INTRODUCTION:Music interventions show promise in dementia care and digital approaches may increase availability and accessibility. We investigated the efficacy of a digital music intervention (DMI) and conventional music therapy (CMT) compared to standard care (SC) across the dementia care continuum. METHODS:In an exploratory parallel-group randomized controlled trial, community-dwelling (HOME, n = 91) and care home-dwelling (CARE, n = 75) persons living with dementia (n = 166) were randomized to DMI, CMT, or SC. Group-based music interventions spanned 10 weeks (2 × 60-minute sessions/week) and included receptive (listening, reminiscing) and expressive (singing, movement) activity. DMI comprised pre-recorded video sessions followed on screen with a non-therapist facilitator; CMT was delivered live by professional music therapists. Outcomes were assessed at baseline (T1), 3 months (T2), and 6 months (T3), measuring cognition, mood, quality of life, and caregiver well-being. Primary outcomes were changes in general cognition (Montreal Cognitive Assessment, Consortium to Establish a Registry for Alzheimer's Disease Chandler total; T1-T2). Primary and sensitivity analyses used linear mixed-effects models in whole, HOME, and CARE samples. RESULTS:No significant effects of CMT or DMI were found for primary general cognition outcomes in primary or sensitivity analyses. Across exploratory secondary outcomes, compared to SC, CMT improved naming (T1-T2) and verbal learning (T1-T3) in the whole sample and executive function in HOME (T1-T2). Compared to a decline in SC, prompted autobiographical memory was maintained by DMI and CMT in the whole sample (T1-T2) and by DMI in CARE (T1-T2). Sensitivity analyses largely supported these findings. No significant differences were observed between DMI and CMT. DISCUSSION:CMT and DMI did not yield effects on primary general cognition outcomes. CMT showed modest but coherent effects on exploratory secondary cognitive outcomes across the dementia care continuum. The only exploratory secondary finding for DMI was maintenance of autobiographical memory against a decline in SC. These findings support existing evidence yet call for further research to optimize interventions.
OBJECTIVE:To examine associations of inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) with incident dementia and mortality, characterize proteomic and metabolomic correlates of carrier status, and evaluate whether these biomarkers relate to dementia and mortality risk. METHODS:We analyzed UK Biobank participants ≥50 years of age with plasma metabolomics (N = 138,676) and proteomics (N ≤ 15,416) data and ≈15 years of follow-up. Cox proportional hazards models adjusted for key confounding factors evaluated associations of iciHHV-6 with dementia and mortality. Multivariable linear models assessed iciHHV-6 associations with metabolomic and proteomic profiles. Mediation and interaction were evaluated using structural equation models and Cox models with biomarker interactions. Least absolute shrinkage and selection operator regression identified independent proteomic and metabolomic predictors using imputed biomarker data. RESULTS:iciHHV-6 was associated with higher dementia risk (hazard ratio [HR] = 1.32), particularly among women (HR = 1.66) and individuals with elevated Alzheimer's disease polygenic risk (HR = 1.49). Branched-chain amino acids (leucine and isoleucine) were elevated among carriers without mediating dementia risk. Proteomic analyses identified 126 nominally associated iciHHV-6-related proteins, many of which (Neurofilament Light Chain (NEFL), Glial Fibrillary Acidic Protein (GFAP), Yes-Associated Protein 1 (YAP1), Sialic Acid-binding Immunoglobulin-like Lectin 5 (SIGLEC5), Interleukin 19 (IL19), A Disintegrin And Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16), Sphingomyelin Phosphodiesterase 1 (SMPD1)) were also associated with dementia and/or mortality. Exploratory pathway analyses suggested enrichment of proteins related to immune regulation and post-translational modification. Predictive models identified NEFL, GFAP, Vascular Endothelial Growth Factor A (VEGF), Brevican (BCAN), remnant cholesterol, and polyunsaturated fatty acids as dementia predictors (area under the curve [AUC] = 0.83), whereas NEFL, Growth Differentiation Factor 15 (GDF15) Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), Ectodysplasin A2 Receptor (EDA2R) and Advanced Glycosylation End-product Specific Receptor (AGER) predicted mortality (AUC = 0.70). DISCUSSION:iciHHV-6 was associated with increased dementia risk, particularly among women and genetically susceptible individuals, with neuroimmune and metabolic biomarker profiles potentially relevant to brain aging and mortality risk.
Introduction:Compromised vascular health is increasingly linked to Alzheimer's disease (AD) risk. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, and provides a practical, non-invasive index of vascular stiffness and overall vascular health. Older African Americans experience a disproportionate burden of vascular disease and AD. Genetic risk factors such as APOE ε4 and ABCA7-80 (rs115550680) further increase AD susceptibility. However, whether these genetic risks influence vascular stiffness and how that may interact with AD pathology remains unknown, especially in African Americans. Methods:A total of 143 older African Americans (mean age = 71.10 ± 6.83 years; 109 women) were included. We examined the effects of both ABCA7-80 and APOE ε4 genotypes on ePWV and plasma phosphorylated tau 217 (p-tau217). All regression models controlled for sex, education, pulse pressure, waist-to-hip ratio, global cognitive status, hypertension status, and APOE genotype (APOE genotype only used for ABCA7-80 regression models). Results:ABCA7-80 risk allele carriers exhibited higher ePWV (F (1,130) = 8.16, p = 0.005, η2 p = 0.064) and higher p-tau217 levels (F (1,130) = 30.11, p < 0.001, η2 p = 0.201). APOE ε4 allele carriers also showed higher p-tau217 levels (F (1,131) = 12.96, p < 0.001, η2 p = 0.092). ABCA7-80 significantly moderated the relationship between ePWV and p-tau217 (F(1,130) = 6.58, p < 0.001), such that higher ePWV was associated with higher p-tau217 among ABCA7-80 risk carriers (β = 0.52, t (130) = 2.69, p = 0.008). Discussion:ABCA7-80 risk, but not APOE ε4, heightens susceptibility to the tau-related effects of compromised vascular health among older African Americans. These findings identify a genetically vulnerable subgroup in which vascular stiffness may disproportionately accelerate AD-related tau pathology and highlight vascular health as a modifiable target for reducing AD risk in African Americans.
INTRODUCTION:Cerebral microbleeds are commonly observed on susceptibility-based magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and are often interpreted as markers of small-vessel disease. However, how microbleed occurrence differs between amyloid-associated vascular pathology and non-amyloid vascular conditions remains incompletely understood. In this study, we performed a comparative analysis between an amyloidosis mouse model and a non-amyloid arteriopathy cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) model to assess whether microbleed occurrence differs across these distinct vascular contexts. METHODS:Multimodal in vivo MRI at 11.7T, including gradient echo (GRE), spin echo, and diffusion-weighted imaging, was performed in 5xFAD mice and a CADASIL mouse model across 9 to 20 months of age. Ex vivo high-resolution GRE imaging and Prussian blue staining were used to validate microbleeds. Quantitative analyses focused on microbleed counts, parenchymal and cerebrospinal fluid volumes, and regional apparent diffusion coefficient (ADC). In addition, blood-brain barrier (BBB) integrity was assessed in the CADASIL mice. RESULTS:Both in vivo and ex vivo GRE MRI consistently revealed hippocampal microbleeds in 5xFAD mice, whereas no microbleeds were detected in CADASIL mice at any examined age. Microbleeds in 5xFAD mice occurred in the absence of brain atrophy or ventricular enlargement. ADC elevation was observed selectively in the midbrain of 5xFAD mice but not in other regions or in the CADASIL cohort. BBB permeability remained normal in CADASIL mice, indicating preserved vascular barrier integrity despite vascular smooth muscle cell loss. DISCUSSION:Cerebral microbleeds emerged selectively in the amyloid model and were absent in a non-amyloid arteriopathy driven by vascular smooth muscle cell degeneration, suggesting that microbleed occurrence may depend on the underlying pathology. These findings show consistency with the possibility that cerebral microbleeds may reflect disease-associated vascular conditions, refining their interpretation as translational MRI biomarkers in AD.
INTRODUCTION:Glymphatic dysfunction is implicated in Alzheimer's disease (AD), but its mechanism remains unclear. This study investigated the associations of the analysis along the perivascular space (ALPS) index, brain reserve, and cognitive outcomes across the AD continuum. METHODS:This study enrolled two cohorts from the local hospital (n = 95) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 178). We calculated the diffusion tensor image ALPS to assess the whole-brain glymphatic function and evaluated its associations with cognition and brain structure. RESULTS:A higher ALPS index was positively associated with better executive, memory, and language abilities (p < 0.05). A lower ALPS index correlated with thalamic atrophy, involving the anterior, lateral, ventral, and midline thalamic nuclei. Thalamic atrophy mediated the link between glymphatic dysfunction and worse cognition via structural association of full or part mediation. CONCLUSIONS:Glymphatic system deterioration correlates with cognitive decline, potentially mediated by thalamic atrophy. The thalamic nuclei may be critical in this pathway.
Chronic microglial neuroinflammation is a core driver of Alzheimer's disease (AD). Wei et al. recently reported a blood-brain barrier (BBB)-penetrating, microglia-targeting nanomodulator (Res@TcMNP/ASO) that simultaneously suppressed NF-κB signaling and enhanced NRF2-dependent antioxidant defense in chronically activated microglia, yet the molecular node coupling these two opposing circuits was not identified. In this perspective, drawing on primary literature spanning microglial inflammation, neuronal genome maintenance, tau regulation, and oncology, I propose that sirtuin 6 (SIRT6) is a plausible upstream candidate for this coordinated effect. SIRT6, a NAD+-dependent chromatin deacetylase, restrains NF-κB through H3K9 deacetylation at RELA target promoters and, in parallel, deacetylates and stabilizes NRF2 to amplify antioxidant transcription; its decline in the aging and AD brain promotes DNA damage and GSK3-driven tau hyperphosphorylation. Because a microglia-restricted carrier confines pathway modulation to the relevant cell population, this delivery strategy is well matched to a SIRT6-centered mechanism, while the context-dependent, potentially oncogenic nature of systemic SIRT6 activation reinforces the rationale for such restricted delivery. I outline specific loss- and gain-of-function experiments to test whether microglial SIRT6 mediates the dual-pathway effects of Res@TcMNP/ASO, offering a falsifiable hypothesis to guide future mechanistic and therapeutic work.
INTRODUCTION:Depression and anxiety often co-occur with Alzheimer's disease, exacerbating the associated cognitive impairment. This study examined moderating effects of dietary protein and fiber intake on relationships between depressive and anxiety symptoms, and cognitive decline. METHODS:Cognitively unimpaired (n = 553; 39.4% male, 70.6 ± 9.6 years) provided baseline fiber and protein intake, and had repeated cognitive testing and symptoms of depression/anxiety measured (baseline and up to eight follow-ups over 144 months). Moderation and simple slope analyses were employed in the cohort as a whole and following stratification by sex. RESULTS:Fiber intake moderated the relationship between change in depressive symptoms and decline in language (β = -0.005, p < 0.001) and Preclinical Alzheimer Cognitive Composite (PACC); scores (β = -0.003, p = 0.010). In males, fiber intake moderated the relationship between change in anxiety symptoms and executive function decline (β = -0.003, p = 0.018), with protein intake moderating change in depressive symptoms and decline in attention (β = 0.006, p = 0.011). DISCUSSION:Adequate dietary fiber and protein intake moderated association between depressive and anxiety symptoms and cognitive decline, supporting their potential role within multidomain strategies aimed at maintaining cognitive health in older adults.
Dementia care is reaching a technological turning point as rapid advances in artificial intelligence (AI), digital biomarkers, and sensor-based monitoring continue to outpace current clinical practice. Yet most tools remain episodic and disconnected from the everyday environments where cognitive change unfolds. Early cognitive drift often goes unnoticed, the mild cognitive impairment (MCI) window remains a major diagnostic gap, and care teams lack continuous, actionable insights. In this perspective, we introduce Agentic Neurotechnology, an integrated framework that combines adaptive multi-agent AI systems with longitudinal cognitive modeling to support proactive and individualized dementia care. We define a five-layer agentic stack consisting of (1) sensing and digital biomarker agents, (2) interpretation and reasoning agents, (3) longitudinal cognitive trajectory models, (4) care navigation agents, and (5) population-level forecasting agents. We further outline the Cognitive Continuum Loop, a closed-cycle process in which detection, interpretation, reasoning, monitoring, intervention, and adaptation occur continuously across the care environment. This framework highlights three actionable windows for cognitive intervention: the Preclinical Risk Detection window, the MCI Detection window, and the Functional Instability Response window. Each stage presents unique opportunities for agentic AI systems that operate continuously rather than through isolated assessments. We conclude by presenting a translational pathway for deploying agentic neurotechnologies across assisted living, primary care, telehealth, and home-based settings. The goal is to enable earlier detection, greater clinical efficiency, and more personalized cognitive support. Agentic Neurotechnology reframes AI not as a passive screening tool but as an active partner in continuous cognitive care.
INTRODUCTION:Blood-based biomarkers (BBMs) of Alzheimer's disease (AD) provide important information about risk for dementia, but little is known about the psychological impact of sharing BBM results to participants with mild cognitive impairment (MCI). Most AD risk disclosure studies have been conducted in cognitively unimpaired individuals and have not used BBMs. This pilot randomized trial tests the hypothesis that disclosing AD risk based on BBMs is not associated with increased psychological harm compared to standard disclosure methods. METHODS:Participants (n = 27, 73 ± 11 years) with MCI were enrolled and randomized to the intervention (n = 16) or control (n = 11) arm. Participants received a risk estimate based on their age, sex, and equivalent Mini-Mental State Examination score for both groups, with plasma phosphorylated tau 181 results included for the intervention group. Participants completed questionnaires assessing depression, anxiety, and hopelessness prior to disclosure and 2 weeks later. A repeated measures multivariate analysis of variance (MANOVA) was used to determine changes in psychological responses over the follow-up period with a time x group interaction term assessing group differences. RESULTS:Participants in the intervention and control group were similar across baseline demographic and clinical factors (P values ≥ 0.23). Repeated measures MANOVA showed a significant reduction in psychological symptoms from baseline to 2-week follow-up (P = 0.006) in the combined sample. Follow-up univariate models showed the reduction was driven by a significant reduction in anxiety (mean ± standard deviation; baseline = 13.3 ± 7.7; follow-up = 9.8 ± 9.9; P = 0.02). Time x group interaction was non-significant (P = 0.31) indicating similar psychological responses across groups. DISCUSSION:In this pilot study of participants with MCI, psychological response to learning risk of progression to dementia did not differ between those who received a risk estimate based on a BBM versus standard clinical information. Two weeks after disclosure, there was an overall decline in anxiety. These preliminary findings suggest that AD risk disclosure using BBMs is not associated with psychological distress.
Minoritized communities are disproportionately impacted by modifiable dementia risk factors but are underrepresented in dementia research globally. In Australia, the number of dementia prevention cohort and intervention studies has rapidly increased in the past two decades, yet the representation of minoritized groups has not been synthesized. The aims of this mixed-methods review were to summarize the demographic characteristics of participants involved in Australian dementia prevention-focused cohort and intervention studies. A systematic search of published literature, funded grant outcomes, and clinical trial registrations was conducted in October 2023 and updated in February 2025 to identify any Australia-based cohort or intervention studies which focused on dementia prevention. Data custodians of eligible studies were contacted and invited to submit de-identified participant-level data for these studies. The demographic characteristics of participants involved in published manuscripts and submitted participant-level data were synthesized. These data were then presented to 23 Australian dementia prevention researchers during a 2-h workshop in March 2025. Using co-creation methodologies, the workshop aimed to generate consensus-based recommendations for governments, institutions, and individual researchers to improve inclusivity and representativeness in future dementia prevention research. Twenty-eight published dementia prevention studies were summarized alongside fourteen studies for which de-identified participant-level data were submitted. Compared to the modern Australian population, participants enrolled in dementia prevention studies have been predominantly female, highly educated, and less diverse in terms of culture, language, ethnicity and gender. Thirty-seven recommendations were generated by Australian researchers and ranked by importance, providing actionable changes for government and institutional policy and researcher practice. This review identified that participants enrolled in Australian dementia prevention research studies do not accurately represent those most at risk for dementia in the general population. Changes to recruitment and engagement practices and policies are recommended to improve the representativeness and inclusivity of Australian dementia prevention research.
INTRODUCTION:Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurocognitive disorders characterized by distinct but often overlapping pathological processes. These include α-synuclein, amyloid-beta 42 (Aβ42), and tau protein aggregation. While cerebrospinal fluid (CSF) biomarkers provide in vivo insight into these pathologies, their relationship with large-scale brain network dysfunction remains poorly understood. This study aimed to investigate the associations between CSF biomarker concentrations and resting-state functional connectivity in patients with DLB, AD, and mixed AD/DLB. METHODS:Sixty-nine DLB patients, 17 AD patients, and 24 patients with mixed AD/DLB underwent clinical and neuropsychological evaluations, lumbar puncture for CSF biomarker analysis (total α-synuclein, Aβ42, pTau181, and tTau), and resting-state functional MRI. Patients were stratified by disease stage for subgroup analyses. Besides CSF total α-synuclein levels, α-synuclein seeding activity was assessed using real-time quaking-induced conversion (RT-QuIC) assays. ROI-to-ROI analyses were conducted using the CONN toolbox to explore associations between CSF biomarker levels and functional connectivity within and between major brain networks. RESULTS:In DLB patients, lower CSF α-synuclein levels correlated with increased connectivity within the default mode network (DMN) (p FDR < 0.05). In dementia-stage DLB (d-DLB), lower Aβ42 levels correlated with reduced connectivity within the salience network (SN) (p FDR < 0.05). In AD, higher tTau levels correlated with decreased connectivity between the DMN and the SN (p FDR < 0.05). No significant associations were observed for CSF pTau181 or any RT-QuIC metric in any group, and the mixed AD/DLB group showed no biomarker-connectivity correlations at all. DISCUSSION:We identified distinct patterns of DMN and SN connectivity changes associated with CSF α-synuclein and Aβ42 levels, respectively. These findings reflect key functional disruptions that may contribute to core clinical symptoms. They underscore the value of combining CSF biomarkers with functional MRI to elucidate DLB pathophysiology.
Vascular cognitive impairment (VCI), including vascular dementia (VaD), encompasses a spectrum of cognitive deficits resulting from cerebrovascular pathology, ranging from mild impairment to dementia. As the second leading cause of dementia worldwide, VCI remains a major therapeutic challenge. A comprehensive search of ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) identified randomized controlled trials (RCTs) conducted or completed between 2012 and 2025. Trials enrolling participants diagnosed with VCI or VaD across all disease stages and all trial phases were included. Forty-one RCTs met the inclusion criteria encompassing diverse therapeutic mechanisms. Investigated agents included neuroprotective and vascular-targeted compounds, neurotransmitter modulators, symptom-focused drugs for behavioral and psychological symptoms of dementia (BPSD), traditional Chinese medicine (TCM) formulations, and agents acting on novel pathways. Recent trials in VCI and VaD show increasing methodological rigor and therapeutic diversity, signaling growing research momentum in the field. Nonetheless, progress is constrained by regional concentration of studies, limited publication of completed results, and inconsistent disease classification across stages. Strengthening global collaboration, ensuring transparent reporting, and standardizing disease staging will be critical to advancing pharmacological development for vascular cognitive disorders.
INTRODUCTION:Cognitive improvement is mediated by repetitive transcranial magnetic stimulation (rTMS) in Alzheimer's disease (AD), and connectome gradient analysis has important potential to explore more comprehensive information for treatment efficacy. However, it remains unclear whether and how rTMS mediates connectome gradient reconstruction and its spatial neurotransmitter associations in subjects on the AD spectrum. METHODS:A total of 84 subjects on the AD spectrum underwent 4 weeks of conventional neuronavigated rTMS targeting the left angular gyrus (20 Hz, 20 sessions over 4 weeks, 20 minutes per session), including 60 subjects with true stimulation and 24 with sham stimulation. This study identified functional connectome gradients and investigated their neuroplasticity between pre- and post-rTMS intervention. A support vector regression model was subsequently used to explore the cognitive prediction value of baseline measures. Finally, connectome‒neurotransmitter association analysis was used to investigate neurotransmitter profiles related to rTMS therapeutic efficacy. RESULTS:These findings showed that rTMS treatment mainly mediated the decreased gradient values in the somatomotor regions and such baseline values of these regions showed preliminary predictive value for memory improvement after treatment (R 2: 0.40-0.63, mean absolute error: 1.54-3.19, root mean square error: 1.98-3.94, p = 0.0002). Moreover, connectome-neurotransmitter association analysis suggested spatial associations between these gradient changes and normative metabotropic glutamate receptor 5 (mGluR5) and 5-hydroxytryptamine receptor 2A (5HT2a) receptor distributions. DISCUSSION:rTMS mediates plasticity in high-order metric levels in the brain and is linked to the spatial distributions of specific neurotransmitter receptors in subjects on the AD spectrum.
INTRODUCTION:Evidence from routine clinical practice regarding stage-dependent responses to lecanemab remains limited. We examined early amyloid positron emission tomography (PET) and clinical trajectories according to disease stage in a real-world cohort. METHODS:Among 89 patients who received lecanemab, 50 individuals with baseline amyloid positivity and follow-up amyloid PET were included in the primary amyloid PET efficacy analysis. Amyloid burden was quantified using the Centiloid scale. Longitudinal Centiloid trajectories were analyzed using linear mixed-effects models including disease stage, time from baseline amyloid PET, and the disease stage × time interaction, with adjustment for cumulative dose exposure, age, sex, and apolipoprotein E (APOE) ε4 carrier status. Cognitive and functional outcomes were assessed using mixed-effects models. RESULTS:Amyloid burden decreased substantially during follow-up. After adjustment for cumulative dose exposure, age, sex, and APOE ε4 carrier status, the disease stage × time interaction was significant (β = +1.62 Centiloid/month; 95% confidence interval, 0.80 to 2.43; p < 0.001), indicating a faster rate of Centiloid reduction in patients with mild cognitive impairment (MCI) than in those with dementia (estimated -2.34 vs. -0.72 Centiloid/month). Conversion to amyloid-negative status (full treatment-related amyloid clearance) occurred in 9 of 50 patients (18.0%) and was more frequent at the MCI stage (p = 0.022). Patients treated at the MCI stage also showed more favorable short-term cognitive and functional trajectories than those treated at the dementia stage. DISCUSSION:In real-world clinical practice, lecanemab treatment was associated with substantial amyloid reduction, with faster amyloid clearance observed at the MCI stage. These findings support the potential value of earlier intervention with anti-amyloid therapy, although longer follow-up and controlled comparisons are needed to determine whether early biomarker changes translate into sustained clinical benefit.
INTRODUCTION:Anti-amyloid beta (Aβ) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc-mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid-related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single-domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood-brain barrier (BBB) penetration and allows Fc-mediated functions to be studied independently. METHODS:We immunized a llama with Aβ aggregates and constructed a phage display library to screen for aggregate-specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre-existing plaques in amyloid precursor protein (APP)/presenilin 1 (PS1) mice. RESULTS:We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind Aβ plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc-less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP/PS1 mice. However, despite robust target engagement, the Fc-less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10-Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc-mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal. DISCUSSION:Our findings demonstrate that Fc effector function is indispensable for microglial-mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next-generation immunotherapies. Furthermore, 2D10-Fc represents a promising therapeutic candidate, combining the high-affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.
INTRODUCTION:Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive and functional decline. Memantine, a commonly prescribed N-methyl-D-aspartate receptor antagonist, appears to slightly delay symptom progression in moderate or advanced stages of AD. Clinical response is highly variable across patients with some benefiting but others not. Induced pluripotent stem cell (iPSC)-derived neurons can provide a donor-dependent model to predict the therapeutic efficacy of memantine. METHODS:We generated iPSC-derived cortical neurons from 19 individuals (12 AD and 7 cognitively unimpaired [CU]). Assays for calcium influx and oxidative stress were developed and optimized for neurons. Memantine was tested under different treatment conditions. Neurons were exposed to glutamate/glycine to induce calcium influx and menadione to generate oxidative stress. Memantine treatment was applied either acutely (1 hour) or as a 24-hour pre-treatment to evaluate its neuroprotective effects. RESULTS:Peripheral blood mononuclear cell-derived iPSCs were successfully differentiated into functional neurons, exhibiting comparable electrophysiological properties between AD and CU lines. Calcium influx assays revealed a heterogeneous response among AD and CU neurons, with AD neurons generally displaying higher baseline fluorescence. Memantine treatment for 24 hours significantly reduced calcium influx, with a -9.85% average reduction and a range of -0.39% to -39%. Similarly, reactive oxygen species assays showed menadione-induced oxidative stress was attenuated by 24-hour memantine pre-treatment for a mean -26.05% reduction and a range of -4.23% to -72.21%. The observed variability indicates differential susceptibility to excitotoxicity reduction and or oxidative stress mitigation across lines. DISCUSSION:This exploratory study establishes a robust in vitro platform to test memantine efficacy using iPSC-derived neurons to model calcium dysregulation and oxidative stress in AD. The observed variability in response highlights the importance of personalized approaches in AD treatment, emphasizing the potential for iPSC-based platforms in precision medicine.
INTRODUCTION Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.METHODS The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APPNL-G-F AD mouse model using a translational gene-delivery approach with a blood-brain barrier-penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.RESULTS PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.DISCUSSION These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.
Evidence suggests that Alzheimer's disease (AD) presents differently across ethnoracial groups, producing disparate risk and resilience profiles that may be measured through neuropsychological data. Extant AD research primarily examines monoracial groups, despite the fact that Multiracial individuals make up more than 10% of the US population. Failure to incorporate data from Multiracial participants (those endorsing two or more racial identities) limits research and clinical efforts to address AD in minoritized communities. A scoping review examined the use of neuropsychological data from Multiracial participants within AD research. Three databases were searched (APA PsycInfo, Embase, and Web of Science) for studies containing ethnoracially minoritized groups. Two independent researchers reviewed articles and included studies that met the following criteria: published in 2000 (the year the US Census formally allowed self-identification of multiple races) or later, in English, US-based cohort (as race is a social construct), reported neuropsychological data, and the research was AD-related. Searches yielded 855 original articles. Following abstract review, 484 articles were screened in full, resulting in 19 articles that met the inclusion criteria. Most excluded articles (66.67%) contained vague racial descriptions (e.g., use of an undefined Other Race group), making it difficult to know whether Multiracial participants existed in the dataset. Roughly one-third (29.03%) of articles were excluded because they described only monoracial groups. Analysis of neuropsychological outcomes showed that most articles included Multiracial participant data in larger group-level analyses (e.g., normal cognition versus dementia) or grouped their data with other, less represented ethnic or racial groups (e.g., Other Races). This review demonstrates the paucity of research and need for intentional consideration of the inclusion of Multiracial participants in AD research. Recommendations to improve reporting of data from Multiracial participants are offered, including considerations for the anticipation and adaptation to changes in the social definitions of ethnicity and race.
INTRODUCTION:Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath-holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype. METHODS:We enrolled 64 patients with cerebrospinal fluid (CSF)-confirmed AD (30 APOE ε3, 34 APOE ε4) and 28 age-matched healthy controls in a cross-sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p-tau181], amyloid beta [Aβ]42/Aβ40 ratio - AmyR). Multivariate regressions examined associations between BHI and AD-related parameters, stratified by APOE genotype. RESULTS:BHI was significantly reduced in both AD groups compared to controls (p < 0.001), with no difference between ε3 and ε4 carriers. In ε3 patients, lower BHI was independently associated with higher plasma p-tau181. In the MRI subgroup analysis, ε3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in ε4 carriers. DISCUSSION:Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular-metabolic dysfunction in APOE ε3 carriers. CVR may represent a non-invasive biomarker of early vascular contributions to cognitive decline in AD.
