INTRODUCTION:Early-onset Alzheimer's disease (EOAD) is mostly caused by mutations in presenilin-1/2 (PSEN1, PSEN2) and amyloid precursor protein (APP) genes. Both genetic and experimental evidence have supported the PSEN-APP amyloid hypothesis as the leading pathogenesis of Alzheimer's disease (AD). Thus far, 276 missense variants from PSEN1, 2, and APP have been identified. Herein, we report the abilities of variant effect predictors (VEPs) for identifying the degree of pathogenicity among alleles linked with EOAD. METHODS:We performed pairwise correlations between 276 in vitro functional assays of missense variants from PSEN1, PSEN2, and APP and clinical data among EOAD patients against 37 VEPs. Furthermore, we used the predicted biophysical data of all three proteins to refine our understanding of the molecular basis of missense variants in dominant negative (DN) or loss-of-function (LoF) effects. RESULTS:We found that VEPs were consistently correlated with age at onset (AAO) among EOAD patients and the amyloid-β (Aβ) 42/Aβ40 ratio biomarker. Regarding the ratio, we observed discrepancies in the predictor variables influencing the Aβ42/Aβ40 ratio, with conflicting evidence as to whether the elevated ratio stems from diminished Aβ40 levels or augmented Aβ42 production. We also identified that with increased predicted pathogenicity, there were decreased Aβ38 levels. Conversely, this study found no direct correlations with Aβ37 and Aβ43. Lastly, structural studies show characteristics of both DN and LoF mechanisms, as there are variants positioned in buried hydrophobic domains and charged surfaces. DISCUSSION:Currently, a major clinical challenge in the field is the lack of reliable approaches for predicting the pathogenicity of variants in EOAD. Our study also illuminates the need for experimental studies to identify the predictor variable causing the increased Aβ42/Aβ40 biomarker. Highlights:We performed correlations of 37 VEPs against in vitro data of EOAD variants.VEPs demonstrate potential as diagnostic tools for early onset Alzheimer's disease.Pathogenic missense variants show characteristics of DN and LoF effects.
INTRODUCTION:The classical complement cascade has been implicated in amyloid beta (Aβ) clearance and in the pathogenesis of amyloid-related imaging abnormalities (ARIA) during anti-amyloid monoclonal antibody therapy. Clinically accessible peripheral biomarkers of this cascade remain uncharacterized in real-world cohorts. METHODS:We conducted a retrospective, hypothesis-generating cohort study of 62 patients with early Alzheimer's disease initiating lecanemab. ARIA risk was evaluated in the safety cohort (N = 62), and absolute amyloid reduction at week 26 was evaluated in the efficacy cohort with paired baseline and 26-week amyloid positron emission tomography (N = 34). Associations of baseline plasma C1q, C3, and apolipoprotein E ε4 (APOE ε4) carrier status with these outcomes were examined using Firth's penalized logistic regression and bootstrap linear regression (2000 iterations), with prespecified sensitivity analyses. Within-subject changes in C3 (N = 30) and C1q (N = 19) were assessed by paired Wilcoxon test. RESULTS:Lower baseline C3 was nominally associated with higher ARIA risk (odds ratio [OR] per 1 SD = 0.44, 95% CI: 0.15 to 0.97, p = 0.040, uncorrected), and this association persisted in international normalized ratio (INR)-adjusted and simplified models. C3 ≤ 25th percentile (≤99 mg/dL) showed a trend (OR: 4.78, 95% CI: 0.98 to 26.34, p = 0.052). In the efficacy cohort, higher baseline C1q was associated with smaller amyloid reduction (β = -6.86, 95% CI: -12.19 to -3.06, p = 0.002); carriers of at least one APOE ε4 allele, a status that in this cohort jointly reflects genotype and dose-titration, showed less amyloid reduction (β = -19.50, 95% CI -31.57 to -8.40, p < 0.001). Within-subject changes in C1q and C3 were not significant (p = 0.248 and 0.114, respectively). DISCUSSION:Lower baseline C3 was consistently associated with ARIA risk across sensitivity analyses and higher baseline C1q with smaller amyloid reduction at week 26. Findings are exploratory given the limited single-center sample.
Physical inactivity is a key modifiable risk factor for Alzheimer's disease (AD). However, emerging evidence suggests a bidirectional relationship where inactivity also serves as an early manifestation of AD pathology. This perspective synthesizes recent findings from long-term epidemiological cohorts, brainstem neuropathology, and digital phenotyping to reconceptualize the role of inactivity in preclinical AD. Early tau accumulation in catecholaminergic nuclei (locus coeruleus and ventral tegmental area) disrupts circuits essential for reward valuation and effort calculation. We hypothesize that this neurobiological failure may manifest as prodromal apathy and declining physical activity years before cognitive impairment. Standard metrics like step counts fail to capture these nuances. We propose a multidimensional digital phenotype - incorporating temporal complexity, circadian rhythms, and life-space mobility - to distinguish "behavioral" from "biologically constrained" inactivity. This framework has critical implications for trial enrichment and the design of personalized lifestyle interventions.
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.
Most persons living with dementia (PLwD) reside in community settings, which has driven the development of a wide range of home-based activity interventions. However, the external validity of these studies remains uncertain because the representativeness of study samples is rarely reported. Assessing representativeness is essential for estimating intervention reach and informing health equity and resource allocation decisions. This review evaluates the extent to which participants in home-based activity trials reflect the population of community-dwelling PLwD and identifies sources of selection bias. A targeted review was conducted using three complementary strategies: analyses of two prior systematic reviews, a PubMed search (2020 to 2025), and a review of relevant follow-up publications. Inclusion was limited to peer-reviewed studies that reported detailed recruitment flowcharts and screening data and had initial recruitment pools exceeding 70 participants. The review revealed that most studies provided limited detail on participant selection and frequently initiated recruitment reporting only after caregiver-care recipient dyads had already been assembled. Among the nine studies included, the mean refusal rate among eligible individuals was 57%. In addition, only 24% of initial referrals, on average, completed the first phase of an intervention. Primary barriers to participation included caregiver refusal, lack of an available caregiver/facilitator, and health-related issues. Based on these observed recruitment flows and pre-selection processes, home-based intervention models are estimated to reach fewer than 20% of the target population. These findings suggest that home-based activity interventions for PLwD are applicable to only a limited segment of the intended population. This "representativeness gap" appears largely attributable to reliance on facilitator-care recipient dyads, which inherently excludes the growing number of PLwD living alone and fails to account for the substantial burdens experienced by primary caregivers. Future research should prioritize the development and evaluation of alternative models, such as technology-assisted and community-supported approaches, to enhance scalability, inclusiveness, and equity.
INTRODUCTION:Despite increased risk for Alzheimer's disease and related dementias (ADRDs), Hispanic/Latino (H/L) populations remain underrepresented in research due to several barriers (e.g., stigma, health literacy). Considering family dynamics and cultural values, young H/L individuals may serve as liaisons to help communicate ADRD information and mitigate barriers to research participation. METHODS:We recruited two groups of predominantly H/L young adults, ages 18-35, to carry out Boot Camp Translation (BCT) of ADRD in Houston, Texas (n = 12), and Las Vegas, Nevada (n = 15). Through BCT, we sought to identify (1) key AD-related messages, (2) target message recipients, and (3) effective strategies to convey these messages. ADRD knowledge was assessed pre- and post-BCT. RESULTS:Members endorsed improvements in subjective understanding (Cohen's d = 1.37; p = .001) and objective knowledge of ADRD (Cohen's d = 0.96; p< .001). Suggested central messaging conveyed urgency and responsibility (e.g., "Alzheimer's is real. Healthy or not: On which side do you want to be?"), provided ADRD educational information (e.g., common symptoms), and represented H/L cultural values (familismo; e.g., "Alzheimer's is not the end. You are not alone"). Identified target age groups differed by city; Houston: 50+ years, 30-49 years, 18-29 years; Las Vegas: 40- and 50-year-olds. Members emphasized visual materials that are intergenerational, representative of the diverse H/L community, informative, and straightforward. DISCUSSION:Extending our prior work with BCT in middle-age and older adults, we leveraged intra-familial communication to better understand ADRD-specific health education in H/L communities. While several messaging strategies appeared consistent across sites, regional differences in target audiences and preferred communication strategies highlight the importance of locally tailored messaging. Results identified culturally relevant avenues by which young adults may communicate ADRD research to older family members, fostering engagement. Future work is needed to examine the efficacy and effectiveness of these strategies in service of increasing H/L representation in ADRD research.
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.
