INTRODUCTION:Progressive cognitive decline associated with aging can be measured by observing alterations in eye movement behavior during reading. This study explores the association between eye movement profiles and cognitive performance in older adults during reading-based tasks in virtual reality. METHODS:Sixty older adults with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls (HC) wore a virtual reality (VR) headset during a reading-based task. Recorded eye movements yielded four gaze features (F2-F5): fixation duration, region of interest (ROI) entry count, regression count, and saccade amplitude. With the reading-task total score (F1), these formed a five-feature set (F1-F5) for logistic regression under leakage-safe stratified 10-fold cross-validation. Concurrent validity was assessed against paper-based Mini-Mental State Examination (MMSE). RESULTS:The reading-task total score was strongly correlated with MMSE (r = 0.92, p < 0.001). Eye-tracking features showed significant group differences, with longer fixation duration, more ROI entries, more reading-order regressions, and larger saccade amplitude in cognitively impaired groups. The three-class combined model reached macro area under the curve (AUC) = 1.000, accuracy = 0.997, and macro F1 = 0.997; for MCI versus HC, eye-tracking-only and combined models reached AUC = 1.000 compared with AUC = 0.895 for the reading-task score alone. DISCUSSION:Integrating gaze features with the reading-task total score can improve cognitive assessment by capturing process-level information. Participants with AD and MCI exhibited longer fixation durations, more ROI entries, and more reading regressions than controls, with the largest effects in AD. The combined model showed its clearest value in the three-class setting.
INTRODUCTION:Amyloid burden may relate to semantic fluency through tau and astrocytic pathways, but their contributions remain unclear. METHODS:In this cross-sectional study, we analyzed 210 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with amyloid positron emission tomography (PET), tau PET, plasma glial fibrillary acidic protein (GFAP), and animal fluency. Joint mediation models estimated indirect effects through language-network tau and GFAP, with subgroup analyses in amyloid beta (Aβ)-positive participants. RESULTS:In the full sample, both tau and GFAP significantly mediated the association between amyloid burden and animal fluency, with a larger, more robust estimate for tau. Direct effects were non-significant. Among Aβ-positive participants, tau mediation remained significant, whereas GFAP mediation was attenuated. The dual-mediator model showed a significant combined indirect effect (average causal mediation effects [ACME] = -0.211). Exploratory analyses suggested possible apolipoprotein E APOE ε4 moderation of the tau-mediated pathway. DISCUSSION:Amyloid-related semantic fluency impairment was associated with language-network tau and astrocytic reactivity, with tau the stronger mediator, supporting biomarker-defined heterogeneity in language vulnerability across the Alzheimer's continuum.
INTRODUCTION:Plasma biomarker rule-out tests can be used early in the Alzheimer's disease (AD) diagnostic pathway to identify people with low likelihood of amyloid pathology. METHODS:A care setting-agnostic cutoff for the Elecsys® Phospho-Tau (181P) plasma (pT181p) immunoassay was determined and validated in two independent, diverse cohorts, representative of real-world clinical practice (N = 604; N = 787, respectively). An additional cutoff was assessed in a subset of people reflective of primary care (n = 312). RESULTS:At a care setting-agnostic cutoff of 0.934 pg/ml, high negative predictive value (NPV) (93.8%) and acceptable positive predictive value (PPV) (46.6%) were observed against amyloid-positron emission tomography (PET). A primary care-specific cutoff of 0.722 pg/ml showed high NPV (97.9%) against amyloid-PET. Amyloid positivity prevalence for each cutoff population was 22.5% and 13.1%, respectively. DISCUSSION:The pT181p immunoassay is a high-performance test that may substantially help improve access to amyloid pathology testing for people requiring confirmation, potentially leading to timely clinical decisions and better outcomes.
INTRODUCTION:Alzheimer's disease (AD) is biologically defined by amyloid beta and tau pathology. Available biomarkers enable early diagnosis but differ in targets, accessibility, and utility. This review synthesizes evidence for plasma biomarkers, magnetic resonance imaging (MRI), and positron emission tomography (PET) to develop a pragmatic, stage-aware framework for early diagnosis and staging. METHODS:We conducted a narrative review of recent literature and professional guidance (2024-2026) covering plasma biomarkers; structural/functional MRI; and amyloid, tau, and fluorodeoxyglucose (FDG) PET. Evidence was organized by biological target, diagnostic role, disease stage, and intended-use population. RESULTS:For symptomatic individuals, high-performance plasma biomarkers (especially phosphorylated tau at threonine 217 [p-tau217]) support scalable triage and biological enrichment. MRI provides anatomical, differential-diagnostic, and treatment-safety information. Amyloid PET offers biological confirmation; tau PET adds regional staging and prognosis; FDG PET characterizes synaptic dysfunction and distinguishes dementia patterns. Emerging endogenously cleaved microtubule-binding region tau containing residue 243 (eMTBR-tau243) and brain-derived p-tau217 remain investigational. In cognitively unimpaired at-risk individuals, routine screening is not implied; use is for research or trial enrichment. DISCUSSION:The preferred pathway is sequential: clinical evaluation and MRI establish context, validated plasma tests guide referral, and PET resolves uncertainty or refines staging when results may change management. This resource-aware integration improves diagnostic specificity and treatment decisions. Prospective implementation studies are needed to validate thresholds and equitable performance across diverse settings.
INTRODUCTION:The associations of modifiable daily lifestyle variables (e.g., smoking, diet, alcohol intake, sedentary behavior, and physical activity) with structural brain atrophy, and interaction with apolipoprotein E (APOE) ε4 genetic risk, remain unclear. METHODS:Among 3265 UK Biobank participants with repeated magnetic resonance imaging (MRI) data (mean follow-up 2.6 years), we assessed the relations between lifestyle, APOE ε4 genotype, and volumetric changes in 15 structural brain phenotypes, using linear regression. RESULTS:APOE ε4 presence showed greater atrophy by 25.1 mm3 in the left hippocampus (β: -0.115 standard deviations, 95% confidence interval [CI] [-0.192, -0.039] and 187.7 mm3 in frontal pole gray matter (β: -0.112, 95% CI [-0.186, -0.039]) (q < 0.05). Unfavorable lifestyle accelerated left hippocampal atrophy, and smoking increased white matter hyperintensity volumes (q > 0.05). No interactions were observed. DISCUSSION:Our study reinforces the independent effect of APOE ε4 on longitudinal brain atrophy. Lifestyle may help preserve structural brain health, and our findings provide no evidence this varies by APOE ε4 genotype.
Introduction:The presenilin 1 (PSEN1) p.Met233Val variant is a Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU)-eligible autosomal-dominant Alzheimer's disease (ADAD) variant for which lecanemab response data are unavailable. Methods:A 34-year-old symptomatic PSEN1 p.Met233Val carrier (APOE ε3/ε3) was prospectively followed through 26 lecanemab infusions over 12 months, with serial magnetic resonance imaging (MRI), amyloid positron emission tomography (PET), and plasma biomarkers. Results:No amyloid-related imaging abnormalities occurred. Composite Centiloid increased modestly (+7.2), masking regional divergence: basal ganglia (-24.5) and medial temporal cortex (-22.1) declined, whereas posterior cortical regions accrued amyloid. Plasma amyloid beta (Aβ) 42/40 rose to 122% by T22, with concurrent decreases in phosphorylated tau at threonine 217 (p-tau217), p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Global Clinical Dementia Rating (CDR) score remained 0.5; caregiver reports noted improvements in spasticity, dystonia, and affective features. Discussion:Lecanemab demonstrated neuroimaging safety and evidence of biological target engagement in this symptomatic PSEN1 p.Met233Val ADAD carrier. These longitudinal neuroimaging and plasma biomarker findings may help inform interpretation of treatment responses in genetically defined ADAD.
INTRODUCTION:Leveraging the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), we describe the linguistic profile of multilingual older Indian adults and the association of second language (L2) age of acquisition (AoA), proficiency, and daily use with cognition. METHODS:Participants (N = 492) completed a language history questionnaire and cognitive battery assessing executive functioning, memory, and language. Models were stratified by education and adjusted for sociodemographic factors. RESULTS:While L1s varied, the most common L2 was Hindi. Most participants acquired L2 during childhood and reported high understanding and speaking proficiencies. Acquisition location, language use, and reading/writing proficiencies differed by education. L2 proficiency was associated with executive functioning among those with (β = 0.09,[0.01,0.19]) and without (β = 0.07,[0.01,0.13]) formal schooling. Early AoA was associated with better language abilities (β = 0.36,[0.001,0.72]) among those without formal schooling. DISCUSSION:In India, multilingualism is heterogenous across educational levels. Aspects of multilingualism were associated with cognition but differed by educational background.
INTRODUCTION:Reduced cerebrospinal fluid (CSF) amyloid beta (Aβ) 40 has been reported in cerebral amyloid angiopathy (CAA) diagnosed by hemorrhagic magnetic resonance imaging (MRI) markers. Whether similar alterations occur when fulfilling Boston Criteria 2.0 solely through non-hemorrhagic markers remains unclear. METHODS:We analyzed 358 memory clinic patients undergoing MRI and CSF assessment. CAA was categorized by hemorrhagic markers (CAA 1.5 H) or exclusively non-hemorrhagic markers (CAA 2.0 NH) per Boston Criteria 1.5 and 2.0, respectively. Primary comparison of CSF-Aβ40 between CAA groups was complemented by secondary (Aβ42, phosphorylated tau [p-tau181], total tau [t-tau]) and exploratory analyses including Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls, adjusted for age, sex, MRI characteristics, and assay type. RESULTS:Sixty-five patients were reclassified as CAA 2.0 NH. Aβ40 was higher in CAA 2.0 NH than CAA 1.5 H (15,808 vs. 13,792 pg/ml, p = 0.033) and did not differ from AD, MCI, or controls. p-tau181 reached significance after adjustment (p = 0.010), likely reflecting AD co-pathology. However, within CAA-2.0-NH, patients with AD CSF profile showed Aβ40 comparable to hemorrhagic CAA. DISCUSSION:Non-hemorrhagic imaging markers alone were not associated with characteristic CAA-related CSF alterations, suggesting biological heterogeneity, limited specificity, or lesion type-dependent variability.
INTRODUCTION:Remote cognitive screening for primary care must balance accuracy with patient burden. We evaluated whether adaptive task administration could reduce testing while preserving classification accuracy. METHODS:Using data from older adults (N = 277; 100 mild cognitive impairment [MCI]; 177 normal cognitive aging) who self-administered MyCog Mobile, we developed a stepped protocol in which the final task is skipped when preceding tasks classify the patient with confidence. Leave-one-out cross-validation (LOO-CV) assessed agreement with the full-battery classification and accuracy relative to the reference diagnosis. RESULTS:Thirty-three percent of participants were classified at the initial decision point, and only 17% required the full battery. LOO-CV showed a negligible change in area under the curve (ΔAUC = 0.008; bootstrapped 95% confidence interval [-0.004, 0.021]) using the adaptive battery. DISCUSSION:Approximately one third of older adults can be accurately classified as with MCI using only two MyCog Mobile tasks under an adaptive approach. Prospective validation, in which the adaptive battery is administered in real time, is warranted.
INTRODUCTION:Earlier anti-amyloid therapy (AAT) initiation results in improved clinical outcomes in Alzheimer's disease (AD). We sought to identify demographic, clinical, and disease-related factors impacting door-to-treatment times (DTTs). METHODS:A retrospective review of AAT data was conducted at private and academic neurological practices. RESULTS:A total of 329 patients (53.2% from private versus 46.8% academic practices), mean age 73.5 ± 7.2 (55.3% female), with most being non-Hispanic White were treated with lecanemab (81.2%) or donanemab (18.2%). DTTs were significantly reduced (p < 0.05) in both practices when diagnosis was confirmed with blood-based biomarkers (BBBs) as well as with greater clinic experience dosing AATs. DTT increased in patients with non-Medicare insurance and was not impacted by diagnosis, referral source, apolipoprotein E genotype status, or clinic distance. DISCUSSION:Patients with private insurance may experience greater delay in DTT, whereas BBBs may reduce DTT relative to traditional confirmatory biomarkers. DTT improves with clinic experience.
Introduction:While the apolipoprotein E (APOE) ε4 allele promotes blood-brain barrier (BBB) permeability and microstructural disruption, its specific contribution to white matter hyperintensity (WMH) pathological heterogeneity remains unknown. Methods:We measured BBB permeability (K trans) in 31 and microstructure in 59 cognitively normal older adults with WMHs and normal-appearing white matter (NAWM) using dynamic contrast-enhanced magnetic resonance imaging and restriction spectrum imaging (RSI). Linear mixed-effects models (LMMs) examined differences between WMHs and NAWM by APOE ε4 status. Results:In APOE ε4 carriers, K trans was elevated and restricted isotropic diffusion (RI) was reduced within WMHs compared to NAWM. This effect was absent in non-carriers. In contrast, reduced restricted directional diffusion and elevated isotropic free water within WMHs was observed in both genotypes. K trans did not correlate with brain microstructure. Discussion:Our data suggest that WMHs comprise both APOE ε4-related and APOE ε4-independent pathological components. These findings implicate neurovascular and non-vascular mechanisms through which APOE ε4 may contribute to WMH pathological heterogeneity.
Introduction:Differentiating the nonfluent/agrammatic and logopenic variants of primary progressive aphasia (PPA; nfvPPA and lvPPA, respectively) remains clinically challenging due to overlapping subtle speech and language impairments. We investigated whether automated connected speech analysis can support differential diagnosis. Methods:We analyzed connected speech from 84 Italian speakers with PPA (23 nfvPPA, 23 semantic variant [svPPA], and 38 lvPPA) using a picture-description task. Prosodic, phonological, and morphosyntactic features were extracted. Machine-learning classifiers were trained for binary (lvPPA vs. nfvPPA) and multiclass (lvPPA, nfvPPA, svPPA) classification. Explainability analyses identified key features. Results:The combination of speech and language features effectively discriminated among PPA variants. Binary classification reached 81.67% accuracy, while multiclass classification reached 63.86% accuracy. Noun rate, local jitter, articulation rate, and total pauses were among the most informative features. Discussion:Automated analysis of connected speech provides objective linguistic biomarkers that enhance diagnostic accuracy and support reliable differentiation of PPA variants in clinical practice.
INTRODUCTION:Centiloid (CL) scaling standardizes amyloid positron emission tomography (PET) quantification across tracers and platforms; however, variability across software implementations may affect diagnostic classification. This study evaluated inter-software variability and diagnostic performance across five platforms using identical 1 8F-florbetapir datasets. METHODS:Retrospectively, 192 patients undergoing 1 8F-florbetapir PET/computed tomography (CT) and magnetic resonance imaging (MRI) were analyzed. CL values were generated using four US Food and Drug Administration (FDA) -cleared platforms and an in-house Centiloid standard pipeline. Agreement was assessed using intraclass correlation coefficient, with bias and limits of agreement evaluated by linear modeling and Bland-Altman analysis. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis and classification against visual interpretation. RESULTS:Agreement was excellent (intraclass correlation coefficient [ICC] 0.969; 95%CI 0.961-0.975). Some platforms produced systematically higher CL values versus others slightly lower. LoA reached ± 30 CL. Diagnostic accuracy was high (area under the curve [AUC]: 0.949-0.975), with sensitivity 0.923-0.968 and specificity 0.667-0.806. DISCUSSION:Despite excellent agreement, systematic differences persist and may affect classification near thresholds, supporting consistent use of a single processing pipeline.
INTRODUCTION:Evidence on the association between serum uric acid (SUA) and dementia risk is inconsistent, and prospective data in older adults are limited. This study examined associations of SUA levels and trajectories with incident dementia. METHODS:This study included 11,411 community-dwelling adults aged ≥70 years without dementia at baseline. Incident dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders - Fourth Revision (DSM-IV) criteria. Sex-stratified Cox proportional hazards models assessed associations of baseline SUA and 3-year SUA changes with dementia risk. RESULTS:Over a median 9-year follow-up, 1000 (8.8%) participants developed dementia. Low SUA levels were associated with higher dementia risk among females (age-adjusted hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.07-1.61; fully adjusted HR: 1.24, 95% CI: 1.01-1.53), but not males. A decline in SUA over time was associated with higher dementia risk among males only (age-adjusted HR: 1.30, 95% CI: 1.03-1.63; fully adjusted HR: 1.29, 95% CI: 1.02-1.62). DISCUSSION:Associations between SUA and dementia risk varied by sex and SUA trajectory, suggesting potential sex-specific biological mechanisms.
INTRODUCTION:Trials of amyloid-targeting treatments (ATTs) for early symptomatic Alzheimer's disease (AD) enrolled selected patients with minimal medical comorbidities. We investigated whether real-world memory clinic patients who received ATTs also had fewer comorbidities than the broader clinic population. METHODS:We extracted data on demographics, comorbidities, and medications from patients who were seen at the Washington University Memory Diagnostic Center from July 1, 2023, through July 1, 2025. We compared the characteristics of patients by biomarker testing status and ATT treatment status. RESULTS:Of 9938 unique patients, 1948 underwent AD biomarker testing and 335 received ATT infusions (304 lecanemab, 31 donanemab). The patients who underwent biomarker testing or received ATTs were more likely to be White individuals and to have fewer comorbidities than patients who did not undergo testing or receive ATTs. DISCUSSION:Real-world ATT patients were healthier than the general clinic population and more similar to clinical trial participants.
INTRODUCTION:The scarcity of large, clinically relevant cohorts is becoming a bottleneck in Alzheimer's disease (AD) research, as their sensitive nature makes open data sharing difficult. Privacy-preserving synthetic datasets generated with machine learning may help address this challenge. METHODS:We compared five frameworks for generating synthetic tabular data from the Alzheimer's Disease Neuroimaging Initiative and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease cohorts, with a set of empirical privacy and utility metrics. Two of the methods, DataSynthesizer and TableDiffusion, provide ε -differential privacy guarantees. RESULTS:Methods with differential privacy achieved high privacy ratings but low levels of utility. Deep learning methods like Tabular Prior-data Fitted Network (TabPFN) and Conditional Generative Adversarial Network (CTGAN) also showed high privacy with limited utility. In contrast, non-private DataSynthesizer and Synthpop offered higher utility at a cost of lower privacy. DISCUSSION:The evaluated methods demonstrated a clear trade-off between privacy and utility. High privacy was generally associated with insufficient utility, highlighting the need for further research into synthetic data generation for AD.
Virtual reality-based cognitive assessment games (VR-CAGs) are an emerging digital paradigm in dementia and Alzheimer's disease research. Although multiple studies report correlations between VR-CAG performance and standard neuropsychological assessments, clinical adoption remains limited, indicating that behavioral evidence alone is insufficient and that consolidated neuroimaging evidence is required. Existing neuroimaging studies link VR-CAG performance to regional brain activation, volumetric change, and brainwave dynamics, but this evidence remains scattered. We conducted a scoping review of 29 neuroimaging studies on VR-CAGs. Three functional neural systems were associated with VR-CAG performance: the spatial map system, the response system, and the executive control system. Two VR-CAG archetypes - hippocampal-based and adaptive navigation - were identified. A reporting and evaluation checklist is proposed to standardize VR-CAG research. Review findings indicate that VR-CAGs based on allocentric and egocentric tasks may be sensitive to hippocampal health, potentially acting as candidate digital markers of dementia-relevant functional cognitive decline.
INTRODUCTION:We assessed plasma biomarkers for the diagnosis of early Alzheimer's disease (AD). METHODS:Subjects were divided into three groups: cognitively unimpaired (CU) (without subjective cognitive decline [SCD]) (n = 113), CU with SCD (n = 152), and mild cognitive impairment (MCI, n = 45). Plasma assays for amyloid beta (Aβ) 40, Aβ42, neurofilament light chain protein, glial fibrillary acidic protein, and phosphorylated tau181 levels were measured using single molecule array (Simoa) technology. Neuroinflammation and blood-brain barrier (BBB) biomarkers were measured using the Corplex cytokine 10-Plex kit and the angiogenesis 6-Plex kit, respectively. RESULTS:Biomarker levels were regressed by cognitive group, age, sex, race, and apolipoprotein E apoE ε4 status, yielded significant positive associations between age and numerous AD, neuroinflammation, cytokine, and BBB plasma markers. DISCUSSION:Linear regression analysis, adjusted for age, sex, race, and ApoE status, revealed significant differences between cognitive groups in levels of several plasma biomarkers and associations with age and sex. Neuroinflammation and BBB dysfunction showed significant positive associations with age across different stages of AD.
INTRODUCTION:Lecanemab has demonstrated clinical efficacy in early Alzheimer's disease (AD), but real-world data remain limited, particularly in Asian populations. METHODS:We prospectively enrolled 127 patients across the AD continuum who initiated lecanemab at a tertiary memory clinic in Korea. Infusion-related reactions (IRRs), amyloid-related imaging abnormalities (ARIAs), and cognitive outcomes were evaluated through clinical assessments, serial magnetic resonance imaging (MRI), and longitudinal Mini-Mental State Examination (MMSE) follow-up. RESULTS:Among 127 patients, 102 completed at least five infusions with follow-up MRI. IRRs occurred in 27 (21.3%) patients, primarily during the first infusion. ARIAs occurred in 9 of 102 (8.8%), including ARIAs with edema in 4 (3.9%) and ARIA with hemorrhage in 7 (6.9%); most events were mild or asymptomatic. Higher microbleed burden and white matter hyperintensity were associated with increased ARIA risk. MMSE scores remained stable over 6 months. DISCUSSION:In this prospective Korean cohort, lecanemab was generally well tolerated. Longer term controlled studies are needed to clarify cognitive outcomes.
