INTRODUCTION:Locus coeruleus (LC) and glymphatic dysfunction have been linked both to Alzheimer's disease (AD) and, recently, to infraslow oscillation (ISO) in sleep spindle (sigma) activity (ISO). Here we hypothesize ISO integrity is a critical link between sleep and AD. METHODS:We analyzed non-rapid eye movement sleep electroencephalogram (EEG) data from AD participants and controls, extracting ISO peak amplitude, intrinsic frequency, and bandwidth from the sigma-power time-course. We assessed group differences and correlations with plasma biomarkers (Aβ42/40, pTau181, pTau217, neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP]). RESULTS:ISO peak amplitude was significantly reduced in AD, while intrinsic frequency and bandwidth were preserved. ISO peak amplitude showed a trend-level association with Aβ42/40, whereas ISO bandwidth was positively associated with NfL, and showed trends with GFAP and lower verbal memory retention. DISCUSSION:Selective weakening of ISO in AD is consistent with LC dysfunction and impaired glymphatic cycling. ISO may be a novel mechanism and electrophysiological marker linking sleep microarchitecture to AD pathology.
INTRODUCTION:A higher incidence of dementia, including Alzheimer's-like pathology, is observed in aged people living with human immunodeficiency virus-1 (HIV-1). However, mechanisms linking HIV-1 to Alzheimer's disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent studies of HIV-1 and AD. METHODS:We created a novel amyloid precursor protein (APP) (Swedish mutation) knock-in (KI) AD mouse on an immunocompromised NOG background, NOG/APPKM670,671NL/IL-34 (NAIL). Following CD34+ hematopoietic stem cell (HSC) reconstitution, humanized hNAIL mice develop human microglia-like cells in the brain and human immune system in the periphery. This allows, for the first time, studies of progressive brain HIV-1 replication in an AD brain. Four-month-old HSC reconstituted mice were infected with the HIV-1ADA strain, and evaluated at 8 weeks post infection to study the role of brain HIV-1 replication on AD-like pathologies. RESULTS:HIV-1 replication increased amyloid-beta (Aβ) load in the brain and reduced synaptic and neuronal integrity. Cell type-specific spatial transcriptomic analysis demonstrated that Aβ and HIV-1 drive distinct transcriptional patterns, whereas dual pathology amplified AD-like pathology. Neurons showed the highest transcriptional change, with genes linked to neuroinflammation, protein trafficking, and synaptic dysfunction. DISCUSSION:The hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.
BACKGROUND:Prevalence of dementia is higher in low- and middle-income countries (LMICs). However, longitudinal studies characterizing cognitive decline and its clinical and epidemiological predictors remain scarce in Brazil. METHODS:Participants were enrolled from 2011 to 2025 and followed through May 2026. A total of 887 participants were classified as cognitively unimpaired (CU) (n = 274), mild cognitive impairment (MCI) (n = 378), or dementia of the Alzheimer's type (DAT) (n = 235). CU and MCI participants were followed until dementia conversion, which was analyzed under competing risks using cumulative incidence functions and Fine-Gray models. RESULTS:Overall, annualized dementia conversion rate in the MCI group was 10.72 per 100 person-years (95% confidence interval [CI]: 8.54% to 13.29%). In addition, 40.39% of participants progressed to dementia during a mean follow-up time of 3.75 years (standard deviation: 3.28), with an estimated cumulative incidence of 29.85% at 3 years (95% CI: 22.74% to 36.96%), accounting for death as a competing event. DISCUSSION:This study adds valuable information for LMICs. However, estimates should be interpreted considering attrition and competing mortality.
INTRODUCTION:While both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) involve vascular dysfunction, the ocular microvascular differences between them remain largely underinvestigated. METHODS:This cross-sectional study included 650 participants (149 AD, 276 CSVD, and 225 cognitively unimpaired individuals). Optical coherence tomography angiography (OCTA) metrics were analyzed to characterize ocular microvascular alterations. RESULTS:CSVD patients exhibited a higher burden of retinal ischemic perivascular lesions (RIPLs) than AD patients (all p < 0.05), whereas AD patients showed reduced choriocapillaris (CC) density (p = 0.031). In the CSVD group, RIPLs were associated with total CSVD score (p = 0.049), while reduced CC density was associated with elevated phosphorylated tau 181 in the AD group (p = 0.001). Machine learning models integrating OCTA metrics effectively differentiated AD from CSVD (area under the curve = 0.86). DISCUSSION:AD and CSVD exhibit distinct ocular microvascular alterations, supporting OCTA-derived measures as potential non-invasive biomarkers. TRIAL REGISTRATION NUMBER:ChiCTR2000041386.
INTRODUCTION:Common Alzheimer's disease (AD) mouse models are widely used, but their molecular correspondence with human AD remains uncertain. METHODS:We analyzed 15 post mortem human brain datasets, four human non-brain or in vitro sensitivity datasets, and nine AD-related mouse-model molecular-profiling datasets; GSE222494 was analyzed separately for single-nucleus localization. Refined107, a meta-refined 107-gene human AD-associated gene subset, was evaluated using recurrence-matched control sampling, independent pathway-level comparison, within cohort out-of-fold (OOF) classification, and ordered cross-cohort transportability. RESULTS:Refined107 comprised 37 Tier 1 and 70 Tier 2 genes and showed greater statistical consistency than recurrence-matched controls. Functional annotation implicated inflammatory, blood-brain barrier, metabolic, neuronal, and developmental programs. Among 636 recurrent human pathways, 226 showed same-direction support in at least one evaluated mouse-model family, indicating partial and model-dependent human-mouse correspondence. Post-selection within-cohort OOF areas under the curve (AUCs) were 0.833 to 0.980, whereas ordered cross-cohort AUCs were 0.288 to 0.720. DISCUSSION:Refined107 represents a statistically consistent, meta-refined human AD-associated gene subset rather than a comprehensive disease signature. Human-mouse pathway correspondence was partial and model-dependent, and within-cohort classification did not translate into robust cross-cohort transportability.
There is currently no consensus on the most important treatment outcomes in patients with mild cognitive impairment (MCI). As part of developing a core outcome set for MCI, we conducted a pragmatic scoping umbrella review to summarize outcomes reported in previous studies. Six electronic databases were searched from inception to August 2023. Systematic and scoping reviews in English with ≥70% of studies describing at least one quantitative outcome of interventions involving adults with MCI were eligible. Verbatim outcomes were extracted from eligible papers within selected reviews. From 170 papers covering 153 studies from 42 reviews, 143 unique outcomes were identified. Global cognition was the only outcome reported by more than 50% of studies. Two-thirds of outcomes were reported by no more than three studies. Heterogeneous outcome reporting limits evidence synthesis and treatment evaluation. A core outcome set for MCI is warranted to standardize outcome reporting and offer stronger evidence for decision-making.
Rapid and reliable identification of multivariate geochemical anomalies is critical for delineating prospective mineralized zones and reducing uncertainty in mineral exploration targeting. Extended isolation forest (EIF) is a powerful unsupervised ensemble learning algorithm that efficiently isolates anomalies from high-dimensional geochemical datasets using randomly oriented hyperplane partitions. Previous studies have demonstrated the effectiveness of EIF in multivariate geochemical anomaly detection and mineral potential modeling. However, its performance can be significantly affected by stochastic variability arising from random partitioning and random subsampling during isolation tree construction, which may result in unstable anomaly patterns and inconsistent exploration targets in complex geological environments. To mitigate this limitation, we developed a robust unsupervised framework for the identification of multivariate geochemical anomalies associated with gold mineralization in the Southwestern Yilgarn Craton, Australia. The proposed framework integrates robust factor analysis (RFA), a Jaccard-based stability index and EIF to enhance the reliability and reproducibility of anomaly detection. RFA was first applied to compositional soil geochemical data to identify the most significant pathfinder elements associated with gold mineralization, which were subsequently used as input variables for the EIF model. The model was then optimized using a Jaccard-based stability criterion to ensure consistent anomaly detection across repeated independent runs. Model performance was assessed using area under the receiver operating characteristic curve (AUC). The obtained AUC value of 0.82 indicates strong predictive capacity, confirming that the generated anomaly map effectively delineates mineralization-related geochemical patterns and provides a reliable proxy for mineral prospectivity mapping. Overall, the proposed framework offers a robust and reproducible unsupervised approach for multivariate geochemical anomaly detection with strong applicability in both greenfield and brownfield mineral exploration settings.
Early disruption of gamma oscillations is increasingly recognized as a contributor to neurodegeneration and cognitive decline in Alzheimer's disease (AD), positioning 40-Hz stimulation as a promising neuromodulatory strategy. However, its neurophysiological and cognitive effects remain highly variable across studies, underscoring the need for a more integrated mechanistic framework. This review synthesizes current evidence on the neurobiological mechanisms engaged by 40-Hz stimulation in AD, including circuit-, cellular-, and system-level processes underlying network dynamics, glial responses, and multi-target biological effects. We further highlight the conceptual distinction between "physiological resonance" and "artificial superimposition" as a potential determinant of deep-brain engagement and therapeutic outcomes. By integrating both supportive and conflicting findings, we highlight disease stage, biological sex, and behavioral state as important contributors to the heterogeneity of 40-Hz stimulation outcomes. Building on these observations, we propose that future research should move toward mechanistic stratification and precision neuromodulation to facilitate clinical translation.
Subjective cognitive decline (SCD) refers to cognitive concerns that may occur with or without objective impairment on standardized testing. Studies suggest that SCD may be an early clinical marker of Alzheimer's disease and related dementias, and that it can predict future objective cognitive decline and progression to dementia. However, the research that supports these conclusions is primarily based on samples with homogeneous socioeconomic and cultural backgrounds. The limited studies in samples with more diverse representations of racial, ethnic, gender, and sexual orientation characteristics show varying SCD prevalence, correlates, and outcomes. Here, we review this literature, focusing on how to apply the findings to advance our understanding of SCD. We further evaluate how our findings inform a roadmap for future research. Overall, we conclude that broader investigations across more diverse populations enhance our understanding of the factors that may differentially contribute to SCD and shape its utility as a clinical metric.
INTRODUCTION:Plasma phosphorylated tau (p-tau), particularly p-tau217, is a highly specific biomarker of Alzheimer's disease (AD) pathology. However, plasma p-tau217 can be elevated in rare non-AD conditions. Brain-derived (BD) p-tau217 may reduce these off-target effects, but its performance against neuropathology has not been evaluated. METHODS:We compared p-tau217, BD p-tau217, their amyloid beta 42 (Aβ42) ratios, BD p-tau217/p-tau217, and BD p-tau217/BD tau in end-of-life plasma from 288 neuropathologically characterized participants using a fully automated immunoassay. Biomarkers were assessed against National Institute on Aging-Alzheimer's Association (NIA-AA) classification, Thal phase, Braak stage, cognitive decline, and tau-PET (positron emission tomography). RESULTS:All markers tracked neuropathological severity, with BD p-tau217 having larger fold-changes than p-tau217 but BD p-tau217/Aβ42 enhancing this further. BD p-tau217/BD tau achieved the highest area under the curve (AUC) for distinguishing Intermediate/High from Not/Low AD neuropathological change (ADNC) (0.89 vs 0.82 for p-tau217). Although BD p-tau217/p-tau217 showed smaller fold-changes, it had the strongest association with continuous tangle burden in AD (R2 = 0.68) and best predicted Clinical Dementia Rating Sum of Boxes (CDR-SB decline) (R2 = 0.26). DISCUSSION:BD p-tau217 and BD-based ratios enhance dynamic range and prognostic performance while maintaining diagnostic accuracy, supporting further clinical evaluation.
As dementia prevalence rises, developing a dementia-capable workforce is a national priority. Training requirements vary widely across states, and many memory care staff receive limited dementia education. Although evidence supports dementia training, little is known about translating policy into practice. This paper describes the implementation and evaluation of a statewide mandated dementia training initiative in Arizona. After passage of AZ HB2764 (2024), developed and supported by the Alzheimer's Association Arizona Chapter, an interdisciplinary team at Hospice of the Valley developed a state-approved program including 6 hours of online modules and a 2-hour in-person training. From August to December 2025, 3409 staff across diverse roles completed the program. Knowledge scores improved (79.74%-95.97%), with high satisfaction (4.89/5); 98.53% reported role applicability, and 94.6% reported improved care ability at 3 months. Findings support mandated, statewide dementia training as a feasible policy strategy to strengthen workforce capacity and improve dementia-capable care.
INTRODUCTION:Repetitive head impacts (RHIs) have been linked to later life neurodegeneration, yet the in vivo structural correlates of cumulative biomechanical loading remain unclear. We examined whether regional ventricular morphology in former American football players reflects exposure burden and traumatic encephalopathy syndrome (TES) classification. METHODS:Participants included 170 male former football players and 54 age-matched asymptomatic male controls from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Subject-specific manual segmentation quantified lateral ventricle, inferior horn, third ventricle, and fourth ventricle volumes. Group and exposure associations were tested using generalized least squares models. RESULTS:Former players showed larger left inferior lateral ventricle volume than controls, with the largest effects among professional players. Greater cumulative linear and rotational acceleration exposure was associated with enlargement across lateral ventricular and inferior horn regions. DISCUSSION:Regional ventricular enlargement may represent an in vivo marker of cumulative biomechanical loading after RHI exposure.
Artificial intelligence (AI) is rapidly entering dementia clinical practice, offering opportunities across the care continuum. However, cognitive decline creates a unique ethical challenge. This perspective article proposes a strategy to ensure the responsible development and deployment of AI tools for dementia. An interdisciplinary workgroup of the Alzheimer's Association Innovation Roundtable synthesized ethical frameworks, regulatory standards, and empirical evidence to generate expert consensus. The result is a six-step strategic pathway tailored to dementia care: establish ethical foundations, conduct stakeholder engagement, lead a co-design approach, conduct an impact assessment, establish iterative design and feedback loops, and provide education and digital literacy. A practical implementation checklist accompanies the framework. Because responsible progress requires both safety and timely innovation, ethical evaluation must balance the risks of premature deployment against those of harmful delay. Operationalizing ethics throughout the AI lifecycle can ensure that innovation advances autonomy, equity, and safety for people living with dementia.
INTRODUCTION:We tested whether quantitative transport mapping (QTM)-derived perfusion velocity would detect earlier and more sex-specific microvascular alterations than cerebral blood flow (CBF) across the Alzheimer's disease (AD) continuum. METHODS:In 182 participants (cognitively normal = 53, subjective cognitive decline [SCD] = 48, mild cognitive impairment [MCI] = 31, AD = 50), seven-delay arterial spin labeling was used to derive CBF and QTM velocity. Age/sex-adjusted models assessed diagnostic and sex effects, associations with plasma biomarkers and Mini-Mental State Examination (MMSE), and mediation of the hippocampal volume-cognition relationship. RESULTS:QTM velocity was reduced already in SCD, including the hippocampus, whereas CBF declined mainly in MCI/AD. Sex × Diagnosis interactions were significant for QTM in gray and white matter, but not for CBF. QTM, especially in females, was inversely associated with plasma NfL/GFAP, related to MMSE, and parietal QTM partially mediated the hippocampal volume-MMSE association. DISCUSSION:QTM is a non-invasive biomarker more sensitive than CBF to early, female-biased microvascular transport dysfunction in AD.
INTRODUCTION:The social exposome is increasingly recognized as a key determinant for cognitive health. Adverse policing represents an understudied aspect of the social exposome, reflecting persistent encounters with punitive surveillance and law enforcement that accumulate as chronic structural stressors across the life span. METHODS:Using data from the Health and Retirement Study (2006-2020), we performed exploratory and confirmatory factor analyses to examine the dimensional overlap between depressive symptoms and cognitive performance among older Black adults aged 65 + (n = 265; mean age = 69; 72% women), stratified by adverse policing exposures. RESULTS:Depressive and cognitive items generally formed separate dimensions, with effort-related depressive items and cognitive performance items frequently co-loading, suggesting an intermediate latent factor linked to psychosocial burden. DISCUSSION:Our findings underscore the importance of integrating social exposome exposures, such as adverse policing, into modelling dementia risk. This will help researchers better characterize how social adversity impacts cognitive health.
INTRODUCTION:Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear. METHODS:Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes-associated protein 1 (YAP1) were achieved using viral vectors. RESULTS:We found SGZ stiffening occured early in 3-month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild-type mice via supplementing high-density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase-1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single-nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin-YAP1 mechanotransduction axis played important roles in the stiffness-induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness-induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients. DISCUSSION:ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro-neurogenic therapeutics of AD.
INTRODUCTION:Developmental neurotoxicant exposures (e.g., lead [Pb]) are suspected contributors to dementia. Dementia is characterized by amyloid beta (Aβ) plaques and dysregulated metabolism. To better understand the relationship between environment and dementia risk, we assessed the impact of perinatal Pb exposure on dementia-related outcomes in the murine brain. METHODS:Female mice were exposed to 32 ppm Pb or control water during gestation and lactation. Offspring were aged out to 3 weeks or 18 months. We measured Aβ in the 18-month cortex and performed untargeted metabolomics in plasma and cortex at 3 weeks and 18 months of age. RESULTS:Diffuse Aβ and Aβ-positive cells were significantly elevated with Pb exposure. Pb-associated metabolites were enriched for those implicated in oxidative stress, inflammation, and lipid metabolism. DISCUSSION:Pb was associated with molecular and metabolic features of dementia. Important biochemical classes provide insights into possible mechanisms by which developmental Pb exposure may contribute to dementia risk.
INTRODUCTION:Longitudinal diagnostic and prognostic validity of plasma phosphorylated tau217 (p-tau217) in Alzheimer's disease (AD) remains uncertain. METHODS:In this multi-cohort study of 2117 individuals, we established baseline plasma p-tau217 thresholds for amyloid-β-positron emission tomography (Aβ-PET) and assessed their longitudinal classification stability and prognostic relevance for AD-related outcomes. RESULTS:Baseline-defined cutoffs achieved high and sustained accuracy (86%-95%) for Aβ-PET positivity over up to 5 years of follow-up. Longitudinally, most p-tau217-positive individuals remained stable (93%-98%), whereas the intermediate zone group progressed more to positive (44%-78%) than p-tau217-negative individuals (4%-21%). Participants with stable-positive and progress-to-positive p-tau217 profiles more frequently exhibited Aβ abnormalities (90%-100% and 64%-96%, respectively) and experienced accelerated tau accumulation, hippocampal atrophy, and incident dementia compared to those with a stable-negative p-tau217 profile. DISCUSSION:These findings support the high stability and Aβ-PET classification performance of longitudinal plasma p-tau217 monitoring in AD, providing a scalable tool for risk stratification and disease monitoring.
