Abstract 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.
Abstract 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.
Abstract 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.
Abstract 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.
Abstract 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.
