate: 2025-10-13
CmpDate: 2025-10-14

Li Y, Yi P, Jin M, et al (2025)

A radiomics model predicts progression from mild cognitive impairment to alzheimer's disease using structural MRI.

Scientific reports, 15(1):35679.

The aim of this study is to build and validate a model based on structural magnetic resonance imaging (sMRI) to predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). A total of 343 patients with MCI were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database as study subjects. Among them, 154 patients progressed to AD during the 48-month follow-up. All subjects were randomly divided into a training set (n = 240) and a validation set (n = 103) in a 7:3 ratio according to enrollment time. The baseline T1-weighted (T1W) structural MR images of each patient were automatically segmented into whole-brain three-dimensional (3D) white and gray matter images based on the training set data. In addition, radiomics signatures were extracted from each structural image. Baseline neuropsychological scores were combined with the radiomics signatures to construct a prediction model using machine learning. The diagnostic accuracy and reliability of the model were evaluated using the receiver operating characteristic (ROC) curve analysis in both the training and validation sets. Stepwise logistic regression analysis showed that clinical dementia rating (CDR), Alzheimer's Disease Assessment Scale (ADAS-cog) and radiomics markers were independent predictors of progression from MCI to AD. ROC curve showed that the AUC values of CDR, ADAS-cog and radiomics markers in the training set and validation set were 0.895 and 0.882, respectively. The sensitivity was 0.933 and 0.977, and the specificity was 0.669 and 0.661, respectively. DeLong test showed that the diagnostic efficacy of the comprehensive model was significantly different from that of the independent predictors (P = 0.023). The integrated model, based on structural analysis of magnetic resonance images, can accurately identify and predict individuals with MCI at high risk of progressing to AD.

RevDate: 2025-10-13

Hu M, Robinson O, Lill CM, et al (2025)

Plasma Proteomic Signatures for Alzheimer's Disease: Comparable Accuracy to ATN Biomarkers and Cross-Platform Validation.

Annals of clinical and translational neurology [Epub ahead of print].

BACKGROUND: There is growing recognition of the potential of plasma proteomics for Alzheimer's Disease (AD) risk assessment and disease characterization. However, differences between proteomics platforms introduce uncertainties regarding cross-platform applicability.

OBJECTIVE: We aimed to identify a detailed plasma biosignature for distinguishing AD from cognitively normal (CN) and another signature for classifying mild cognitive impairment (MCI) decliners and non-decliners. We also explored the cross-platform applicability of these models between two proteomic platforms.

METHODS: Elastic net was performed on 190 plasma analytes measured using the Luminex xMAP platform in 566 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to model MCI stable/decliner and AD/CN classification. MCI decliner was defined as progression to AD during follow-up (mean 4.2 ± 3.2 years). External cross-platform validation was conducted with 1303 participants from the Spanish Ace study, using the SOMAscan 7k platform.

RESULTS: An 11-analyte signature for distinguishing AD from CN achieved a 93.5% accuracy on ADNI and 95.2% on Ace. The ApoE and BNP proteins were the two most important contributors to the classifier. The MCI classification signature performed less well, with 65.9% accuracy on ADNI and 51.0% accuracy upon validation testing in Ace.

DISCUSSION: Compared with prior proteomic-based studies on the same dataset, our findings attained higher specificity and sensitivity for AD classification while utilizing a smaller panel of analytes. We also confirmed the reliability and consistency of this signature within a different population from a different platform. The plasma proteomic platforms explored were, however, not sufficient to determine MCI decliners versus non-decliners.

RevDate: 2025-10-13

Kimata AR, Chan M, Zheng B, et al (2025)

Effect of Fornix Stimulation on Acute Memory Encoding.

Journal of neurophysiology [Epub ahead of print].

The reported memory-related effects of stimulating different nodes within the classical Circuit of Papez have been inconsistent, though the possibility of immediate or chronic memory benefit remains. We undertook memory experiments during deep brain stimulation (DBS) in human subjects with mild, early Alzheimer's Disease (2 males, 3 females; n=5) to rigorously investigate the effects of fornix stimulation on acute memory function. We sought to assess whether some of the reported variability may be attributed to the stimulation protocol, and to determine whether stimulation alters memory formation per se, rather than influencing a process required for but not directly related to memory encoding. We tested fornix stimulation during both awake DBS surgery and post-operatively, in subjects participating in a broader clinical trial (ADvance II). In both settings, using a parametric episodic memory task with distinct encoding, attention, and delayed recall phases, we found that fornix stimulation generally impaired memory, with higher frequencies producing the greatest detriments on memory performance. Furthermore, stimulation specifically interacted with trial-by-trial memory encoding, rather than with other functions such as visual-spatial processing, attention, or short-term working memory. Therefore, in both contexts and across a wide range of stimulation frequencies, open-loop fornix stimulation directly impaired acute, item-specific memory encoding, though the effects of more chronic stimulation on memory and cognitive function are yet to be determined.

RevDate: 2025-10-13

Su C, He H, Zeng Q, et al (2025)

A Scandium-Doped Gold Nanocluster with Enhanced Electrochemiluminescence Triggered by Low Potentials for Ultrasensitive Detection of an Alzheimer's Biomarker in Urine.

Analytical chemistry [Epub ahead of print].

The development of high-performance electrochemiluminescence (ECL) systems operating at low triggering potentials remains a critical challenge for advancing their practical applications in bioassays. In this study, a novel ECL system based on a scandium-doped gold nanocluster (Sc@AuNC) and N,N-diisopropylethylamine (DIPEA) had been designed for ultrasensitive detection of urinary Alzheimer's disease-associated neuronal thread protein (AD7c-NTP). By using DIPEA as a low-oxidation-potential coreactant and synergistic doping of Sc to promote free radical generation in the coreactant through accelerated electron transfer, the Sc@AuNC/DIPEA system achieved a 40.89-fold enhancement in ECL intensity and a higher ECL quantum yield (ΦECL) of 35.19% at 0.75 V, surpassing conventional AuNC systems. Utilizing this system, a sandwich-type ECL immunoassay (ECLIA) platform was developed, demonstrating a linear detection range of 0.001 to 100 ng/mL for AD7c-NTP with a detection limit of 0.45 pg/mL (S/N = 3). Owing to the low triggering potential, the ECL system exhibited inherent anti-interference capability by minimizing electrochemical side reactions and preserving biomolecular integrity, as evidenced by stable signals in complex urine matrices. Critically, the satisfactory recovery of clinical urine samples and high correlation with ELISA kits confirmed the utility of the constructed detection platform. This work not only advances ECL technology through coreaction acceleration but also provides a practical, scalable strategy for early Alzheimer's disease screening.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Gloger EM, Smith PJ, SC Segerstrom (2025)

Higher interleukin-6 (IL-6) is associated with decline in psychomotor processing speed but not executive functioning in older adults: Gender-specific effects.

The journals of gerontology. Series B, Psychological sciences and social sciences, 80(11):.

OBJECTIVES: Elevated peripheral inflammatory markers among older adults are associated with cognitive decline, particularly for women, for whom cognitive decline is more prevalent and rapid. Few prospective studies have examined gender-specific associations between inflammation and cognitive decline or examined stable, mean differences (i.e., between-person effects) versus fluctuations (i.e., within-person effects) in inflammation.

METHODS: Participants (N = 235) were older adults (Mage= 75.1, range = 60-92) from a longitudinal study that included neuropsychological assessments and blood draws every six months for up to 12 years. Systemic inflammation was operationalized as serum interleukin-6 (IL-6). The Trail Making Test measured psychomotor processing speed (TMT-A), task-switching (TMT-B), and executive functioning (TMT-B-TMT-A). Multilevel models tested associations between cognition and inflammation and moderation by gender. Models controlled for relevant covariates (e.g., age, gender, education, body mass index, cardiovascular medication count).

RESULTS: Higher mean IL-6 was associated with slower TMT-A performance for women (γ = .036, p = .04) but not men (γ = -.01, p = .45). Higher mean IL-6 was associated with slower TMT-B performance (γ = .036, p = .02), but not after covariate adjustment (γ = .016, p = .28) and there was no significant moderation by gender. There were no significant associations between within-person IL-6 and any outcome, between- or within--person IL-6 and TMT B-A performance, or any 3-way interactions between gender, IL-6, and study wave on any outcome.

DISCUSSION: Psychomotor speed, but not executive function, was sensitive to changes in systemic inflammation in a gender-specific way. -Gender-specific differences in neurological aging remain a fruitful direction and critical target for future intervention research aimed at addressing preclinical Alzheimer's disease and accelerated aging.

RevDate: 2025-10-14

Alkhammash A, Alotaibi G, Algethami A, et al (2025)

Decoding apoptosis-associated pathways in inflammatory and neurodegenerative diseases: A network pharmacology based drug discovery approach.

European journal of pharmacology, 1007:178231 pii:S0014-2999(25)00985-9 [Epub ahead of print].

Neurodegenerative diseases, particularly Alzheimer's disease (AD), continue to pose significant global health challenges due to their progressive nature, multifactorial etiology, and limited therapeutic options. Contemporary research increasingly emphasizes the potential of phytochemicals derived from medicinal plants in mitigating the complex pathology of such disorders. This study employs a comprehensive network pharmacology approach integrated with molecular docking and simulation techniques to explore the therapeutic potential of bioactive compounds from 12 ethnomedicinal plants, including Ginkgo biloba, Withania somnifera, Curcuma longa, and others. A total of 1218 potential targets were identified via SwissTargetPrediction, which were cross-referenced with Alzheimer's-related genes retrieved from OMIM and GeneCards databases, revealing 479 overlapping targets. Subsequently, protein-protein interaction (PPI) network analysis identified top hub genes including AKT1, CASP3, TNF, and BCL2 as central to disease modulation. Gene ontology and KEGG pathway enrichment analyses highlighted critical biological processes such as apoptosis regulation, inflammatory response, and synaptic signaling. Docking and simulation studies revealed strong binding affinities between selected phytochemicals such as Quercetin, Luteolin, Rosmarinic acid and core targets, suggesting their role in neuroprotection. Particularly, compounds like Quercetin and Rosmarinic acid demonstrated notable interactions with TNF and AKT1, as evidenced by their high docking scores and stable RMSD values. The plant-compound-target-pathway network further consolidated their multi-targeted regulatory potential. Overall, this integrated computational framework provides mechanistic insights into the neurotherapeutic actions of selected natural compounds, paving the way for future experimental validations and drug development strategies targeting Alzheimer's disease.

RevDate: 2025-10-13

Ye Q, Gast G, Holmes TC, et al (2025)

Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuits mapping.

Neurobiology of disease pii:S0969-9961(25)00356-0 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We know now there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations for human AD behavioral defects, such as sex differences and higher level visual deficits. These recent developments in neural circuits level concepts and technology present new opportunities for studying AD pathogenesis for early identification of the disease and for developing novel therapeutic interventions.

RevDate: 2025-10-13

Antonopoulos G, More S, Eickhoff SB, et al (2025)

Region-wise stacking ensembles for estimating brain-age using structural MRI.

Computers in biology and medicine, 198(Pt A):111182 pii:S0010-4825(25)01535-5 [Epub ahead of print].

Predictive modeling using structural magnetic resonance imaging (MRI) data is a prominent approach to study brain-aging. Machine learning frameworks have been employed to improve predictions and explore healthy and accelerated aging due to diseases. The high-dimensional MRI data pose challenges to building generalizable and interpretable models as well as for data privacy. Common practices are resampling or averaging voxels within predefined parcels which reduces anatomical specificity and biological interpretability. Effectively, naive fusion by averaging can result in information loss and reduced accuracy. We present a conceptually novel two-level stacking ensemble (SE) approach. The first level comprises regional models for predicting individuals' age based on voxel-wise information, fused by a second-level model yielding final predictions. Eight data fusion scenarios were explored using Gray matter volume (GMV) estimates from four large datasets. Performance measured using mean absolute error (MAE), R[2], correlation and prediction bias, showed that SE outperformed the region-wise averages. The best performance was obtained when first-level regional predictions were obtained as out-of-sample predictions on the application site with second-level models trained on independent and site-specific data (MAE = 4.75 vs baseline regional mean GMV MAE = 5.68). Performance improved as more datasets were used for training. First-level predictions showed improved and more robust aging signal providing new biological insights and enhanced data privacy. Overall, the SE improves accuracy compared to the baseline while preserving or enhancing data privacy. Finally, we show the utility of our SE model on a clinical cohort showing accelerated aging in cognitively impaired and Alzheimer's disease patients.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Ravndal A, Fjell AM, Vidal-Piñeiro D, et al (2025)

Sex differences in healthy brain aging are unlikely to explain higher Alzheimer's disease prevalence in women.

Proceedings of the National Academy of Sciences of the United States of America, 122(42):e2510486122.

As Alzheimer's disease (AD) is diagnosed more frequently in women, understanding the role of sex has become a key priority in AD research. However, despite aging being the primary risk factor for AD, it remains unclear whether men and women differ in the extent of brain decline with age. Using 12,638 longitudinal brain MRIs from 4,726 participants aged 17 to 95 y across 14 cohorts, we examined sex differences in structural brain changes over time, controlling for differences in head size. Men showed greater cortical thickness (CT) decline in the cuneus, lingual, parahippocampal, and pericalcarine regions; surface area decline in the fusiform and postcentral regions; and in older adults, greater subcortical decline in the caudate, nucleus accumbens, putamen, and pallidum. In contrast, women only showed greater surface area decline in the banks of the superior temporal sulcus and greater ventricular expansion in older adults. These results suggest that sex differences in age-related brain decline are unlikely to contribute to the higher AD diagnosis prevalence in women, necessitating research into alternative explanations.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Hao X, Ding N, Zhang Y, et al (2025)

Acupuncture Strategies in a Mouse Model of Alzheimer's Disease.

Journal of visualized experiments : JoVE.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Numerous studies have demonstrated that alterations in intestinal flora can influence the central nervous system (CNS) through multiple pathways, ultimately contributing to the onset and progression of AD. Recent research suggests the limitations of pharmacological therapies, emphasizing the need for multi-targeted interventions in AD treatment. Traditional Chinese medicine (TCM) highlights the physiological and pathological relationship between the brain and the intestine. Therefore, therapeutic strategies targeting gastrointestinal regulation to enhance brain function are of great importance for delaying the pathological progression of AD. This protocol introduces a brain-intestine coordination acupuncture method. The experimental results showed that this acupuncture protocol could modulate intestinal flora, suppress intestinal inflammation and neuroinflammation in AD model mice, thereby achieving bidirectional therapeutic effects on brain-intestine regulation. Moreover, a mouse bag fixation device for acupuncture treatment was described in this study, which can reduce stress reaction and improve experimental efficiency.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Zeng Z, Wei M, Zheng K, et al (2025)

A Liposome Membrane Permeability Assay for Investigating the Effects of Phosphatidylinositol Phosphate Groups on Membranotropic Action of Venom PLA2.

Journal of visualized experiments : JoVE.

We developed a novel, cost-effective, and highly sensitive assay for assessing liposomal membrane permeability based on ligand substitution reactions involving ligands encapsulated in the inner volume of liposomes, which we combined with a hydrolytic activity assay (using coenzyme A acylation) and molecular modeling simulation to investigate whether phosphates of the inositol ring in phosphatidylinositol protect membranes from the damaging effects of aberrantly expressed enzymes. Aberrant expression of phospholipases A2 (PLA2) leads to demyelination of axons that triggers the development of multiple sclerosis and Alzheimer's disease. To mimic the effects of aberrantly expressed PLA2, we used the basic subunit of viper venom PLA2, HDP-2P. The HDP-2P was tested on phosphatidylcholine (PC) liposomes enriched with phosphatidylinositol, phosphatidylinositol-4-phosphate (PI-4-P), or phosphatidylinositol-4,5-diphosphate (PI-4,5-P2). While HDP-2P showed minimal hydrolytic activity and only slightly increased permeability in PC liposomes, enrichment of PC liposomes with PI enhanced both hydrolysis and permeability. Remarkably, PI-4-P and PI-4,5-P2 dramatically inhibited HDP-2P's hydrolytic activity and completely reduced permeability. Molecular modeling simulations revealed that phosphates of the inositol ring in phosphatidylinositol sterically block phospholipid access to HDP-2P's active site, preventing hydrolysis. Both in vitro and in silico data suggest that phosphorylated phosphatidylinositols are associated with reduced PLA2 activity, indicating a potential mechanism for mitigating excessive PLA2 activity -- presumably as a means of protecting cell membranes from degeneration.

RevDate: 2025-10-13

Pu R, Song X, L Chai (2025)

Graph Signal Entropy for Analyzing Functional Brain Abnormalities of Alzheimer's Disease Patients.

IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society, PP: [Epub ahead of print].

A majority of research shows that the brain complexity of Alzheimer's disease (AD) patients is smaller than that of healthy controls (HCs). In this paper, we propose a novel method based on graph signal entropy to investigate the complexity of functional brain networks in AD patients. By using a spectral graph wavelet filter to decompose the subjects' BOLD signal, we generate distinct functional brain networks for each graph frequency band. We then use the multivariate dispersion entropy to examine the abnormal complexity of AD patients across different graph frequency bands. Experimental results reveal that in the low and mid-frequency bands, the brain complexity of AD patients is generally larger than that of HCs, which challenges the conventional understanding that AD is consistently associated with reduced complexity. Moreover, widely reported abnormal brain regions in AD, such as the hippocampus and parahippocampal gyrus, exhibit significant differences only at specific frequency bands, indicating the necessity of frequency-resolved analysis. These findings uncover new characteristics of functional brain networks in AD patients and provide deeper insights into the disease's complex neural mechanisms.

RevDate: 2025-10-13

Zhu J, Li Z, Zheng Z, et al (2025)

Accurate Generation of Conformational Ensembles for Intrinsically Disordered Proteins with IDPFold.

Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Epub ahead of print].

Intrinsically disordered proteins (IDPs) play pivotal roles in various biological functions whose dynamic structures are closely associated with many human diseases, including cancer, diabetes, and Alzheimer disease. Structural investigations of IDPs typically involve a combination of molecular dynamics (MD) simulations and experimental data to mitigate intrinsic biases in simulation methods. However, the high computational cost of these simulations and the limited availability of experimental data significantly restrict their applicability. Despite the recent advancements in structure prediction for structured proteins, understanding the conformational properties of IDPs remains challenging, partly due to the poor conservation of disordered protein sequences and the scarcity of experimental characterization. Here, IDPFold is introduced as a method capable of generating conformational ensembles for IDPs directly from their sequences using fine-tuned diffusion models. IDPFold eliminates the reliance on multiple sequence alignments (MSA) or experimental data, offering a more detailed characterization of structural features in IDP ensembles. Evaluated across 27 IDP systems, IDPFold achieves Rg error of -0.06 and an RMSD of 0.65 ppm on Cα secondary chemical shifts with experimental values, significantly better than all existing generative deep learning approaches. IDPFold can be used to elucidate the sequence-disorder-function paradigm of IDPs.

RevDate: 2025-10-13

Verrienti G, Lombardozzi G, Albergo G, et al (2025)

Trazodone in neurology, a new life for an old molecule - an updated, comprehensive, systematic review of clinical trials.

International journal of psychiatry in clinical practice [Epub ahead of print].

INTRODUCTION: The triazolopyridine derivative trazodone is approved for the treatment of major depressive disorder (MDD) in adults; according to the available literature, this molecule, through a specific dose-dependent profile of action, was found to be a potential therapeutic option in some neurological conditions. This systematic review aimed to synthesise the available evidence on the use of trazodone in neurological patients.

METHODS: PubMed was searched for articles published from inception until March 2025. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials specifically investigating trazodone in neurological populations were included, following PRISMA guidelines for systematic reviews.

RESULTS: Out of 69 records initially retrieved, 14 studies met the inclusion criteria, comprising 13 randomised controlled trials and 1 retrospective study, with a total of 608 patients. Most of the included studies focused on individuals with dementia, while others explored its use in different neurological disorders.

CONCLUSIONS: Despite being an older antidepressant, trazodone remains widely prescribed. Beyond treating depression in neurological patients, it may may be useful in the treatment of some neurological aspects. However, current evidence remains limited. Further high-quality research is necessary to better define the therapeutic potential of trazodone in the management of neurological conditions.

RevDate: 2025-10-13

Chen Y, Ding L, Gu Z, et al (2025)

Aβ Deposition in Extracellular Space Disrupts Glial-Neuron Communication and Triggers Alzheimer's Disease.

Aging and disease pii:AD.2025.0873 [Epub ahead of print].

Disruptions in glial-neuron communication are linked to brain diseases; however, the exact mechanisms are not yet fully understood. This review highlights the critical role of glia-neuron interactions in sustaining normal brain functions. Under physiological conditions, astrocytes, microglia and oligodendrocytes, collaboratively regulate the homeostasis of brain structures and functions through diverse communication mechanisms. Conversely, under pathological conditions, disorders in glial-neuron communication can precipitate in neurodegenerative diseases, such as Alzheimer's Disease (AD). In AD, astrocytes use APOE to increase amyloid-beta (Aβ) deposition in the brain extracellular space (ECS) and neuron death, while microglia overactivation causes Tau overexpression and oligodendrocyte demyelination, leading to communication issues. Toxic proteins, Aβ and Tau, block brain ECS and hinder the drainage of interstitial fluid (ISF) cause the vicious cycle. The obstruction of ISF drainage certainly impedes neurotransmitter transmission, nutrient delivery, and waste removal, ultimately leading to neuronal death and cognitive decline in AD, which is also a direct factor contributing to the failure of drug delivery. Age-associated formaldehyde (FA) may act as a detrimental factor that exacerbates Aβ aggregation and promotes tau hyperphosphorylation, further aggravating ECS and ISF dysfunction. Interestingly, the interrupting the pathological cycle of FA-promoted Aβ aggregation and Aβ-induced FA generation by phototherapy and nanomedicine has been found to restore the ECS architecture and ISF drainage, which effectively improves AD symptoms. Hence, the re-establishing ECS structure and communication between neurons and glial cells may offer a promising therapeutic strategy for treating AD.

RevDate: 2025-10-13

Collier JM, McFarland M, Krishna S, et al (2025)

Impairment of astrocyte homeostasis and lysosomal function in Alzheimer's disease pathogenesis.

Aging and disease pii:AD.2025.0694 [Epub ahead of print].

Physiological functions of astrocytes, the most abundant cell type in the brain, are important in maintaining many central nervous system (CNS) functions. In this review, we summarized astrocytes' normal physiological roles. However, under the pathological conditions of Alzheimer's Disease (AD), astrocytes pause their homeostatic roles to address and contain abnormal changes in AD brains in response to Aβ deposits, neuroinflammation, and neurodegeneration. The chronic perturbation in AD brains causes various populations of astrocytes to permanently forgo their physiological roles throughout different regions of the brain to contain disease progression. This transition leads to reactive astrogliosis, in which astrocytes transform into reactive phenotypes that eventually contribute to pathological severity. The transformations in astrocytes can negatively impact their morphology and mobility, inflammatory response, energy metabolism, and their ability to properly degrade Aβ deposits. We reviewed recent literature exploring the underlying mechanisms on how AD induces astrocyte morphological, transcriptional, and functional changes. Together, these findings reveal that loss of astrocyte homeostatic function and transformations into neurotoxic states contribute to AD pathology throughout each stage of disease progression. Thus, aims to restore astrocyte homeostatic functions by developing astrocyte-specific therapeutic targets to attenuate AD pathology and clinical manifestations are warranted.

RevDate: 2025-10-13

Thadathil N, Wolf NA, Wolf R, et al (2025)

Neuronal Necroptosis Drives Neuroinflammation and Cognitive Decline Independent of Neuronal Cell Death.

Aging and disease pii:AD.2025.0805 [Epub ahead of print].

Markers of necroptosis increase in neurons with neurodegenerative diseases and aging. Using a novel knockin mouse model that overexpresses the terminal necroptosis effector gene MLKL specifically in neurons (nMlkl-KI), we studied the impact of inducing necroptosis in neurons of young/adult mice on cognition. At 6-months of age, nMlkl-KI mice exhibited a 7-fold and 3-fold increase in MLKL monomer expression in the cortex and hippocampus, respectively. Correspondingly, MLKL-oligomer levels increased 3- to 4-fold in these brain regions, indicating necroptosis activation. The increased necroptosis was associated with an induction of neuroinflammation as shown by an increase in transcript levels of inflammatory markers and increased Iba-1 expression in the cortex and hippocampus. At 12-months of age, nMlkl-KI mice exhibited significant cognitive impairment compared to control mice as measured by a continuous home-cage discrimination learning with the Noldus PhenoTyper. For example, cumulative learning index during the reversal phase and cognitive flexibility were dramatically reduced in nMlkl-KI mice as compared to the control mice. Unbiased stereological analysis revealed no loss in neuronal number in the cortex and hippocampus, suggesting neuronal dysfunction rather than neuronal death was responsible for the reduced cognition observed in the nMlkl-KI mice. Transcriptomic analysis of the cortex revealed an upregulation of pathways associated with age-related neurodegenerative diseases (e.g., Parkinson's, Alzheimer's, Huntington's) as well as chemokine and TNF signaling in the nMlkl-KI mice. In contrast, the neuroactive ligand-receptor interaction pathway was downregulated. Collectively, these data show for the first time that the overexpression of MLKL in neurons leads to a loss in cognition in the absence of neuronal cell death, demonstrating that increased MLKL can interfere with neuronal functions involved in cognition.

RevDate: 2025-10-13

Lu M, Kim MJ, Collins EC, et al (2025)

Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

JAMA neurology pii:2839837 [Epub ahead of print].

IMPORTANCE: Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit.

OBJECTIVE: To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD.

This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025.

INTERVENTIONS: Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks.

MAIN OUTCOMES AND MEASURES: Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker.

RESULTS: Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]).

CONCLUSIONS AND RELEVANCE: The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04437511.

RevDate: 2025-10-13

Harrass S, Quansah M, Kumar S, et al (2025)

Lactobacilli Probiotics Prevent Amyloid-Beta Fibril Formation In Vitro.

Probiotics and antimicrobial proteins [Epub ahead of print].

Alzheimer's disease (AD) is characterized by the buildup of extracellular aggregated amyloid-β (Aβ) peptides, following sequential enzymatic cleavage of amyloid precursor protein, along with intraneuronal accumulation of hyperphosphorylated Tau proteins and subsequent neuronal loss. Despite extensive research, the precise mechanisms underlying Aβ and Tau-mediated neurodegeneration remain elusive. Inhibiting protein aggregation has been a primary focus for mitigating neuronal toxicity. Probiotics have emerged as a promising preventative measure against cognitive decline in AD, with several in vivo and clinical trials demonstrating the efficacy of select bacterial strains in slowing AD progression. However, these studies lack direct molecular evidence on the effects of probiotics on Aβ aggregation kinetic. Inhibiting protein aggregation is key to reducing neuronal toxicity. While probiotics have shown promise in preventing cognitive decline in Alzheimer's disease, supported by in vivo and clinical studies, direct molecular evidence of their impact on Aβ aggregation kinetics remains lacking. In this study, we conducted bioinformatic and physicochemical assessments, including molecular docking of proteins derived from 13 probiotic strains against Aβ and Tau, identifying four strains predicted to efficiently inhibit Aβ aggregation. Kinetic studies confirmed that both the probiotic formulation and its derived supernatant significantly inhibited the conversion of monomeric Aβ and Tau into aggregated forms. To explore bioavailability, we administered the probiotic formulation to healthy individuals and detected its presence in stool samples, demonstrating survival through the gastrointestinal tract. These findings suggest that specific probiotic strains may serve as therapeutic candidates for targeting Aβ and/or Tau aggregation, with further studies warranted to assess their potential clinical utility in AD.

RevDate: 2025-10-13

Ntondini TL, Naki T, S Alven (2025)

The therapeutic efficacy of nanoparticles in the treatment of alzheimer's disease.

Acta neurologica Belgica [Epub ahead of print].

The build-up of beta-amyloid plaques in the brain leads to Alzheimer's disease (AD), a neurodegenerative condition. AD affects more than 30 million individuals globally every year. No cure for AD has been discovered yet. The available therapeutic options are administered to slow down the progress of the disease. The currently available treatment plans are used to relieve symptoms and improve cognitive abilities, thus slowing progression. Nanotechnology is highly effective and has demonstrated significant benefits across various medical applications. Nanoparticles have been explored as promising drug delivery systems for the targeted delivery of anti-AD therapeutics and for the precise diagnosis of the condition. Nanoparticles, such as dendrimers, lipid-based nanoparticles, polymer-based nanoparticles, and metal-based nanoparticles, have been designed and reported to inhibit Aβ aggregation, fibril formation, and disaggregating mature fibrils, prevent neuroinflammation and Aβ1-42-induced cell damage, treat oxidative stress and lower hallmark of Aβ, and display excellent capability to bypass blood-brain barrier (BBB). This review is focused on the preclinical therapeutic outcomes of nanoparticles and the challenges encountered in the treatment of AD. This review highlights the significant advancements of nanoparticles that are currently undergoing clinical trials for management of AD.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Aktan Süzgün M, Tang Q, A Stefani (2025)

Sleep Abnormalities and Risk of Alzheimer's Disease.

Current neurology and neuroscience reports, 25(1):67.

PURPOSE OF REVIEW: This review aimed at investigating sleep abnormalities as risk factors for Alzheimer's disease (AD), with a focus on their potential utility in early disease detection and risk modification.

RECENT FINDINGS: Impaired sleep quality, circadian misalignment, and disruptions in sleep architecture are significantly associated with an elevated risk of AD. Moreover, excessive or insufficient sleep, reductions in slow-wave and REM sleep, and fragmented rest-activity rhythms have been linked to early alterations in amyloid-β and tau biomarkers, even in cognitively unimpaired individuals. Various sleep disorders have also been identified as independent contributors to AD risk, particularly among genetically susceptible populations. Sleep and circadian disturbances, as well as changes in sleep architecture, represent easily detectable and modifiable risk factors for Alzheimer's disease. Integrating sleep and sleep-based metrics into preventive strategies may enhance early identification and offer novel avenues for intervention, modulating the risk of Alzheimer's disease.

RevDate: 2025-10-13

Tran HA, Weber D, T Grune (2025)

[Micronutrients in old age-physiological specificities and nutritional status].

Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz [Epub ahead of print].

Aging is a biological and degenerative process with numerous changes in molecular and cellular mechanisms in various organ systems. These changes result in a progressive loss of anatomical structures and physiological functions. Among others, they occur in the cardiovascular system, gastrointestinal tract, skin, muscles, bones, respiratory tract, immune system, endocrine systems, and the brain. The alterations in aging can lead to diseases such as coronary heart disease, sarcopenia, osteoporosis, Alzheimer's disease, and cancer. To delay these age-related alterations and thus prevent diseases, a healthy lifestyle with a balanced diet is important. An adequate diet includes the sufficient intake of micronutrients. This article first provides an overview of physiological characteristics of aging and then addresses the supply of micronutrients in old age.In older age, the supply of vitamin D, vitamin B12, magnesium, iron, folate, and calcium may be critical. These micronutrients play a role in the immune system, bone metabolism, cell metabolism, energy production, and many other metabolic processes. Micronutrient deficiencies can enhance the aging process. Healthy older people should use the German Nutrition Society (DGE) reference values to meet their daily micronutrient needs. Older people with illnesses should follow the reference values of the guidelines for their specific illnesses to cover their micronutrient needs.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Zhang J, Ou J, Lu X, et al (2025)

Sleep disorders and the risk of cognitive decline or dementia: an updated systematic review and meta-analysis of longitudinal studies.

Journal of neurology, 272(10):689.

BACKGROUND: The evidence on the relationship between sleep disorders and the risk of cognitive decline or dementia remains inconsistent.

OBJECTIVES: This systematic review and meta-analysis aimed to provide updated evidence on the association between sleep disturbances and cognitive decline.

METHODS: PubMed, EMBASE, and Web of Science were systematically searched from their respective inceptions to 18 February 2025. Cohort studies investigating longitudinal associations between sleep disorders and cognitive decline or dementia were included. Pooled relative risks (RRs) with 95% confidence intervals were calculated. Sensitivity analyses were conducted to evaluate the robustness of the pooled estimates. Publication bias was assessed using Egger's and Begg's tests, and meta-regression analysis was performed to explore potential sources of heterogeneity across studies.

RESULTS: Seventy-six eligible cohort studies with eight types of sleep disturbances were included in the meta-analysis. Insomnia was associated with an increased risk of dementia (RR = 1.13). Both short sleep duration (7 h; RR = 1.27) and long sleep duration (8 h; RR = 1.23 for cognitive decline, RR = 1.43 for all-cause dementia, and RR = 1.66 for Alzheimer's disease (AD) were significant risk factors for cognitive decline and dementia. Excessive daytime sleepiness significantly increased the risks of vascular dementia (VD) (RR = 1.85), all-cause dementia (RR = 1.41), and cognitive decline (RR = 1.37). Sleep-related movement disorders indicated the strongest association, markedly increasing the risk of VD (RR = 2.53). Poor sleep quality was also a significant risk factor for AD (RR = 1.24), all-cause dementia (RR = 1.17), and cognitive decline (RR = 1.18).

CONCLUSION: This meta-analysis highlights sleep management as a pivotal modifiable factor in reducing the risk of all-cause cognitive decline. Systematic screening and early intervention for sleep disturbances should be prioritized as essential preventive strategies in clinical populations.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Lai PH, Chang TC, Zhan HT, et al (2025)

Impact of Specialty and Nonspecialty Palliative Care on Quality of Dying With Alzheimer's Disease or Related Dementias: A Systematic Review and Meta-Analysis.

Medical care, 63(11):851-865.

BACKGROUND: Older adults with Alzheimer's disease and related dementias can benefit from palliative care (PC). Whether specialty and nonspecialty PC have the same effect on outcomes is unclear. We examined the effects of these 2 interventions on comfort, symptom management, satisfaction with care, and potentially burdensome transitions, including hospital admission, emergency department visit, intensive care unit admission in the end-of-life, and in-hospital death.

METHODS: This PRISMA-adherent systematic review involved a search of PubMed, Medline, EMBASE, Cochrane Library, ProQuest, and CINAHL for studies published from January 1, 2013, to November 4, 2024. Primary studies that reported at least one of the 7 patient-level outcomes were included: Comfort Assessment in Dying with Dementia (CAD-EOLD), Symptom Management at the End-of-Life (SM-EOLD), Satisfaction with Care at the End-of-Life in Dementia (SWC-EOLD), hospital admissions, emergency department visits, intensive care unit admissions, and in-hospital death.

RESULTS: Nineteen articles involving 142,772 participants were included. The evidence, comprising studies of adequate to strong quality, revealed that both specialty and nonspecialty PC did not differ in terms of comfort, symptom management, or satisfaction with care. However, both approaches significantly reduced the likelihood of intensive care unit admissions and in-hospital deaths. Specialty PC was associated with decreased emergency department visits (OR 0.53, 95% CI 0.28-1.00; I2=86%).

CONCLUSIONS: Future research is needed to understand factors influencing PC interventions that can improve comfort, symptom management, and care satisfaction for these individuals and their families.

RevDate: 2025-10-13

Halbgebauer S, Fazeli B, Klose V, et al (2025)

Age-Specific Control and Alzheimer Disease Reference Curves and z-Scores for Glial Fibrillary Acidic Protein in Blood.

Clinical chemistry pii:8284939 [Epub ahead of print].

BACKGROUND: Serum glial fibrillary acidic protein (GFAP) is a biomarker for astrocytic injury and astrogliosis. Concentrations are elevated in numerous neurological disorders, including a pronounced increase in Alzheimer disease (AD). However, GFAP levels in the serum also increase with age. Consequently, the integration of GFAP levels into clinical routine and their interpretation demands age-adjusted reference values.

METHODS: Serum from 1273 subjects (952 noninflammatory and nonneurodegenerative neurological controls and 321 subjects with AD) was analyzed for GFAP using the microfluidic Ella system. Age-dependent serum GFAP reference values were estimated by additive quantile regression analysis and visualized with percentiles and z-scores.

RESULTS: AD exhibited elevated serum GFAP levels in comparison to control patients (P < 0.0001). This remained the case when the newly generated age-corrected z-scores were applied (P < 0.0001). In the control cohort, a nonlinear elevation of serum GFAP with increasing age was observed (Spearman correlation coefficient 0.62, 95% CI 0.58-0.66, P < 0.0001). In contrast, the AD cohort exhibited a more linear increase (0.16, 95% CI 0.05-0.26, P = 0.004). Age-dependent cut-offs for serum GFAP were determined for different AD age groups. The calculated areas under the curve (AUCs; 0.97) demonstrated excellent diagnostic test performance in the early-onset age group. This effect was less marked in the elderly subjects (AUC 0.72).

CONCLUSIONS: Our novel GFAP z-scores enable the integration and interpretation of serum GFAP levels in clinical practice, moving from the group to individual level. They support both intra- and interindividual interpretation of single GFAP levels in neurological diseases with astrocytic pathology, including an accurate discrimination of AD.

RevDate: 2025-10-13

Krunic A, Bellio TA, Cohen BZ, et al (2025)

Brain DNA Methylation Atlas of App[NL-G-F] Alzheimer's Disease Model Mice Across Age and Region Reveals Choline-Induced Resilience.

Aging cell [Epub ahead of print].

Alzheimer's disease (AD) is the most common type of dementia. Current treatments for AD are inadequate, and there is a need to design preventive strategies that would improve the resistance or resilience to AD pathology. Because aberrant brain DNA methylation (DNAm) is associated with hallmarks of AD, we tested the hypothesis that a nutritional approach using choline, an essential nutrient and methyl donor, would modulate DNAm to ameliorate AD pathologies. Previous studies showed that perinatal choline supplementation (PCS) reduced AD-like neuropathology and inflammation while improving cognitive performance in AD mouse models. Here we investigated hippocampal and cerebral cortical DNAm patterns by reduced representation bisulfite sequencing from 3 to 12 months in wild-type (WT) and App[NL-G-F] AD model mice fed a 1.1 g/kg control or 5.5 g/kg PCS diet from conception to weaning. App[NL-G-F] mice showed extensive CpG DNAm changes, which were associated with the age-dependent progression of amyloidosis. PCS induced genotype-specific DNAm patterns and reversed DNAm changes in multiple genes in App[NL-G-F] mice. By associating DNAm with matched transcriptomics, we found that DNAm in App[NL-G-F] mice correlated with the expression of microglial genes, while DNAm-associated genes modulated by PCS were related to synaptic function. Moreover, we found that methylation levels of several CpGs were associated with levels of beta amyloidosis, relating epigenetic changes to neuropathology. Overall, our data suggest that DNAm in the brain serves as an epigenetic mechanism for abnormal gene expression in App[NL-G-F] mice and indicate that PCS may promote resilience to synaptic dysfunction through modulating DNAm.

RevDate: 2025-10-13

Bellio TA, Krunic A, Campion MS, et al (2025)

Perinatal Choline Supplementation Promotes Resilience Against Progression of Alzheimer's Disease-Like Brain Transcriptomic Signatures in App[NL-G-F] Mice.

Aging cell [Epub ahead of print].

Alzheimer's disease (AD)-the leading cause of dementia-has no cure, inadequate treatment options, and a limited understanding of prevention measures. We have previously shown that perinatal dietary supplementation with the nutrient choline ameliorates cognitive deficits and reduces amyloidosis across the brain in App[NL-G-F] AD model mice. Here, we analyzed transcriptomic abnormalities in these mice and tested the hypothesis that they may be attenuated by perinatal choline supplementation (PCS). Wild-type (WT) and App[NL-G-F] dams consumed a diet containing 1.1 (control) or 5 g/kg (supplemented) of choline chloride from 2 weeks prior to mating until weaning. At 3, 6, 9, or 12 months of age, the offspring RNA was sequenced in the hippocampus and cerebral cortex. As compared to WT, the App[NL-G-F] mice reared on the control diet had age-dependent upregulation of expression of mRNAs and lncRNAs related to inflammation and reduced expression of mRNAs related to neuronal function. As compared to App[NL-G-F] mice on the control diet, PCS App[NL-G-F] mice increased expression of synaptic genes and downregulated inflammation-related genes starting at 6 months in the cortex; increased expression of GABAergic function and ATP metabolism genes, and decreased expression of inflammatory genes in the hippocampus at 12 months. These changes counteracted the effects of App[NL-G-F] genotype seen in mice on the control diet. The expression of many of these choline-protected genes correlated with clinical dementia rating, inflammation, and tauopathy in human postmortem dorsolateral prefrontal cortex AD samples, indicating their relevance to the disease process. The results suggest that adequate choline intake could be a preventive strategy for AD.

RevDate: 2025-10-13

Habibnia M, Catalina-Hernandez E, Cabrerizo-Idiazabal M, et al (2025)

Biophysical analysis of angiotensin II and amyloid-β cross-interaction in aggregation and membrane disruption.

FEBS letters [Epub ahead of print].

Amyloid-β (Aβ) aggregation is a hallmark of Alzheimer's disease. Endogenous peptides in the same environment may influence Aβ aggregation via direct interaction. This study explores the cross-interaction between Aβ and angiotensin II (AngII), a neuropeptide of the renin-angiotensin system, using biophysical assays and in silico modeling. Thioflavin T fluorescence, circular dichroism, and Congo Red assays show that AngII modestly reduces Aβ aggregation and membrane disruption in a dose-dependent manner. Liposome leakage assays confirm decreased membrane disruption. Modeling suggests AngII binds preferentially to disordered Aβ conformers. These findings indicate that AngII may modulate early amyloidogenic events and contribute to amyloid homeostasis, offering insights into the interplay between neuropeptides and amyloid pathology.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Zhang R, Wang R, Zhai S, et al (2025)

Bioinformatic analysis and experimental validation of hub autophagy-related genes as novel biomarkers for type 2 diabetes mellitus and Alzheimer's disease.

PeerJ, 13:e20143.

BACKGROUND & OBJECTIVES: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share considerable similarities in their proposed patho mechanisms. Autophagy, an intrinsic cellular process involved in the degradation of dysfunctional organelles and abnormal proteins, has been implicated in the pathogenesis of both AD and T2DM. This study aims to identify potential shared biomarkers related to autophagy in AD and T2DM by analyzing hub differentially expressed autophagy-related genes (DEARGs) and examining their potential functions.

METHODS: Gene expression profiles for AD and T2DM were acquired from the Gene Expression Omnibus (GEO) database (training sets: GSE109887 for AD and GSE104674 for T2DM; validation sets: GSE122063 for AD and GSE64998 for T2DM). Autophagy-related genes (ARGs) were extracted from multiple databases. DEARGs were identified and integrated with module genes derived from weighted gene co-expression network analysis (WGCNA) to determine key shared ARGs. Then, the STRING database was used to construct a protein-protein interaction (PPI) network, from which hub genes were identified. These hub genes were validated using independent microarray datasets through differential expression analysis, and ROC curves were generated to assess their diagnostic value. Moreover, the expression of the hub genes was validated in brain tissues of T2DM mouse models using qRT-PCR.

RESULTS: A total of 33 shared DEARGs were identified, among which 12 were designated as hub genes (ANXA5, CCND1, MAP2K1, HSPB1, BNIP3, BAG3, YAP1, MET, FBXW7, CCL2, PFKFB3, CDKN1A) in both AD and T2DM patients. Validation using other datasets confirmed that ANXA5, BAG3, and CDKN1A remained significantly upregulated, while MET remained downregulated in both AD and T2DM patients. Additionally, PFKFB3 showed an inverse expression pattern between the two diseases. The diagnostic performance of these five hub genes was assessed using ROC curves, with all five exhibiting values of area under the curve (AUC) exceeding 0.7 for T2DM in both training and validation sets. However, only MET and PFKFB3 demonstrated good diagnostic efficacy in AD patients. In animal models, qRT-PCR analysis revealed that the expression of ANXA5, BAG3, and MET was consistent with the bioinformatics results. In contrast, the expression of PFKFB3 and CDKN1A did not differ significantly between db/db model mice and db/m control mice.

CONCLUSIONS: Our integrated bioinformatics analyses, supported by preliminary experimental validations, identified several hub ARGs shared between AD and T2DM. Among these, ANXA5, BAG3, and MET exhibited consistent expression trends across datasets and experimental models, while CDKN1A and PFKFB3 showed inconsistent expression patterns. These findings underscore the complexity of autophagy-related crosstalk in AD-T2DM comorbidity and highlight the need for further research to clarify their diagnostic and therapeutic potential.

RevDate: 2025-10-13

Arruda GS, Morris K, Martins A, et al (2025)

Ultrasensitive Alzheimer's disease biomarker detection with nanopillar photonic crystal biosensors.

Optica, 12(10):1587-1596.

The recent development of drugs able to mitigate neurodegenerative diseases has created an urgent need for biomarker tests that can be readily used by practitioners. Although biomarker detection directly in patients' blood is now possible, low-cost point-of-care tests remain a challenge because relevant biomarkers, especially amyloid- β (A β) peptides, are small, they occur at very low concentrations, and detecting a single marker is insufficient. Here, we demonstrate a photonic resonant sensor able to detect 0.2 pg/ml of A β 42 and A β 40 in 1% human blood serum, equivalent to 20 pg/ml in undiluted serum, which is the clinically required level. This high performance is achieved by combining gold nanoparticle amplification with a dielectric nanopillar photonic crystal structure in a dimer configuration, while also employing an immunoassay approach for high selectivity and specificity. The design combines high resonance Q-factor, amplitude, and sensitivity, ideally suited for sensing. We also show the detection of A β 42 and A β 40 peptides in the same channel, which is highly relevant for assessing disease progress and opens a route toward multiplexing. Together with the handheld operation we have demonstrated previously, these photonic innovations make a major contribution to the ability to detect and monitor the progression of neurodegenerative diseases such as Alzheimer's.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Ashford MT, Aaronson A, Jin C, et al (2025)

Digital efforts in Spanish for enrolling Latino adults in the Brain Health Registry.

Alzheimer's & dementia (New York, N. Y.), 11(4):e70096.

INTRODUCTION: Previous culturally informed digital inclusion efforts in English effectively enrolled Latino adults into the Brain Health Registry (BHR), an online Alzheimer's disease (AD)-related registry. Because these efforts were in English only, we did not successfully reach individuals from the U.S. Latino community whose language preference is Spanish. The English-language effort had limited success enrolling Latino participants from diverse sociodemographic backgrounds (e.g., gender, education, nativity). Therefore, we tested the hypothesis that Spanish-language efforts would increase the sociodemographic diversity of enrolled Latino participants.

METHODS: The BHR is an online registry that collects longitudinal cognitive and health data. We worked in partnership with a Latino Community Science Partnership Board to develop Spanish-language, culturally informed digital inclusion efforts, including a Spanish translation of BHR, Facebook advertisements, and culturally informed recruitment websites. Here, we (1) report on the Spanish-language digital advertisement results, (2) compare the characteristics of participants enrolled through Spanish (July 2021 through June 2022) versus English (September 2020 to June 2022) advertisements, and (3) compare the characteristics of those using the BHR assessment portal in Spanish versus in English.

RESULTS: Culturally informed Spanish-language advertisements enrolled 1059 participants, including 986 who identify as Latino. Compared to participants enrolled through culturally informed English-language efforts (N = 6985), participants enrolled via Spanish-language efforts were significantly older, had less education, and had a higher percentage of male participants and those born outside the United States. Compared to participants who opted to use the BHR website in English (N = 37,199), those who opted to use the website in Spanish (n = 1088), were significantly younger, reported fewer years of education, and more frequently self-identified as male and Latino. However, these efforts failed to increase BHR task completion.

DISCUSSION: Culturally informed digital efforts in Spanish are effective at increasing sociodemographic diversity of a Latino, digital research cohort. Similar efforts can be adapted to other studies and settings to improve the generalizability of AD research.

HIGHLIGHTS: Implemented culturally informed, Spanish-language digital enrollment efforts.The efforts enrolled 986 Latino individuals in 12 months.Compared demographics of those enrolled through Spanish versus English advertising.Spanish efforts increased enrollment of older Latino adults born outside the United States.Efforts increased enrollment but did not increase completion of study tasks.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Franco FN, de Cassia Cardoso L, Silva BNM, et al (2025)

The antioxidant effect of resveratrol on leukocytes from patients with Alzheimer is independent of SIRT1 signaling pathway.

Biochemistry and biophysics reports, 44:102291.

Alzheimer's Disease (AD) is the most prevalent dementia in aging. Among its aspects is cognitive and functional decline, resulting from an increase in Reactive Oxygen Species (ROS) and Nitrogen (RNS). Resveratrol (RSV) is a polyphenolic compound that has been recognized as a potent antioxidant. The objective was to verify the oxidative profile of AD in leukocytes, correlating the main oxidative parameters with the functionality of these elderly individuals and verify the antioxidant effect of RSV. For this, ROS and RNS, the antioxidant enzymes catalase and glutathione peroxidase (GPx), as well as the action of the SIRT1 on leukocytes of elderly people without and with AD, in the presence and absence of RSV, were evaluated. It was observed that RSV, despite acting in the AD group, had its antioxidant power reduced compared to the group without AD. RSV was able to increase GPx in both groups. Analyzing SIRT1, we observe the silencing of this signaling pathway in leukocytes from AD. AD was more dependent on the Katz index. Therefore, we observed that oxidative stress predisposes to an increased loss of autonomy and independence in AD and that the antioxidant effect of RSV is reduced.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Mishra K, Tripathi S, Tiwari AK, et al (2025)

Cerium-based nanoparticles for neurodegeneration: emerging redox therapeutics beyond pharmaceuticals.

RSC advances, 15(45):37540-37569.

Delivering therapeutic agents across the blood-brain barrier (BBB) remains a formidable hurdle in the treatment of neurodegenerative diseases, which are primarily driven by mitochondrial dysfunction, oxidative stress, and neuroinflammation. Although our understanding of these disease mechanisms has advanced, effective treatments are still limited due to the restrictive nature of the BBB. In this context, nanotechnology has emerged as a promising approach, offering engineered nanocarriers capable of traversing the BBB and enabling targeted drug delivery to the brain. Amongst the various nanomaterials explored, cerium-based nanoparticles have gained particular attention as promising candidates for neurodegenerative disease therapy. Their multifunctionality stemming from reversible redox behaviour, enzyme-mimicking activity, sustained antioxidant effects, and anti-inflammatory properties, combined with their ability to penetrate the BBB and provide neuroprotection, positions them as a powerful platform for future therapeutic strategies. This review begins with a concise overview of the shared pathological mechanisms underlying neurodegenerative diseases, highlights BBB-related drug delivery challenges, and discusses nanocarrier strategies for brain targeting, focusing on cerium-based nanoparticles. We then delved into the structural features, synthesis techniques, and distinctive redox properties of cerium-based nanomaterials, with emphasis on cerium oxide and cerium vanadate. Their therapeutic potential is explored across Alzheimer's and Parkinson's diseases, as well as in stroke, multiple sclerosis, and glioblastoma. Key insights into their physicochemical properties, BBB permeability, and neuroprotective mechanisms are provided. We also address current limitations, including nanoparticle stability, toxicity, and translational barriers, and conclude with future directions for optimizing cerium-based nanozymes in neurotherapeutics.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Wang Z, Chen Y, Wang J, et al (2025)

Pro-inflammatory S100A9 contributes to retinal ganglion cell degeneration in glaucoma.

Frontiers in immunology, 16:1667097.

S100A9 is a pro-inflammatory protein involved in neuroinflammation and central nervous system (CNS) neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Glaucoma, the leading cause of irreversible blindness, shares common pathogenic mechanisms with CNS disorders. These parallels suggest a potential role for S100A9 in glaucoma; however, its precise contribution remains unclear. In this study, we investigated the association between S100A9 and glaucoma by enrolling 121 patients with glaucoma, administering intravitreal injections of recombinant murine S100A9 (rmS100A9), and employing an elevated intraocular pressure (EIOP)-induced glaucoma mouse model. We found that circulating S100A9 levels were elevated in patients with glaucoma and positively associated with disease stage. Retinal S100A9 expression was significantly elevated and correlated with progressive retinal ganglion cell (RGC) loss in EIOP glaucoma mice. Furthermore, intravitreal injection of rmS100A9 led to direct RGC degeneration. Both enrichment analyses and experimental validation indicated that S100A9 may contribute to glaucomatous injury by promoting neuroinflammatory responses in retinal microglia and astrocyte via activation of the Toll-like receptor 4 (TLR4) pathway. These results raise the possibility that S100A9 as a potential target for future therapeutic exploration in glaucoma.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Hoegy P, Chen YH, Q Lu (2025)

The role of small GTPases in Alzheimer's disease tau pathologies.

Frontiers in cellular neuroscience, 19:1650400.

Microtubule-associated protein (MAP) tau stabilizes neuronal microtubules in axonal transport and contributes to healthy synapses. In Alzheimer's disease (AD), tau proteins become hyperphosphorylated, reduce microtubule binding, and aggregate into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). Although the steps of this dysregulation of tau are well established, the mechanisms by which each step is regulated remain incompletely understood. Misfolded protein aggregates, such as amyloid β-peptides (Aβ), are degraded by autophagy and lysosomal pathways, in which small GTPases play essential roles. However, how tau aggregates and spreads from nerve cells and whether small GTPases similarly play pivotal roles are not as clear. Here we review the recent evidence to propose that small GTPases are important in tau protein posttranslational phosphorylation, aggregation, and clearance. As such, small GTPases may prove to be important therapeutic targets that can reduce the AD tau burden.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Akhtar M, Nabi R, R Ahmed (2025)

Response to "Letter to the editor related to the article "Trends in mortality due to ischemic heart diseases among patients with Alzheimer's disease in the United States from 1999 to 2020. International journal of cardiology. Cardiovascular risk and prevention, 25, 200390″.

International journal of cardiology. Cardiovascular risk and prevention, 27:200518 pii:S2772-4875(25)00156-4.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Panigrahi B, PK Sarangi (2025)

Transcranial Doppler in Dementia: A Promising Tool for Early Detection and Subtyping.

Cureus, 17(9):e91973.

Dementia remains a leading cause of morbidity among older adults, and early diagnosis is crucial for timely intervention, improved outcomes, and appropriate care planning. While advanced neuroimaging techniques are considered the gold standard for early detection and subtyping, their limited availability in many regions underscores the need for accessible alternatives. Transcranial Doppler (TCD) and transcranial sonography (TCS) offer low-cost, noninvasive, and portable approaches to assess cerebral hemodynamics and structural brain changes. As evidence continues to evolve, these sonographic tools hold promise as complementary approaches to conventional imaging, particularly where advanced modalities are unavailable.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Charles AA, Thurmann KE, O'Neill AC, et al (2025)

Abnormal Internal Carotid Artery Kinking in a Cadaver: Morphogenesis and a Potential Link to Alzheimer's Disease.

Cureus, 17(9):e91906.

We report the case of a 95-year-old female cadaver with a documented history of Alzheimer's disease (AD) and an anteroinferior kinking of the right internal carotid artery (ICA). On dissection, the right ICA bifurcated at the superior one-third of C3 and demonstrated a marked kink with an inferior deviation of 45° followed by superior redirection of 60°, consistent with morphologic criteria for kinking. A digital caliper was used to obtain vessel measurements. The right ICA lumen measured 4.2 mm in diameter with a focal wall thickness of 2.5 mm, exceeding the Mannheim consensus plaque threshold of 1.5 mm and consistent with advanced atherosclerosis. No histologic sections were available to confirm carotid plaque composition, and the diagnosis of AD was based on past medical history without neuropathologic staging. Nevertheless, the coexistence of severe ICA kinking and extensive plaque formation raises the possibility that chronic vascular insufficiency contributed to the decedent's cognitive decline. This interpretation remains speculative, particularly in the context of advanced age and likely coexisting vascular risk factors. This case underscores the importance of recognizing congenital and acquired ICA anomalies during morphologic and clinical evaluation. Quantitative assessment of ICA variation may help refine diagnostic considerations in dementia and support further investigation into the vascular contributions to neurodegeneration.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Ye X, Yan Y, Wang Y, et al (2025)

EEG-based minimum spanning tree analysis reveals network disruptions in Alzheimer's disease spectrum: an observational study.

Frontiers in aging neuroscience, 17:1604345.

INTRODUCTION: Alzheimer's disease (AD) is characterized by disrupted brain connectivity, but the network changes across disease stages remain poorly understood. This observational cross-sectional study investigated alterations in functional brain networks across the AD continuum using minimum spanning tree (MST) analysis of resting-state EEG (rsEEG) data.

METHODS: We analyzed rsEEG data from 65 participants (30 healthy controls, 14 mild cognitive impairment due to AD [MCI-AD], 21 AD). Phase Lag Index (PLI)-based connectivity and MST metrics (such as diameter, eccentricity, and maximum degree) were computed across five frequency bands. Group differences were assessed using Kruskal-Wallis tests, and correlations with cognitive measures, disease severity, and cerebrospinal fluid (CSF) biomarkers were examined.

RESULTS: Significant alterations in rsEEG network topology were observed across HC, MCI-AD, and AD groups. AD patients showed increased theta band connectivity (higher mean PLI, diameter, and eccentricity) and decreased beta band connectivity (lower mean PLI and eccentricity) compared to HC. MCI-AD group exhibited higher delta band maximum degree and altered beta band network organization compared to HC and AD. These network changes correlated with cognitive performance and disease severity. Beta band mean PLI and theta band eccentricity effectively discriminated between AD/MCI-AD and HC. Significant correlations were also found between specific MST metrics and CSF biomarkers (t-Tau, p-Tau, Aβ1-42).

CONCLUSION: AD progression is characterized by frequency-specific alterations in brain network topology, particularly in theta and beta bands, detectable through rsEEG-based MST analysis. These findings suggest EEG-derived network measures may serve as potential biomarkers for early AD diagnosis and monitoring disease progression.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Pang X, Ji Y, Hu C, et al (2025)

Correction: Altered dynamic functional network connectivity patterns in Alzheimer's disease: insights into neural dysfunction.

Frontiers in aging neuroscience, 17:1693649.

[This corrects the article DOI: 10.3389/fnagi.2025.1617191.].

RevDate: 2025-10-13
CmpDate: 2025-10-13

Cong S, Wang M, Yan L, et al (2025)

Current application status of non-invasive brain stimulation techniques in Alzheimer's disease: a bibliometric analysis.

Frontiers in aging neuroscience, 17:1585885.

OBJECTIVE: Alzheimer's disease (AD) poses a significant global public health challenge. Non-invasive brain stimulation (NIBS) has emerged as a promising therapeutic strategy and constitutes a rapidly evolving research domain for AD intervention. This study aims to synthesize recent advancements in NIBS technologies for AD through comprehensive knowledge mapping. By mapping the research landscape, identifying key trends, and analyzing collaborative networks, we seek to explore emerging frontiers and translational potential of NIBS in AD research, thereby informing evidence-based clinical practice.

METHODS: Using the Science Citation Index Expanded (SCI-E) of Web of Science Core Collection (WOSCC) database. The analysis included an evaluation of publication trends, journal distribution statistics, country/region and institutional collaboration networks, author and co-cited author networks, co-citation document networks, as well as keywords and research hotspot analysis. Then CiteSpace, GraphPad Prism, VOSviewer, Microsoft Excel and NoteExpress were used for follow-up bibliometric analysis.

RESULTS: A total of 632 studies were included in this study. Research on NIBS applications in AD peaked during 2020-2021. The predominant journals disseminating NIBS-AD research were Journal of Alzheimer's Disease, Frontiers in Aging Neuroscience, and Clinical Neurophysiology. Italy, China, and the United States led in research contributions during this period. At the institutional level, Harvard Medical School and the University of Brescia published the most. There are 529 authors in this field, among which Professor Giacomo Koch maintains a continuous academic leadership position. Keyword analysis revealed high-frequency terms, "Alzheimer's disease," "transcranial magnetic stimulation," and "mild cognitive impairment." "Impairment" and "non-invasive brain stimulation" emerged as citation burst terms from 2022 onward, signaling current investigative priorities centered on NIBS-induced cognitive modulation, therapeutic target selection, and underlying neurophysiological mechanisms.

CONCLUSION: This study comprehensively reviews current research status, hotspots and trends of NIBS in AD. The results suggest that researchers should focus on the cognitive impact of NIBS technology on AD patients, the best therapeutic targets and potential mechanisms. Strengthening global collaboration among international, institutional and scientific researchers should be promoted to promote the in-depth development of this field.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Nakagawa Y, Sugiyama A, Hirano S, et al (2025)

Cognitive-predominant spinocerebellar ataxia type 8 with posterior cingulate cortex hypoperfusion mimicking early-onset Alzheimer's disease: A case report.

Journal of Alzheimer's disease reports, 9:25424823251385561.

Spinocerebellar ataxia type 8 (SCA8) is an autosomal dominant neurodegenerative disorder caused by CTG/CAG repeat expansion in ATXN8OS/ATXN8 genes. The primary clinical feature is cerebellar ataxia, but approximately 30% of patients present with cognitive impairment, characterized by attentional disturbances and executive dysfunction. These cognitive deficits remain poorly understood, and no functional neuroimaging studies have been reported. We report a case of SCA8 presenting predominantly with cognitive impairment and showing marked hypoperfusion in the posterior cingulate cortex (PCC) on N-isopropyl-p-[[123]I]-iodoamphetamine single-photon emission computed tomography, closely resembling early-onset Alzheimer's disease. This case suggests PCC dysfunction may contribute to cognitive decline in SCA8.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Alba LCO, Anlacan VMM, Navarra CJA, et al (2025)

YouTube as an educational resource: Evaluating the quality and reliability of videos for family caregivers of persons living with Alzheimer's disease dementia.

Journal of Alzheimer's disease reports, 9:25424823251368887.

BACKGROUND: YouTube is increasingly used by patients and caregivers as a source of health information. However, the quality and reliability of content on Alzheimer's disease dementia (ADD) remain uncertain.

OBJECTIVE: This study aimed to determine whether YouTube videos on ADD provide reliable and high-quality information for caregivers and to assess whether the most popular videos are also the most trustworthy.

METHODS: In December 2024, YouTube was systematically searched for ADD-related videos. Two independent physicians reviewed each video, scoring it using modified DISCERN (mDISCERN) for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized by goal and assessed for quality, accuracy, comprehensiveness, and specific content.

RESULTS: There were 117 videos included in the study. Using the mDISCERN scale, 70 videos (59.8%) were deemed with good reliability, 33 videos (28.2%) have moderate reliability, and 14 videos (12%) have poor reliability. Using the GQS, 61 videos (51.1%) have high quality, 16 videos (28%) were assessed as excellent quality, 34 videos (29%) as moderate quality, and 7 videos (6%) as low quality. Videos from academic institutions, news agency and physicians exhibited higher mDISCERN and GQS scores compared to other groups and a significant correlation was seen between mDISCERN and GQS (p < 0.001).

CONCLUSIONS: The videos on ADD produced by healthcare professionals and academic institutions have high quality and good reliability, covering disease properties, treatment choices, and patient experiences. However, video popularity does not significantly correlate with content reliability and quality.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Elyasi F, Aarabi M, Adelani M, et al (2025)

Neuroleptic Malignant Syndrome: A Case Report of the Oldest Man in Literature.

Clinical case reports, 13(10):e71206.

A diagnosis of neuroleptic malignant syndrome (NMS) was made in a 96-year-old man, representing the oldest documented case in the existing medical literature. Even at very low doses of antipsychotic medications, older adults are more likely to develop NMS. This increased susceptibility may exacerbate other risk factors, such as preexisting neurological disorders or the concurrent use of cholinesterase inhibitors.

RevDate: 2025-10-13

Leech G, Acosta AL, Mahato S, et al (2025)

Photoactivatable Ru(ii) polypyridyl complexes as dual action modulators of amyloid-beta peptide aggregation and Cu redox cycling.

Chemical science [Epub ahead of print].

The misfolding and aggregation of the amyloid-β (Aβ) peptide is a major hallmark of Alzheimer's disease (AD), yet therapeutic strategies targeting this process have faced long-standing challenges related to efficacy and specificity. Here, we investigate two photoactivatable Ru(ii) polypyridyl complexes (RuP) that operate as dual-action modulators of AD pathology by addressing both Aβ aggregation and Cu-Aβ associated ROS generation. The RuP contain an extended planar imidazo[4,5-f] [1,10]phenanthroline ligand, which is important for pre-association with the Aβ peptide via hydrophobic and π-π interactions, as well as sterically hindered ligands 6,6'-dimethyl-2,2'-bipyridyl (6,6'-dmb) for RuP1 and 2,9-dimethyl-1,10-phenanthroline (2,9-dmp) for RuP2, which cause steric strain at the metal center. Photoactivation of the RuP results in loss of either a 6,6'-dmb or 2,9-dmp ligand exposing cis-exchangeable coordination sites for binding to the Aβ peptide, which immediately redirects the Aβ peptide away from its β-sheet-rich fibrillization pathway, promoting the formation of amorphous, off-pathway aggregates that exhibit increased sensitivity to proteolytic degradation. We find that the photoactivated RuP are closely associated with the amorphous aggregates, and that this is a common endpoint regardless of Aβ peptide aggregation state (monomer, oligomer, or fibril). Importantly, we show that the ejected ligands also inhibit the redox cycling and ROS generation of Cu-Aβ species. Together, these results highlight the potential of photoactivatable RuP as multifunctional therapeutic candidates, offering a rational approach to intercepting Aβ aggregation and Cu-mediated oxidative stress, and advancing the design of light-responsive treatments for neurodegenerative diseases.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Ali S, Piana M, Pardini M, et al (2025)

Graph neural networks in Alzheimer's disease diagnosis: a review of unimodal and multimodal advances.

Frontiers in neuroscience, 19:1623141.

Alzheimer's Disease (AD), a leading neurodegenerative disorder, presents significant global health challenges. Advances in graph neural networks (GNNs) offer promising tools for analyzing multimodal neuroimaging data to improve AD diagnosis. This review provides a comprehensive overview of GNN applications in AD diagnosis, focusing on data sources, modalities, sample sizes, classification tasks, and diagnostic performance. Drawing on extensive literature searches across PubMed, IEEE Xplorer, Scopus, and Springer, we analyze key GNN frameworks and critically evaluate their limitations, challenges, and opportunities for improvement. In addition, we present a comparative analysis to evaluate the generalizability and robustness of GNN methods across different datasets, such as ADNI, OASIS, TADPOLE, UK Biobank, in-house, etc. Furthermore, we provide a critical methodological comparison across families of GNN architectures (i.e., GCN, ChebNet, GraphSAGE, GAT, GIN, etc.) in the context of AD. Finally, we outline future research directions to refine GNN-based diagnostic methods and highlight their potential role in advancing AI-driven neuroimaging solutions. Our findings aim to foster the integration of AI technologies in neurodegenerative disease research and clinical practice.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Li Y, Xu X, Tang L, et al (2025)

GAP-43 is associated with faster amyloid-associated neurodegeneration and cognitive decline in Alzheimer's disease.

Frontiers in neurology, 16:1629389.

BACKGROUND: It has been proposed that amyloid-β (Aβ) deposition may trigger neurodegeneration and cognitive decline. The elevated levels of presynaptic growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) were significantly associated with Alzheimer's disease (AD). To examine whether GAP-43 was associated with faster amyloid-associated neurodegeneration or cognitive decline, it was necessary to further explore whether Aβ deposition affected CSF GAP-43 through inflammation.

METHODS: A total of 671 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) were enrolled with available baseline CSF GAP-43, microglia activation [measured by CSF soluble triggering receptor expressed on myeloid cells (sTREM2) and progranulin (PGRN)], neurodegeneration (measured by CSF t-tau), and Aβ pathology (measured by amyloid-PET). To compare CSF GAP-43 levels across different Aβ and clinical stages, the analysis of variance (ANOVA) and Bonferroni post hoc tests were conducted. Multiple linear regression models were used to explore the association of CSF GAP-43 with sTREM2, PGRN, amyloid-PET, p-tau, t-tau and cognitive measures at baseline. Moreover, mediation models with 10,000 bootstrapped iterations were performed to investigate whether CSF GAP-43 was related to accelerated amyloid-associated neurodegeneration, then further contribute to cognitive decline, and how Aβ deposition affected CSF GAP-43 leading to neurodegeneration.

RESULTS: Compared with the amyloid- (A-) group, CSF GAP-43 was significantly higher at baseline in the amyloid+ (A+) group. When stratified by diagnosis, similar results were observed in A+ cognitively normal (CN) and A+ mild cognitive impairment (MCI), compared with A-CN or A-MCI participants. We found that baseline of CSF GAP-43 was positively related to CSF sTREM2, PGRN, amyloid-PET and t-tau, whereas it was negatively associated with cognition. Besides, CSF GAP-43 mediated the faster progression of amyloid-associated neurodegeneration and cognitive decline. Furthermore, the mediation analysis revealed that CSF sTREM2/PGRN was related to CSF t-tau mediated by CSF GAP-43 in the A+ group.

CONCLUSION: Our findings provided evidence that CSF GAP-43 was related to the accelerated amyloid-associated neurodegeneration, and further contributed to cognitive decline. We also demonstrated that Aβ deposition may act as a trigger for synaptic dysfunction by promoting inflammation.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Gallingani C, Tondelli M, Vannini P, et al (2025)

The association between anosognosia and neuropsychiatric symptoms in neurodegenerative dementias: a narrative review.

Frontiers in neurology, 16:1649627.

Anosognosia, or unawareness of disease, is a common clinical feature in neurodegenerative dementias. Frequently reported as an early symptom, its presence has been associated with faster dementia progression and greater cognitive impairment. Similarly, neuropsychiatric symptoms (NPS) encompass non-cognitive behavioral and psychiatric disturbances that commonly affect individuals with dementia. Both aosognosia and NPS are clinically relevant in neurodegenerative diseases due to their significant implications in disease management and caregiver burden. In this narrative review, we examined studies investigating the direct relationship between anosognosia and NPS across different neurodegenerative dementias, including Alzheimer's Disease (AD), Frontotemporal Dementia (FTD) and α-synucleinopathies, such as Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). A total of 46 studies were identified, the majority of which focused on AD. Despite considerable heterogeneity in participant selection, assessed domains, and measures of anosognosia and NPS investigated, consistent association emerged between anosognosia and global NPS scores as well as individual symptoms. Across studies, the most common finding was a negative association between anosognosia and depression and a positive association between anosognosia and apathy. Possible underlying mechanisms and shared neuroanatomical substrates of these findings are discussed. The review provides a deepened insight into key symptoms with critical implications for dementia research, clinical management, and caregiving strategies.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Hecker J, Prokopenko D, Lee S, et al (2025)

FBAT DAP-G: fine-mapping of genetic associations in family-based studies using the Deterministic Approximation of Posteriors algorithm.

Bioinformatics advances, 5(1):vbaf233.

MOTIVATION: Family-based study designs enable genetic association analyses that are robust against population stratification and admixture. The Family-Based Association Test (FBAT) framework extended and generalized the Transmission Disequilibrium Test concept for trios (affected offspring and their parents) to general pedigrees, arbitrary phenotypes, and multi-variant analyses. Following the successful identification of disease susceptibility loci in classical family studies, FBAT approaches can be a valuable tool in modern large-scale biobanks that contain significant proportions of related individuals, often with heterogeneous genetic ancestries. However, recent methods for established downstream analyses, such as statistical fine-mapping, are primarily tailored towards genetic association results obtained from regression models in unrelated individuals, and suitable methodologies for FBAT results have not been established in the literature. Here, we introduce and implement a framework for statistical fine-mapping in FBAT-based family-based association studies.

RESULTS: Our approach is based on the established Deterministic Approximation of Posteriors algorithm and utilizes the association z-scores obtained from FBAT. We illustrate the method in simulation studies and an application to the Apolipoprotein E locus in a family-based association study of Alzheimer's Disease.

The fine-mapping approach FBAT DAP-G is implemented in the FBAT package https://github.com/FBATsw/FBAT/. The original code of DAP-G is available at https://github.com/xqwen/dap.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Reddi Sree R, Kalyan M, Anand N, et al (2025)

Correction to "Newer Therapeutic Approaches in Treating Alzheimer's Disease: A Comprehensive Review".

ACS omega, 10(39):46197.

[This corrects the article DOI: 10.1021/acsomega.4c05527.].

RevDate: 2025-10-13
CmpDate: 2025-10-13

Ye S, Xu W, Jiang Z, et al (2025)

Prediction of new-onset atrial fibrillation in sepsis patients by machine learning: A systematic review.

Digital health, 11:20552076251384237.

AIMS: New-onset atrial fibrillation (NOAF) occurs in approximately 23% of patients with sepsis and is independently associated with increased mortality. Therefore, early prediction of NOAF has significant clinical value. However, current artificial intelligence (AI) models predominantly rely on tabular data. These unimodal AI models face limitations in predicting NOAF as they fail to fully utilize the predictive potential arising from the interplay of multimodal data.

METHODS: We reviewed current Machine Learning (ML) and Deep Learning (DL) approaches for atrial fibrillation (AF) prediction. It summarizes the selected features in ML models for predicting AF in ICU patients, and the advantages of time-window selection in DL models using electrocardiogram (ECG) signals. Notably, we compared these models in terms of feature selection, prediction horizons, and performance when applied to tabular data and ECG signal features. To enhance the predictive capability of ML for NOAF in patients with sepsis, we drew inspiration from multimodal models developed for other diseases, such as Alzheimer's disease, and proposed integrating tabular data and ECG signal data within a multimodal framework.

RESULTS: This study systematically analyzed the application of ML and DL in AF prediction. After screening, 12 studies (6 ML, 6 DL) were included. ML models, based on electronic medical records (EMR) or ECG features, achieved prediction windows ranging from minutes to hours with AUCs of 0.74-0.90. DL models processing raw ECG signals extended prediction windows to days, achieving AUCs of 0.74-0.96, with performance improving with larger datasets. A Transformer-based multimodal model (integrating clinical data and ECG) was proposed to enhance AF prediction in sepsis patients, though further validation is needed for cross-modal data fusion feasibility.

CONCLUSIONS: Transitioning from unimodal predictive models to multimodal frameworks that combine tabular clinical data and raw ECG signals is feasible within the current deep-learning framework. This approach has the potential to significantly improve the early prediction capabilities of NOAF in sepsis patients.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Frentz I, Marcolini S, Licher S, et al (2025)

Dementia risk prediction in the general population: external validation of a prediction model in the population-based LifeLines Cohort Study.

JAR life, 14:100028.

BACKGROUND: Models for dementia prediction in primary care are necessary to identify individuals at risk for developing dementia, but their implementation in clinical practice is partly limited due to lack of external validation or use of high-cost variables. We externally validated the predictive performance of a simple yet promising dementia risk prediction model.

METHODS: We assessed discriminative ability with a c-statistic with 95 % confidence interval, using age, history of stroke, subjective memory complaints and need for assistance with a relatively complex task as predictors. This was done on 10,007 individuals that participated in the Lifelines-cohort study. Assessment of dementia in the Lifelines Cohort Study is self-reported in the follow-up questionnaires.

RESULTS: Mean follow-up at LifeLines timepoint 1b was 1.5 years, mean follow-up at LifeLines timepoint 2a was 3.3 years and mean follow-up at LifeLines timepoint 3a was 9.1 years. Overall, 36 participants self-reported dementia development. Discriminative ability of the model overall dementia development yielded a c-statistic of 0.62 [95 % CI=0.48-0.70], and performed slightly better at follow-up 2a 0.67 [95 % CI=0.57-0.78]. However, calibration of the model in this external validation cohort was poor, with systematic overestimation of the predicted risk.

CONCLUSION: In this study the basic dementia risk prediction model overestimated the risk of dementia, but had reasonable discriminative ability in the Lifelines cohort. Within this validation cohort the potential of the model is underestimated due to low incidence of reported dementia. Further validation is required to determine the true value of the model. Studies assessing its implementation feasibility in primary care should also be conducted.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Vijayaram S, Mahendran K, Razafindralambo H, et al (2025)

Probiotics, gut microbiota, and brain health: Exploring therapeutic pathways.

AIMS microbiology, 11(3):501-541.

The gut microbiome plays a significant role in regulating gastrointestinal (GI) function and modulating the gut-brain axis, which describes the bidirectional communication between the GI tract and the central nervous system (CNS). Its involvement in digestion, immunity, and neurophysiology is well recognized. This study offers novel insights by focusing on psychobiotics, a class of probiotics with targeted neuroactive properties. These microorganisms influence brain function through defined mechanisms, including modulation of neuroinflammation, neurotransmitter production (GABA, serotonin), regulation of the hypothalamic-pituitary-adrenal (HPA) axis, and vagus nerve signaling. Our work critically examines recent advances in applications of psychobiotics for neurological disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and autism spectrum disorder. By integrating evidence from microbiome research, neuroimmunology, and clinical studies, we identify promising microbial strains and mechanistic pathways with therapeutic potential. This study contributes original perspectives by highlighting underexplored microbe-host interactions and proposing targeted microbial interventions as adjuncts to conventional neurotherapies. Further research is needed to validate strain-specific effects, long-term efficacy, and safety profiles in clinical settings.

RevDate: 2025-10-13
CmpDate: 2025-10-13

Dastgheib ZA, Lithgow BJ, ZK Moussavi (2025)

Correction: Differential impact of repetitive transcranial magnetic stimulation on alzheimer's disease symptomology: evidence from electrovestibulography.

Cognitive neurodynamics, 19(1):164.

[This corrects the article DOI: 10.1007/s11571-025-10310-5.].

RevDate: 2025-10-13

Lee BH, Barha CK, Chaiton J, et al (2025)

Previous parity differentially influences cognition in later life depending on dementia status.

NPJ dementia, 1(1):29.

Sex influences cognitive aging and dementia, yet research on the impact of female-specific factors, such as parity and fetal sex, on later-life cognition remains limited and equivocal. Inconsistencies in the literature may reflect varying effects across cognitive domains and dementia status. This study reviewed data from female participants of the University of British Columbia Hospital Clinic for Alzheimer and Related Dementias (UBCH CARD) to examine how parity and son-to-daughter ratio affect performance on medial temporal lobe-dependent (episodic memory) and prefrontal lobe-dependent (executive function) tasks depending on dementia status. Among females with dementia, higher parity was associated with reduced episodic memory but enhanced executive function performance, whereas a greater son-to-daughter ratio was associated with reduced executive function performance. These relationships were not observed in cognitively normal females or those diagnosed with mild cognitive impairment. These results emphasize the importance of integrating sex-specific factors into research and the development of precision therapeutics.

RevDate: 2025-10-13

Zapata-Restrepo LM, Miller BL, Rivas J, et al (2025)

Case of early onset Alzheimer's disease associated with a novel PSEN1 variant identified in Colombia.

NPJ dementia, 1(1):31.

Early-onset Alzheimer's disease (EOAD) is a rare form of dementia that often progresses more quickly than late-onset cases, and is more commonly associated with autosomal dominant mutations. A 47-year-old male presented with progressive cognitive and behavioral decline, a family history of EOAD, and was later found to have a novel pathogenic PSEN1 variant (c.519 G > T, p.Leu173Phe). Initial evaluations, including neuroimaging and laboratory tests, were unremarkable. Neuropsychological testing later revealed memory impairment, executive dysfunction, and neuropsychiatric symptoms. These features, alongside the identified mutation, are consistent with phenotypic presentations of EOAD involving the third transmembrane domain of PSEN1. Pharmacological treatment with cholinesterase inhibitors and antipsychotics yielded limited benefit. Notably, the extended follow-up time, of more than 10 years from the early symptomatic stage, is a unique and valuable feature of this case study, providing rare longitudinal insight into the natural course of genetically confirmed EOAD.

RevDate: 2025-10-13

Paudel P, Sah A, P Paudel (2025)

ApoE Polymorphism Analysis in Health and Disease of South Asian Populations: A Systematic Review and Meta-Analysis.

Clinical genetics [Epub ahead of print].

This systematic review and meta-analysis assesses the distribution and health implications of apolipoprotein E (ApoE) ε2, ε3, and ε4 alleles, which play crucial roles in lipoprotein metabolism, in South Asian populations, with a focus on neurodegenerative diseases, movement disorders, traumatic brain injury, mental health disorders, cardiovascular disorders, metabolic disorders, and trauma-related disorders. A total of 53 studies identified through comprehensive searches in PubMed, Embase, and Google Scholar up to July 31, 2024, were included on the basis of predefined eligibility criteria after Risk of Bias Assessment via the New York Ottawa Scale. ε3/ε3 was found to be the most prevalent genotype, followed by ε3/ε4 and ε2/ε3. ε4-containing genotypes were associated with susceptibility to Alzheimer's disease, coronary artery disease, vascular dementia, and obesity, though high heterogeneity in some associations necessitates cautious interpretation, whereas the ε2/ε3 and ε2 alleles showed protective effects in some conditions. These studies had several limitations, including data gaps for specific health conditions, underrepresentation of some South Asian countries, and heterogeneity in outcomes. Despite gaps in the data for some countries and specific health conditions, this review reveals distinct South Asian patterns in ApoE polymorphism-disease associations, highlighting the need for targeted genetic research and tailored public health strategies to advance personalized medicine and healthcare policies in this region. There was no specific funding for this study. The study was registered in PROSPERO (registration number CRD42024575197).

RevDate: 2025-10-13
CmpDate: 2025-10-13

Kosa AC, Lopez-Gutierrez L, Ando K, et al (2025)

Differential effects of age and sex on tau pathology propagation in the htau mouse model: A neuropathological and proteomic study.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70784.

INTRODUCTION: Aging is the main risk factor for Alzheimer's disease (AD), acting through still poorly understood mechanisms. AD is associated with the development of a tau pathology, a hallmark lesion propagating in the brain along neuroanatomically connected pathways. This study investigates changes in gene expression and patterns of tau pathology after induction of tau pathology propagation and the effects of age and sex on this propagation.

METHODS: Young and old humanized htau mice were intracerebrally injected with pathological tau from human AD brain to induce tau pathology.

RESULTS: Young and old htau male mice showed similar patterns of tau pathology propagation, whereas the density of tau pathology was increased in young compared to old female mice. Proteomic analysis demonstrated differential expression of proteins involved in endocytosis, autophagosome formation, and tau splicing.

DISCUSSION: The increased tau pathology formation in young female mice suggests that involvement of selected biological mechanisms could occur early in women during their midlife to explain their sensitivity to the development of tau pathology.

HIGHLIGHTS: Tau pathology induced by human PHF-tau is mainly composed of 3R-tau in htau mice. Splicing factors favoring 4R-tau are downregulated in mice with tau pathology. Tau pathology propagation is increased in young females compared to old females. Proteins implicated in endocytosis and autophagy are modified when tau pathology propagates. Some protein expressions are similarly modified in young females and during normal aging.

RevDate: 2025-10-13

Wang F, Liu J, Bai D, et al (2025)

A Phase 1 Study of the Pharmacokinetics, Safety, and Tolerability of Posdinemab (JNJ-63733657) in Healthy Chinese Adults.

Journal of clinical pharmacology [Epub ahead of print].

Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum Cmax was 1401 µg/mL, median tmax was 0.08 days, mean AUCinf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.

RevDate: 2025-10-13

Alcalde-Herraiz M, Woolf B, Xie J, et al (2025)

Phosphodiesterase-5 Inhibition and Alzheimer's Disease Risk: A Mendelian Randomisation Study.

Aging cell [Epub ahead of print].

While preclinical studies suggest that Phosphodiesterase 5 (PDE5) inhibition may reduce cognitive impairment, findings from observational studies on whether PDE5 inhibitors reduce Alzheimer's disease (AD) risk have been inconsistent. We performed a two-sample cis-Mendelian Randomisation (MR) analysis to estimate the causal effect of PDE5 inhibition on AD risk. The analysis was performed across four different genome-wide association studies (GWAS) of AD to enhance reliability through triangulation. Additionally, a sex-stratified MR analysis using data from UK Biobank was performed to assess potential sex-specific effects. No evidence of a causal association between PDE5 inhibition and AD risk was found in the main analyses. Similar findings were obtained in the sex-stratified analysis. Our study uses genetic data to triangulate the evidence and suggests that PDE5 inhibitors are unlikely to decrease the risk of AD. Further research is needed to thoroughly understand the impact of PDE5 inhibitors on the risk of Alzheimer's disease.

RevDate: 2025-10-12
CmpDate: 2025-10-12

La Barbera L, Krashia P, Loffredo G, et al (2025)

Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease.

Molecular neurodegeneration, 20(1):105.

BACKGROUND: Smaller midbrain volumes predict Alzheimer's Disease (AD) progression and faster conversion from Mild Cognitive Impairment (MCI) to dementia. Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, Αβ and tau appears to be a strong predictor for conversion from MCI to dementia. Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.

METHODS: Using adult C57BL/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra pars compacta (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-β (Aβ) accumulation. The lesion performed in Tg2576 mice, as opposed to that in C57BL/6N mice, provides valuable insights into how neuroinflammation is influenced by Aβ accumulation versus the exclusive impact of impaired monoaminergic signaling.

RESULTS: The concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.

CONCLUSIONS: These results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance towards a precision medicine approach in disease management.

RevDate: 2025-10-12
CmpDate: 2025-10-12

Zhang W, Shi B, Xie Y, et al (2025)

Remimazolam alleviates hippocampal neuronal injury in an in vitro Alzheimer's disease model by promoting PINK1/Parkin-mediated mitophagy.

European journal of medical research, 30(1):962.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau proteins. Remimazolam (RMZ), a novel ultra-short-acting benzodiazepine, exhibits neuroprotective effects by enhancing mitochondrial autophagy independently of traditional GABAergic mechanisms. This study investigates the protective role of RMZ against Aβ1-42-induced neuronal damage through PINK1/Parkin-mediated mitophagy. In hippocampal HT22 cells, RMZ significantly attenuated Aβ1-42-induced cytotoxicity, reduced apoptosis, suppressed reactive oxygen species (ROS) production, and decreased lactate dehydrogenase (LDH) release. Moreover, RMZ ameliorated mitochondrial membrane depolarization and tau hyperphosphorylation, while enhancing mitophagy, evidenced by an increased LC3-II/LC3-I ratio, elevated Beclin-1 expression, and decreased P62 levels. Mechanistically, RMZ upregulated PINK1 and Parkin expression, facilitating mitochondrial recruitment and clearance of damaged mitochondria. Importantly, knockdown of PINK1 abolished RMZ's protective effects, confirming the pathway's specificity. These findings suggest that RMZ promotes mitochondrial homeostasis and offers a promising strategy for AD therapy via PINK1/Parkin-mediated mitophagy.

RevDate: 2025-10-12

Elamin SA, Al Shibli AN, Shaito A, et al (2025)

Anti-amyloid monoclonal antibody therapies in Alzheimer's disease - a scoping review.

Neuroscience pii:S0306-4522(25)01003-6 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, and with advancements in the medical field, Anti-amyloid monoclonal antibodies (AA mAbs) targeting amyloid-β have emerged as potential disease-modifying agents altering AD pathology. This scoping review mapped the characteristics, patterns, and gaps in clinical trials investigating the efficacy and safety of AA mAbs in AD treatments, with focus on cognitive, functional, biochemical, imaging, and safety outcomes. It highlighted patterns, gaps, and limitations of the existing literature. A systematic search of PubMed/MEDLINE, Embase, Scopus, and Web of Science was conducted for studies published since inception to February 2022, and eligible studies that investigated efficacy and safety outcomes of AA mAbs in treatment of AD were included. A majority of the included trials reported a combination of cognitive, functional, biochemical, and imaging outcomes. Across the sample, reductions in amyloid burden were frequently reported (10 trials), with a smaller subset of studies reporting significant cognitive and functional improvements (4 trials), primarily lecanemab and aducanumab in addition to one pooled analysis of solanezumab. ARIA-E and ARIA-H were frequently reported among the safety concerns, particularly in high-dose and APOE ε4 carrier populations. Notable limitations were observed in the reviewed literature including a disconnect between biomarker changes and consistent clinical benefits and, importantly, limited population diversity and patient-reported outcomes. This review highlights the need for rigorous, diverse, and patient-centered research. Addressing these gaps is critical in ensuring safe, effective, and equitable treatment for all patients living with Alzheimer's disease.

RevDate: 2025-10-12

Escobar-López M, R Salazar-Varas (2025)

Analysis of EEG coherence according to the onset of Alzheimer's disease.

Neuroscience pii:S0306-4522(25)00979-0 [Epub ahead of print].

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, the effects of which can be slowed down by an early and correct diagnosis. Greater diagnostic accuracy depends on a better understanding of the disease. In this regard, electroencephalography is a promising low-cost tool to explore brain activity and support the diagnosis of AD. When analyzing EEG signals, age is a factor that is not usually taken into account despite being one of the main risk factors. In this work, an analysis of brain connectivity is proposed in the different frequency bands by analyzing the study groups (healthy control and Alzheimer's disease) in two separate processes according to the age of the patients (U65 and A65). The results obtained suggest that changes in brain connectivity due to AD are different depending on whether AD is present before or after the age of 65 years. Furthermore, it is observed that theta, high Alpha and high Beta are more affected for the U65 group, mainly in the frontal and parietal areas; and low Alpha, low Beta and, especially gamma are more affected for the A65 group in the frontotemporal and frontoparietal areas. Therefore, the importance of dividing the analysis by age lies in its ability to identify changes in brain connectivity based on the age at which AD occurs. Finally, using the information obtained in the analysis, a classification framework is performed to validate the EEG coherence analysis with an overall performance of 87.8% accuracy, 88.8 % sensitivity, and 87.2 % specificity.

RevDate: 2025-10-12

Kunath N, Ramfjord HAB, Kvisvik EV, et al (2025)

ITPR1 autoantibody-associated autoimmunity as a cause of newly emerging cognitive decline mimicking Alzheimer's disease: Case report and brief review of the literature.

Journal of neuroimmunology, 409:578774 pii:S0165-5728(25)00255-3 [Epub ahead of print].

BACKGROUND: Since its first description in 2014, anti-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1, also termed IP3R1) autoimmunity has been recognized as causing a clinically heterogeneous spectrum of symptoms. While first described in patients with autoimmune cerebellar ataxia, this facultative paraneoplastic disease has been associated also with peripheral neuropathy, dysautonomia, sleep disorders, neuropsychiatric/psychotic symptoms, and cognitive decline.

METHODS: Retrospective case study.

RESULTS: We report the case of a 58-year-old patient who was admitted with acute confusion, rapidly progressive cognitive decline, and hallucinations. A history of mild cognitive impairment over several years and low cerebrospinal fluid (CSF) amyloid beta-42 and elevated CSF tau protein were suggestive of Alzheimer's disease (AD). However, pleocytosis, intrathecal IgG synthesis and blood-CSF barrier dysfunction prompted screening for antineuronal antibodies, which revealed ITPR1-IgG1/anti-Sj antibodies in both serum and CSF. Brain MRI showed limbic hyperintensities and hippocampal atrophy. No neoplastic disease was found. Immunosuppressive treatment stabilized the disease course but did not lead to symptom improvement.

CONCLUSIONS: This case underscores the clinical importance of CSF analysis and testing for anti-neural autoantibodies, including less common reactivities, in case of rapid cognitive decline even in patients with known or suspected neurodegenerative disease, such as AD, with ITPR1 representing a novel autoimmune target antigen.

RevDate: 2025-10-12
CmpDate: 2025-10-12

Ebadpour N, Abavisani M, Karav S, et al (2025)

Exosome/Extracellular Vesicles-Based Therapeutics in Alzheimer's Disease: Neuroprotective Roles and Future Perspectives.

Journal of molecular neuroscience : MN, 75(4):137.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is marked by memory loss, cognitive decline, and characteristic pathological features including β-amyloid (Aβ) plaques, tau tangles, and neuroinflammation. Despite extensive research, effective therapies remain elusive. Exosome/EVs-based therapeutics have emerged as a promising avenue for AD treatment. Neuron-derived exosomes/extracellular vesicles (EVs) (NDEs) and stem cell-derived exosomes/EVs exhibit neuroprotective effects by promoting Aβ degradation, modulating tau pathology, and reducing inflammation. Notably, NDEs carry insulin-degrading enzyme (IDE) and cellular prion proteins (PrPC), aiding Aβ clearance. However, exosomes also present challenges, such as the potential propagation of pathogenic tau and complement-mediated neurotoxicity. Neural and mesenchymal stem cell-derived exosomes further demonstrate therapeutic efficacy by altering amyloid precursor protein processing and activating PI3K/Akt/mTOR signaling to reduce AD pathology. Despite these advancements, clinical translation requires a deeper understanding of exosome/EVs biology, improved isolation techniques, and personalized strategies. Continued research may establish exosomes as a transformative approach in AD therapy.

RevDate: 2025-10-11

De Lucia N, Petraglia L, Komici K, et al (2025)

Mild Behavioral Impairment as a Predictor of Functional Status.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(25)00471-3 [Epub ahead of print].

OBJECTIVES: Mild behavioral impairment (MBI) occurs in absence of dementia, but no studies explored whether MBI may limit the individuals' ability to complete everyday tasks necessary to live independently. In this study we elucidated on the relevance of specific behavioral markers on functional decline in both cognitively normal (CN) older adults and with mild cognitive impairment (MCI), and evaluated whether individuals with MBI present worse cognition and neurodegenerative dysfunctions compared to subjects without MBI.

DESIGN: Observational cross-sectional study.

SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

PARTICIPANTS: Amnesic MCI (aMCI; n = 232) participants and CN (n = 418) individuals.

MEASUREMENTS: Neuropsychological assessment, volumetric MR brain scan, Flortaucipir PET for in vivo assessment of regional tau deposition, functional assessment questionnaire (FAQ), and neuropsychiatric inventory.

RESULTS: MBI occurred in 53.5% aMCI and 19.6% CN. In aMCI, the most prevalent behaviors were affective dysregulation (34.4%), impulse dyscontrol (30.6%), and decreased drive/motivation (15.9%), whereas affective dysregulation (13.1%) and impulse dyscontrol (10.2%) were most prevalent in CN. In aMCI, affective dysregulation, decreased drive, social inappropriateness and abnormal perception MBI domains significantly predicted the FAQ score, whereas only decreased drive/motivation MBI domain showed a predicted role on FAQ in CN. No effects of MBI were detected on regional tau deposition or brain volumes in aMCI.

CONCLUSIONS: Our findings suggest that the occurrence of MBI might predict a high risk of dysfunction in daily life in both aMCI and CN. An early detection of functional impairment may improve the success of disease-modifying interventions.

RevDate: 2025-10-11

Kong J, So M, Park H, et al (2025)

Electroencephalography functional network for screening amyloid positivity in mild cognitive impairment: a cross-sectional study.

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology pii:S1388-2457(25)01226-X [Epub ahead of print].

OBJECTIVE: Monoclonal antibodies targeting amyloid-β (Aβ) show disease-modifying potential in Alzheimer's disease (AD), making early identification of Aβ-positive individuals at the mild cognitive impairment (MCI) stage essential. Functional network metrics derived from electroencephalography (EEG) may reflect Aβ-related network disruption and serve as viable screening tools.

METHODS: This study included patients with cognitive decline who underwent [18]F-flutemetamol PET/CT, EEG, and neuropsychological testing at Korea University Anam Hospital (2020-2024). Participants were categorized into subjective cognitive decline (SCD), MCI, or dementia. Resting-state EEG was analyzed using the weighted phase lag index to compute functional connectivity, followed by graph theoretical analysis to assess global network properties. Machine learning models were used to classify Aβ status in the MCI group based on EEG-derived features.

RESULTS: Among 100 participants (19 SCD, 55 MCI, 26 dementia), 53 were Aβ-positive. In MCI, Aβ-positive individuals (n = 28) showed significantly reduced delta-band network strength, global/local efficiency, clustering coefficient, and transitivity (all p < 0.05). Classification models reached an AUC of up to 0.850.

CONCLUSIONS: Resting-state EEG network analysis provides a non-invasive, cost-effective approach for screening Aβ positivity in MCI.

SIGNIFICANCE: EEG-based global network measures may aid in early AD diagnosis and patient selection for anti-Aβ therapies.

RevDate: 2025-10-11

Guan T, He J, Zeng L, et al (2025)

Rural-urban disparities in cardiovascular and other competing risk of death among cancer patients.

Journal of advanced research pii:S2090-1232(25)00775-1 [Epub ahead of print].

INTRODUCTION: Rural-urban disparity of cancer is a major public health problem, with an unclear gap in noncancer death. It is important to evaluate rural-urban disparities in cardiovascular diseases (CVDs) and other competing death among cancer patients.

OBJECTIVES: Observing urban-rural disparities and trends in noncancer deaths in the U.S. cancer population.

METHODS: To address rural-urban disparities, we used proportions of deaths, age-adjusted mortality rates (AAMR), cumulative mortality rates, subdistribution hazard ratio (sHR), standardized mortality ratios (SMRs), absolute excess risks (AERs) and mediation analysis.

RESULTS: Between 1990 and 2017, there were 2,022,482 patients of 24 cancer sites, with a median follow-up of 11·8 years. Rural proportions of noncancer and CVD deaths in cancer patients were higher than urban ones. Rural AAMR of noncancer and CVD deaths surpassed urban one in cancer patients, who had higher cumulative mortality rates than urban counterparts in noncancer (sHR:1·21, 95 % confidence interval [CI]:1·19-1·22), CVDs (sHR:1·25, 95 % CI: 1·23-1·28), diabetes mellitus (sHR:1·24, 95 % CI:1·15-1·34), Alzheimer's disease (sHR:1·30, 95 % CI:1·21-1·39), pneumonia and influenza (sHR:1·30, 95 % CI:1·21-1·39) and chronic obstructive pulmonary disease and allied cond (sHR:1·32, 95 % CI:1·26-1·39). Compared with the general population, both rural (SMR:4·58, AER:218·03) and urban (SMR: 3·74, AER: 166·61) cancer patients had higher risks of noncancer death. Mediation analyses identified median household income and SEER stages as the mediators.

CONCLUSION: Rural cancer patients had higher risks of noncancer death than urban counterparts, especially CVD-related deaths. Future targeted policy and public health interventions are needed to diminish the rural-urban gap in such death disparities.

RevDate: 2025-10-11

Rolfsen ML, Mart MF, Kieffer H, et al (2025)

Post Intensive Care Syndrome Awareness and Communication: Surveys of ICU Providers and Patients.

Chest pii:S0012-3692(25)05487-X [Epub ahead of print].

BACKGROUND: Survivors of critical illness often experience new or worsening impairments in various domains of health following discharge, collectively referred to as the Post Intensive Care Syndrome (PICS). While this condition is common, it remains unclear whether providers are routinely communicating about survivorship and PICS to patients and families, and whether patients are remembering these conversations.

RESEARCH QUESTION: How often do Intensive Care Unit (ICU) providers discuss the concept of PICS with at-risk patients or families, and how often do patients remember being told about the concept of PICS?

STUDY DESIGN AND METHODS: We distributed online surveys to ICU healthcare providers at nine U.S. institutions and to patients who survived critical illness in the preceding year at a single site.

RESULTS: We collected a convenience sample of 382 provider responses and 148 patient responses. The providers were registered nurses (53.7%), physician fellows or attendings (33%), and advanced practice providers (13.4%). Patients had predominantly been admitted to surgical (41.1%), cardiovascular (41.1%), and medical (14.4%) ICUs. We found that 73.8% of providers reported having previously heard the term "Post Intensive Care Syndrome." In comparison, only 16.6% of patients remembered ever being told the term. When asked how often they would discuss with patients or families the possibility of any new or worsening impairments following critical illness, less than a third (29.9%) of providers said they do so at least half the time. Only about a third (35.6%) of patients remembered such conversations.

INTERPRETATION: Awareness of PICS is inconsistent among providers and low among patients. Few ICU team members report routinely talking to patients or families about the common, disabling impairments that often occur following critical illness. Few patients remember being told about the possibility of PICS. Further investigation is needed to determine how best to improve this communication gap.

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Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

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