J. Alzheimers Dis. [JOURNAL]
Sun
200 papers
Gut microbiota alterations in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis.
Liu Y, Wang X, Huang W … +6 more , Li R, Zhang H, Jiakesileke S, Zhang P, Petersen JD, Cao W
J Alzheimers Dis · 2026 Jul · PMID 42390364 · Publisher ↗
BackgroundAltered gut microbiota has been implicated in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but findings across human studies are inconsistent.ObjectiveTo synthesize observational evidence on gu...
BackgroundAltered gut microbiota has been implicated in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but findings across human studies are inconsistent.ObjectiveTo synthesize observational evidence on gut microbiota differences in older adults with AD or MCI compared with cognitively normal (CN) controls, and to assess the interpretive value of reported microbiome measures across disease stages.MethodsWe searched PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library for observational studies published from 1 January 2012 to 10 December 2025 reporting fecal microbiota profiles in AD, MCI, and CN adults (mean age ≥60). Random-effects meta-analysis was used for α-diversity; β-diversity and taxonomic changes were summarized narratively.ResultsTwenty-three studies were included (AD = 698, MCI = 485, CN = 1060). In AD versus CN, pooled α-diversity estimates showed no robust statistically significant differences (Shannon SMD = - 0.23, 95% CI: - 0.57 to 0.11; Chao1 SMD = -0.36, 95% CI: -0.74 to 0.02; ACE SMD = -0.38, 95% CI: -0.88 to 0.11). In MCI versus CN, differences were small and non-significant (Shannon SMD = -0.01, 95% CI: -0.18 to 0.15; Chao1 SMD = -0.17, 95% CI: -0.37 to 0.02). β-diversity and taxonomic findings more often suggested community-structure disruption and altered microbial composition in AD, whereas MCI findings were less consistent.Conclusionsα-diversity is not supported as a useful biomarker for distinguishing AD or MCI from CN aging. Community-structure and taxonomic patterns may be more informative, but heterogeneity limits interpretation. Future studies should use standardized, function-oriented, and biomarker-informed approaches to clarify AD-continuum microbiome changes.
Stage-dependent relationship between sleep duration and cortical tau deposition in cognitively impaired individuals: A cross-sectional study.
Zheng Y, Kang L, Yang X … +8 more , Zhou R, Chen H, Wang W, Xu X, Xu W, Liu J, Li B, Deng Y
J Alzheimers Dis · 2026 Jul · PMID 42383821 · Publisher ↗
BackgroundChanges in sleep characteristics are critical in the course of Alzheimer's disease (AD).ObjectiveWe aimed to explore the relationship between sleep duration and tau pathology progression in patients with AD and...
BackgroundChanges in sleep characteristics are critical in the course of Alzheimer's disease (AD).ObjectiveWe aimed to explore the relationship between sleep duration and tau pathology progression in patients with AD and mild cognitive impairment (MCI).MethodsThis cross-sectional study included 172 patients (70 with MCI and 102 with AD). Sleep duration and disturbances were assessed through standardized questionnaires, while tau deposition and cerebrospinal fluid clearance were evaluated using tau-PET and diffusion tensor image analysis along the perivascular space (DTI-ALPS), along with comprehensive cognitive assessments. The data were adjusted for variables such as demographic factors, clinical symptoms, and medications.ResultsSleep duration showed a positive association with tau deposition in the MCI stage (total sleep: β = 0.18, p = 0.014; nighttime sleep: β = 0.20, p = 0.007) but negatively associated in the AD stage (total sleep: β = -0.18, p = 0.039; nighttime sleep: β = -0.20, p = 0.039). Patients with sleep disturbances demonstrated lower tau burdens (group difference = 0.62, p = 0.005). Mediation analysis revealed a significant indirect effect of depression in the sleep-tau relationship (total sleep: β = -0.26, p = 0.040; nighttime sleep: β = -0.24, p = 0.040).ConclusionsThis study first revealed the stage-dependent characteristics of sleep-tau relationships, highlighting the MCI stage as a critical research focus.Clinical TrialThe study was registered with ClinicalTrials.gov (NCT05623124). URL: https://clinicaltrials.gov/study/NCT05623124.
Multilayer brain connectivity and long-term cognitive changes in individuals at risk for Alzheimer's disease.
Kpetou R, Raposo Pereira F, Segobin S … +7 more , La Corte V, Villain N, Groussard M, Jauny G, Platel H, Hinault T, Insight-Pread Study Group
J Alzheimers Dis · 2026 Jul · PMID 42383593 · Publisher ↗
BackgroundAmong aging individuals, some develop Alzheimer's disease (AD) while others remain cognitively stable. Understanding how structural and functional brain changes interact, could clarify this heterogeneity partic...
BackgroundAmong aging individuals, some develop Alzheimer's disease (AD) while others remain cognitively stable. Understanding how structural and functional brain changes interact, could clarify this heterogeneity particularly among individuals at increased risk for AD.ObjectiveThis study aims to explore how structure-function connectivity changes relate to subsequent long-term cognitive trajectories in older adults with SMC and varying amyloid burden.MethodsWe analyzed data from the INSIGHT-preAD cohort, which includes older individuals with subjective cognitive complaints followed neuropsychologically over five years. Multiplex connectome integrating resting-state EEG functional connectivity and diffusion-weighted imaging-based structural connectivity was used to characterize brain network organization. We computed the multiplex participation coefficient (PC) as an index of structure-function similarity and examined its association with individual cognitive trajectories across the follow-up period.ResultsSignificant differences in multiplex connectivity were observed among amyloid positive participants who later progressed to AD compared to amyloid positive stable (e.g., non-progressors) and amyloid negative controls. Specifically, higher PC values in the delta band were observed in amyloid positive individuals who later developed AD. This pattern, particularly within the default mode network, was associated with subsequent cognitive decline suggesting that delta band structure-function similarity may represent a potential candidate marker of cognitive vulnerability and progression in AD.ConclusionsMost studies investigating AD have primarily examined functional or structural connectivity separately. By integrating both modalities using a multiplex approach, our study provides interesting preliminary evidence that structure-function connectivity may capture network-level changes associated with cognitive trajectories along AD continuum.
The creation and verification of a detection model for mild cognitive impairment by employing eye-tracking and gait metrics.
Tan H, Zhang G, Du C … +9 more , Li X, Bai Y, Mao L, Yang F, Qi Q, Zhao N, Shi W, Zhao Y, Chang M
J Alzheimers Dis · 2026 Jun · PMID 42381285 · Publisher ↗
BackgroundMild cognitive impairment is a prodromal stage of dementia, and early identification is crucial for prognosis.ObjectiveThis study aims to create and validate a machine learning model for diagnosing mild cogniti...
BackgroundMild cognitive impairment is a prodromal stage of dementia, and early identification is crucial for prognosis.ObjectiveThis study aims to create and validate a machine learning model for diagnosing mild cognitive impairment (MCI) using eye movement and gait analysis data.MethodsTo facilitate model training and internal validation, a cohort of 235 patients was recruited from the Memory Clinic at Xi'an NO.3 Hospital between August 2024 and November 2025. In addition, data from 71 patients were randomly selected to form an independent test set. Feature selection was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) and multivariable logistic regression. Subsequently, various machine learning classifiers were compared. Model performance was assessed using metrics such as the area under the receiver operating characteristic curve (AUC) and decision curve analysis. To evaluate model interpretability, SHapley Additive exPlanations (SHAP) were employed.ResultsThe study involved 235 participants, divided into mild cognitive impairment (MCI) (n = 130) and healthy control (HC) (n = 105) groups. The final prediction model used four features: gait speed during a dual-task test, ground reaction force in a single-task test, antisaccade task accuracy, and noise rate in a saccade-to-pursuit task. The Gaussian Naive Bayes (GNB) classifier showed excellent performance with an AUC of 0.952 (95% CI: 0.923-0.981) in the validation group and 0.944 (95% CI: 0.912-0.967) in the test set.ConclusionsThe GNB model, combining eye movement and gait parameters, enables early MCI detection with high accuracy and practical clinical use.
Compartment-specific analysis reveals disrupted astrocytic calcium transients in anesthetized Alzheimer's disease mice.
Abedin MJ, Lee YF, Zhang M … +4 more , Russ AN, Gerashchenko D, Bacskai BJ, Kastanenka KV
J Alzheimers Dis · 2026 Jun · PMID 42377442 · Publisher ↗
BackgroundAlzheimer's disease (AD) is characterized by presence of extracellular amyloid plaques, intracellular tau tangles, and extensive neuronal cell death. In addition to neurons, astrocytes modulate neuronal network...
BackgroundAlzheimer's disease (AD) is characterized by presence of extracellular amyloid plaques, intracellular tau tangles, and extensive neuronal cell death. In addition to neurons, astrocytes modulate neuronal network activity through tripartite synapses. Also, astrocytes are increasingly recognized for their involvement in AD pathology. Aberrant astrocytic calcium signaling has been implicated in AD pathological processes, including disrupted synaptic transmission, dysregulated glutamate homeostasis, and impaired vascular function via astrocytic endfeet. Previous investigations have assessed compartment-specific astrocytic calcium transients, yet most employed a restricted range of metrics. Thus, comprehensive analyses of calcium dynamics within individual astrocytic compartments in mouse models of amyloidosis are lacking.ObjectiveTo analyze spontaneous calcium transients within distinct astrocytic compartments in APP/PS1 mice.MethodsUsing in vivo multiphoton imaging of Yellow Cameleon 3.6, a genetically encoded calcium indicator targeted to astrocytes in APP/PS1 mice, we analyzed spontaneous calcium transients in cortical astrocytes at 4-6 months of age. We quantified event rate, activity duration, area under the curve (AUC), and peak amplitude across four compartments: soma, processes, microdomains, and endfeet. Correlation analyses were used to assess astrocyte synchrony and distance-dependent activity relationships.ResultsIn APP/PS1 mice, somas exhibited increased activity duration and peak amplitude, while processes and microdomains showed reduced duration, AUC, and amplitude despite higher event rates. Endfeet showed reductions in all parameters. Correlation analyses revealed enhanced astrocyte synchrony in APP/PS1 mice, with distance-dependent correlation decay observed only in nontransgenic controls.ConclusionsThese findings highlight compartment-specific disruptions of astrocytic calcium activity caused by amyloidosis.
ε4-specific associations between agitation, cerebrospinal fluid biomarkers, and cognitive decline in cognitively impaired patients.
Du X, Wang Y, Zhao J … +3 more , Liu Y, Peng D, Alzheimer's Disease Neuroimaging Initiative
J Alzheimers Dis · 2026 Jun · PMID 42377429 · Publisher ↗
BackgroundThe associations between agitation, cerebrospinal fluid (CSF) biomarkers, and cognitive decline, and whether these relationships vary by genotype, remain unclear in Alzheimer's disease (AD) and mild cognitive...
BackgroundThe associations between agitation, cerebrospinal fluid (CSF) biomarkers, and cognitive decline, and whether these relationships vary by genotype, remain unclear in Alzheimer's disease (AD) and mild cognitive impairment (MCI).ObjectiveTo investigate the association between CSF biomarkers and agitation in cognitively impaired individuals, with a focus on the potential moderating role of ε4 status.MethodsWe analyzed 491 cognitively impaired individuals (359 MCI and 132 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available CSF biomarker data. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI), focusing on agitation.ResultsAmong ε4 carriers, agitation was significantly associated with higher CSF GAP-43 (OR = 1.584, 95% CI: 1.159-2.195, p = 0.005) and p-tau levels (OR = 1.49, 95% CI: 1.073-2.101, p = 0.02). These associations were not observed in non-carriers. In addition, ε4 carriers with agitation showed a higher risk of progression to dementia compared with other groups (HR = 4.422, 95% CI: 2.542-7.692, p < 0.001).ConclusionsCSF GAP-43 and p-tau levels are associated with agitation in ε4 carriers. Agitation in this subgroup is also associated with an increased risk of progression to dementia, suggesting that it may reflect underlying disease-related processes.
Depressive-cognitive interactions modulate amygdala and hippocampus functional connectivity in mild cognitive impairment.
Jian W, Sun H, He Y … +7 more , Lan X, Dong L, Wang Z, Jiang S, Cai Q, Li H, Yao D
J Alzheimers Dis · 2026 Jun · PMID 42377424 · Publisher ↗
BackgroundDepressive symptoms frequently co-occur with cognitive impairment in older adults. Although depression and cognition interact in brain activity, the underlying functional connectivity mechanisms in mild cogniti...
BackgroundDepressive symptoms frequently co-occur with cognitive impairment in older adults. Although depression and cognition interact in brain activity, the underlying functional connectivity mechanisms in mild cognitive impairment (MCI) remains unclear.ObjectiveTo investigate how depressive symptoms modulate the relationship between cognition and amygdala/hippocampus functional connectivity in MCI.MethodsThis study included 138 participants (45 healthy controls and 93 MCI patients) who underwent resting state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment using the Montreal Cognitive Assessment-Basic (MoCA-B) for cognitive function and Hamilton Depression Rating Scale (HAMD) for depressive symptoms. Seed-based functional connectivity analysis was performed using bilateral amygdala and hippocampus as seed regions to quantify the HAMD × MoCA-B non-monotonic interactions on whole-brain connectivity. Simple slopes analyses were conducted to characterize directionality changes across depression severity levels.ResultsWhole-brain analyses revealed significant HAMD × MoCA-B interaction effects (cluster p value < 0.05, voxel p value < 0.01, GRF corrected) demonstrating symptom-dependent reorganization of cognition-FC relationships. Amygdala connectivity decreased to anterior/middle cingulate and precuneus but increased to triangular part of inferior frontal gyrus (IFGtri), medial superior frontal gyrus, and cerebellar lobule IX. Hippocampal connectivity decreased to cuneus, insula, thalamus, and caudate but increased to opercular part of inferior frontal gyrus (IFGop), orbitofrontal cortex, and cerebellar lobule VIII.ConclusionDepressive symptoms alter amygdala and hippocampal FC relationships with cognition in MCI. Depression-dependent hippocampal/amygdala connectivity changes with the frontoparietal network (FPN-A)-particularly IFGop/IFGtri and cerebellum-suggest their role as critical hubs for emotional-cognitive integration, highlighting them as potential neuromodulation targets for cognitive and depressive symptoms in MCI.
The blood-brain barrier-penetrating fusion protein BBB-ABP selectively binds amyloid-β oligomers and prevents in vitro neurotoxicity.
Rennie K, Tauskela JS, Ménard M … +4 more , Aylsworth A, Comas R, Whitfield J, Chakravarthy B
J Alzheimers Dis · 2026 Jun · PMID 42377097 · Publisher ↗
BackgroundSoluble amyloid-β oligomers (Aβo) are considered the most neurotoxic species of Aβ and key drivers of Alzheimer's disease (AD) pathogenesis. Selective targeting of Aβo offers a promising therapeutic strategy. W...
BackgroundSoluble amyloid-β oligomers (Aβo) are considered the most neurotoxic species of Aβ and key drivers of Alzheimer's disease (AD) pathogenesis. Selective targeting of Aβo offers a promising therapeutic strategy. We previously identified an amyloid-binding peptide (ABP) that binds Aβo and engages Aβ deposits in AD mouse and human brain tissue. To facilitate brain penetration, ABP was fused to the blood-brain barrier (BBB) transporter FC5 and an Fc fragment, generating BBB-permeable constructs (mouse FC5-mFc2a-ABP and humanized FC5-hFc-ABP, referred to as BBB-ABP). Previous in vivo studies demonstrated the ability of BBB-enabled ABP to engage and clear Aβ from the central nervous system.ObjectiveThis study aimed to evaluate the in vitro functionality of BBB-ABP and its ability to prevent Aβo-induced neurotoxicity and synaptic dysfunction.MethodsBinding specificity was assessed using ELISA and western blot overlay assays. Functional assays were performed in SH-SY5Y cells and primary neurons to evaluate Aβo sequestration, protection against Aβo-induced toxicity, and effects on synaptic activity measured via multi-electrode arrays.ResultsBBB-ABP retained selective binding to Aβo and effectively prevented its interaction with neuronal proteins and its binding to dendritic spines in live primary neurons. BBB-ABP significantly reduced Aβo-induced toxicity in SH-SY5Y cells and primary neurons, including under conditions of NMDA-induced stress. Aβ exposure did not significantly alter spontaneous synaptic activity, precluding assessment of electrophysiological rescue by BBB-ABP.ConclusionsThese findings demonstrate that BBB-ABP maintains Aβo-selective binding and is capable of preventing the interaction of Aβo with neurons, thereby mitigating Aβo-induced toxicity in vitro, supporting its further development as a therapeutic candidate for AD.
Process-level eye-movement dynamics enhance sensitivity to early Alzheimer's disease-related cognitive vulnerability.
Chen PY, Shieh WY, Weng LC … +3 more , Tsai HH, Wang WX, Liu CY
J Alzheimers Dis · 2026 Jun · PMID 42377089 · Publisher ↗
BackgroundEarly Alzheimer's disease (AD)-related cognitive vulnerability is characterized by subtle disruptions in attentional and executive processing that may precede overt declines in global cognitive scores. Identify...
BackgroundEarly Alzheimer's disease (AD)-related cognitive vulnerability is characterized by subtle disruptions in attentional and executive processing that may precede overt declines in global cognitive scores. Identifying process-sensitive behavioral markers capable of capturing these early alterations remains a major challenge in psychogeriatric assessment.ObjectiveTo examine whether eye-movement-derived process-level measures, particularly fixation-shift dynamics, are associated with early cognitive vulnerability in older adults and whether they provide incremental value beyond conventional cognitive screening scores in an AD-related context.MethodsThis cross-sectional study enrolled 109 adults aged ≥65 years, categorized as cognitively normal (CN, n = 33), mild cognitive impairment (MCI, n = 35), and dementia due to AD (ADD, n = 41). Participants completed a standardized online interactive cognitive task while eye movements were recorded using a non-head-fixed, desktop-based eye-tracking system. Cognitive-only, eye-movement-only, and combined multimodal models were compared using receiver operating characteristic (ROC) analysis and area under the curve (AUC).ResultsThe combined multimodal model consistently outperformed single-modality approaches. Discriminative performance was high for CN versus ADD (AUC = 0.925) and for CN versus cognitively impaired participants overall (AUC = 0.897). Fixation-shift dynamics emerged as a robust process-level marker, demonstrating particular sensitivity in distinguishing CN individuals from those with MCI.ConclusionsFixation-shift eye-movement dynamics capture early AD-related cognitive vulnerability beyond conventional total cognitive scores. This multimodal framework may support psychogeriatric screening and clinical triage by detecting subtle cognitive inefficiencies that precede measurable declines on standard cognitive tests.
National trends and disparities in mortality among U.S. older adults, with coexisting Alzheimer's disease and hypertension, 1999-2023.
Rashid MI, Abbas M, Tahir R … +7 more , Alam T, Noor A, Ishrat Z, Mudasir M, Ahsan Sarfraz M, Mehboob U, Osman Abufatima I
J Alzheimers Dis · 2026 Jun · PMID 42377087 · Publisher ↗
BackgroundHypertension (HTN) is a major modifiable risk factor associated with cognitive decline including Alzheimer's disease (AD), which continues to be the leading cause of dementia and death in the United States (U.S...
BackgroundHypertension (HTN) is a major modifiable risk factor associated with cognitive decline including Alzheimer's disease (AD), which continues to be the leading cause of dementia and death in the United States (U.S.). However, the national mortality burden of coexisting AD and HTN across demographic and geographic groups remains poorly defined.ObjectiveWe aimed to study these trends to provide insights for better prevention, management, and policy planning.MethodsA retrospective analysis was conducted using the CDC WONDER Multiple Cause-of-Death database (1999-2023), focusing on adults aged ≥65 years with AD and HTN. Temporal trends were assessed using Joinpoint regression to estimate annual percent changes. Mortality patterns were examined by sex, race, region, urban-rural status, state, and place of death.ResultsBetween 1999 and 2023, 504,360 deaths among U.S. adults aged ≥65 years listed both AD and HTN on death certificates, with age-adjusted mortality rates rising from 14.5 to 60.0 per 100,000. Women consistently experienced higher mortality than men (67.5 versus 48.1 per 100,000 in 2023). Non-Hispanic African American adults had the greatest overall burden (57.1) among races. Geographically, mortality was highest in non-metropolitan areas (48.7) and the West region (52.6), More than half of all deaths occurred in nursing homes or long-term care facilities.ConclusionsMortality for coexisting AD and HTN has quadrupled in the U.S. over the past two decades with substantial variations across groups, highlighting the substantial burden of deaths where AD and HTN coexist and the importance of effective HTN control and dementia care across the lifespan.
Carboxy terminal of ECRG4 is a potential initiator for amyloid pathology in Alzheimer's disease through interacting with APP intracellular domain.
Chung MLK, Takeda S, Ryu J … +3 more , Murayama S, Koshimizu U, Kondo T
J Alzheimers Dis · 2026 Jun · PMID 42377071 · Publisher ↗
BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) and the formation of neurofibrillary tangles. Although the amyloid cascade hypothesis und...
BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) and the formation of neurofibrillary tangles. Although the amyloid cascade hypothesis underscores the centrality of Aβ accumulation, the precise initiators of this process remain unknown.ObjectiveIn this study, we investigate the potential role of Esophageal Cancer-Related Gene 4 (ECRG4) in AD. We hypothesized that ECRG4, which is associated with cognitive impairment and upregulated in AD, directly contributes to amyloid pathology.MethodsWe performed cell-based assays, co-immunoprecipitation, in vivo experiments using APP knock-in mouse, and immunohistochemistry of human hippocampal sections.ResultsECRG4(133-148) associated with the amyloid precursor protein (APP) intracellular domain (AICD), leading to increased APP/Aβ accumulation. Furthermore, intracerebral injection of synthetic ECRG4(133-148) into AD model mice significantly augmented APP/Aβ deposition. Notably, the co-localization of ECRG4(133-148)-containing peptides with AICD-containing peptides increased with AD severity in human hippocampal tissue.ConclusionsOur findings establish that the carboxy-terminal fragment of ECRG4 acts as a potential initiator of amyloid pathology in AD through its interaction with AICD.
Long-term effects of multisession gamma transcranial alternating current stimulation in Alzheimer's disease.
Cantoni V, Grassi M, Premi E … +5 more , Cupidi C, Zummo E, Cotelli MS, Benussi A, Borroni B
J Alzheimers Dis · 2026 Jun · PMID 42377068 · Publisher ↗
This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous r...
This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.
Glymphatic system metrics derived from DTI-ALPS are associated with cognitive impairment, brain atrophy, and plasma tauopathy biomarkers of type 2 diabetes patients: Analysis in dual-cohort.
Gao Y, Liang W, Wang G … +16 more , Xu Z, Liu Y, Wang Y, Wang Y, Zhang Y, Deng Y, Zhou J, Wang Y, Li H, Gao L, Tu M, Yu M, Li S, Zheng J, Wang JZ, Xu H
J Alzheimers Dis · 2026 Jun · PMID 42370748 · Publisher ↗
BackgroundGlymphatic dysfunction is implicated in neurodegenerative disorders and may contribute to the elevated risk of mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM) patients. The diffusion tensor i...
BackgroundGlymphatic dysfunction is implicated in neurodegenerative disorders and may contribute to the elevated risk of mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM) patients. The diffusion tensor imaging along the perivascular space (DTI-ALPS) index has been proposed as a non-invasive imaging surrogate that may reflect aspects of glymphatic system activity.ObjectiveWe investigated the relationship between ALPS index, cognition, brain structure, and plasma Alzheimer's disease biomarkers in T2DM patients.MethodsTwo independent cohorts were analyzed: Cohort 1 included 60 age, sex, and education matched participants (20 T2DM with MCI, 20 T2DM with normal cognition, and 20 healthy controls); Cohort 2 comprised 35 elderly T2DM patients assessed for plasma AD biomarkers. All participants underwent MRI for ALPS index calculation and structural imaging. Cognition was evaluated using the Mini-Mental State Examination and Montreal Cognitive Assessment.ResultsThe ALPS index was significantly lower in T2DM patients with MCI compared to cognitively normal T2DM patients and healthy controls, and showed discriminative ability for MCI. Lower ALPS index correlated with poorer cognitive scores and was associated with brain atrophy. Mediation analysis indicated that the volume of the right opercular inferior frontal gyrus mediated the relationship between ALPS index and cognition scores. Furthermore, the ALPS index negatively correlated with plasma pTau217 adjusted by age and sex in T2DM patients.ConclusionsA lower ALPS index is associated with cognitive impairment, brain atrophy, and plasma tauopathy, which may serve as a promising non-invasive imaging biomarker for early identification of neurodegeneration risk in T2DM patients.
Corrigendum to "Electromagnetic field induced activation of amyloid-β degrading enzyme, neprilysin, for accelerated Alzheimer's disease therapy".
J Alzheimers Dis · 2026 Jun · PMID 42366768 · Publisher ↗
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An application study: 21-item Subjective Cognitive Decline Questionnaire in detecting mild cognitive impairment.
Hao L, Xing Y, Han Y
J Alzheimers Dis · 2026 Jun · PMID 42363811 · Publisher ↗
BackgroundSubjective cognitive decline (SCD) is a common early complaint in mild cognitive impairment (MCI). Evidence for the 21-item SCD-Questionnaire (SCD-Q21) to discriminate MCI from normal controls (NCs) is limited....
BackgroundSubjective cognitive decline (SCD) is a common early complaint in mild cognitive impairment (MCI). Evidence for the 21-item SCD-Questionnaire (SCD-Q21) to discriminate MCI from normal controls (NCs) is limited.ObjectiveTo investigate the discrimination performance of Chinese SCD-Q21 and compare it with SCD-Q9 for community-based MCI early detection, assess the added value of simple covariates, and determine an optimal SCD-Q21 cut-off.Methods294 NCs and 83 people with MCI were assessed and collected demographic and clinical data. Participants completed SCD-Q21, SCD-Q9, Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scale; clinical adjudication used Montreal Cognitive Assessment-Basic, Clinical Dementia Rating, and Activities of Daily Living. Group comparison, logistic regression and ROC analyses were applied. Optimal cut-offs were derived using the Youden index and AUCs were compared using DeLong tests. Within-MCI analyses contrasted screen-positive versus screen-negative subgroups.ResultsTotal SCD-Q21 scores were higher in MCI, although five items [question 1 (Q1), Q2, Q3, Q11, and Q17] did not differ between groups. In multivariable binary logistic regression models, lower education (OR = 0.786), higher body mass index (BMI) (OR = 17.874), and higher SCD-Q21 total scores (OR = 1.114) were independently associated with MCI, whereas SCD-Q9 was not. Standalone AUCs were 0.662 (SCD-Q21) and 0.640 (SCD-Q9). Combing age, sex, education, BMI, and HAMA/HAMD with SCD instrument yielded AUC ∼0.91. SCD-Q21 ≥ 7 gave 69.88% sensitivity and 62.93% specificity. Screen-negative MCI cases showed lower vascular/metabolic comorbidity and lower HAMA/HAMD scores.ConclusionsSCD-Q21 provides independent information but modest stand-alone discrimination. As part of a brief multivariable triage including education, BMI, vascular risk review, and anxiety rating, it supports efficient case-finding in community settings.
Potential and biases of large language model simulation for public surveys on Alzheimer's disease therapies.
Sato K, Niimi Y, Ihara R … +3 more , Suzuki K, Iwata A, Iwatsubo T
J Alzheimers Dis · 2026 Jun · PMID 42363810 · Publisher ↗
BackgroundWhile large language models (LLMs) have a potential to simulate public-opinion, their reliability for sensitive medical topics like novel Alzheimer's disease (AD) treatments remains unclear.ObjectiveThis study...
BackgroundWhile large language models (LLMs) have a potential to simulate public-opinion, their reliability for sensitive medical topics like novel Alzheimer's disease (AD) treatments remains unclear.ObjectiveThis study compared LLM-generated and human answers on AD-therapy dilemmas; assessed model and prompting parameter influences; and identified demographic bias.MethodsUsing survey data on late 2023 from 1671 Japanese Trial Ready Cohort Webstudy participants who are presumably cognitively unimpaired, LLM persona profiles guided four LLMs (Gemini-1.5-flash, Gemini-2.0-flash, GPT-4.1-mini, GPT-4o-mini). The models answered a binary question about acceptance towards patient-prioritization or a 5-point Likert question on concern about amyloid-related imaging abnormalities (ARIA) under varied prompt settings. Aggregate similarity was measured with Jensen-Shannon Divergence (JSD) for binary and Earth Mover's Distance (EMD) for Likert scale; while individual agreement used Cohen's κ and Spearman's ρ.ResultsWhile some LLM models achieved fair group-level agreement in both tasks (JSD ≤ 0.05, EMD < 1.0), individual agreement was negligible across any LLM settings (κ, ρ ≈ 0). Adding detailed attributes like living condition, clinical status, or related personal opinions offered limited improvement. Performance was largely stable for most demographic levels, but deteriorated for minority subgroups, such as those with low education or requiring long-term care.ConclusionsOur study demonstrates that current LLMs can approximate aggregate attitudes toward novel AD therapies but cannot predict individual opinions. They can amplify biases in some small subgroups. LLMs may be useful for pre-testing public survey in the field of AD/dementia treatment but should not replace authentic human data.
Relationship between new-onset falls and neuroimaging markers of Alzheimer's disease in the UK Biobank.
Shaw JS, Bray MJC, Sair HI … +5 more , Luna LP, Hunzinger KJ, Oh ES, Rosenberg PB, Peters ME
J Alzheimers Dis · 2026 Jun · PMID 42363808 · Publisher ↗
BackgroundWhile Alzheimer's disease (AD) is a known risk factor for falls, the association between falls and incident AD is a growing area of study.ObjectiveThe primary aim of this analysis was to examine associations be...
BackgroundWhile Alzheimer's disease (AD) is a known risk factor for falls, the association between falls and incident AD is a growing area of study.ObjectiveThe primary aim of this analysis was to examine associations between new-onset falls in older adults and neuroimaging and plasma biomarkers of AD. A secondary aim was to evaluate associations between new-onset falls and neuroimaging markers of motor dysfunction.MethodsData from the UK Biobank study was utilized. Participants were 70 years of age or older at the date of neuroimaging and had no reported history of falls at study enrollment. To determine falls status, participants self-reported data on falls history within the last year prior to neuroimaging.Results15,447 individuals were included in our analysis (No falls, N = 12,522; One fall, N = 2,199, Multiple falls, N = 726). Compared to individuals in the No falls group, individuals in the One fall and Multiple falls group had significantly higher volumes of white matter hyperintensities, while individuals in the Multiple falls group had significantly lower left and right hippocampal volumes. One or more fall was associated with higher plasma levels of pTau181, which did not remain significant after adjusting for multiple comparisons. Plasma amyloid-β 42/amyloid-β 40 ratio did not differ significantly between groups.ConclusionsIn a sample of older adults without history of falls at study enrollment, new-onset falls were associated with decreased hippocampal volumes, which is associated with prodromal AD, as well as an increased volume of white matter hyperintensities, which may also emerge secondary to AD pathology.
Logical memory is associated with amyloid-β positivity in patients with early Alzheimer's disease eligible for lecanemab.
Kawabe N, Hosoki S, Watanabe C … +6 more , Maekawa K, Fukushima H, Matsuishi K, Iwata K, Kohara N, Kawamoto M
J Alzheimers Dis · 2026 Jun · PMID 42363806 · Publisher ↗
BackgroundLecanemab is an anti-amyloid monoclonal antibody, approved for early Alzheimer's disease (AD), with evidence indicating greater benefit at earlier stages. Sensitive cognitive measures are needed to identify und...
BackgroundLecanemab is an anti-amyloid monoclonal antibody, approved for early Alzheimer's disease (AD), with evidence indicating greater benefit at earlier stages. Sensitive cognitive measures are needed to identify underlying amyloid pathology.ObjectiveTo investigate whether the Logical Memory (LM) subtest of the Wechsler Memory Scale-Revised (WMS-R) can help characterize amyloid positivity in lecanemab-eligible individuals.MethodsWe retrospectively analyzed 91 individuals who attended our center between December 2023 and March 2025; 45 met eligibility criteria (Mini-Mental State Examination ≥ 22, Clinical Dementia Rating 0.5 or 1.0, magnetic resonance imaging compatibility). Amyloid status was determined by positron emission tomography, classified as amyloid-positive (Aβ+, n = 35) or amyloid-negative (Aβ-, n = 10). All participants underwent neuropsychological assessment, including LM. Groups were compared, and LM Aβ status discrimination was evaluated using receiver operating characteristic analyses and multivariable logistic regression.ResultsGroups did not differ in age, sex, or education. LM immediate (LMIR) and delayed recall (LMDR) scores were lower in the Aβ+ group (LMIR median: 5.0 versus 9.0, p = 0.011; LMDR: 0.5 versus 3.0, p = 0.017). Receiver operating characteristic analyses identified cutoffs of 7.5 for LMIR (area under the curve [AUC]: 0.79, sensitivity: 79%, specificity: 77%) and 1.5 for LMDR (AUC: 0.76, sensitivity: 75%, specificity: 77%). Lower LM scores were associated with increasing amyloid positivity. Logistic regression showed significant associations for both LMIR and LMDR (odds ratio: 0.80 and 0.64, 95% confidence interval: 0.64-0.95 and 0.38-0.91, respectively).ConclusionsWMS-R LM scores were significantly associated with amyloid-β accumulation in individuals with early AD meeting lecanemab eligibility criteria.
Postoperative changes in cervical hemodynamics and cognitive function following cervical lymphatic-venous surgery in Alzheimer's disease.
Zheng X, Tang C, Li H … +13 more , Wang B, Zheng Y, Song W, Wu A, Xin L, Zhang D, Yang R, Du S, He P, Li Y, Wu L, Shi Q, Bernardes GJL
J Alzheimers Dis · 2026 Jun · PMID 42360117 · Publisher ↗
BackgroundAlzheimer's disease (AD) has been increasingly linked to cervical venous and lymphatic dysfunction, impairing cerebral perfusion and clearance of neurotoxic metabolites. Deep cervical lymphatic-venous anastomos...
BackgroundAlzheimer's disease (AD) has been increasingly linked to cervical venous and lymphatic dysfunction, impairing cerebral perfusion and clearance of neurotoxic metabolites. Deep cervical lymphatic-venous anastomosis (dcLVA) is a microsurgical approach aimed at restoring lymphatic-venous communication.ObjectiveTo evaluate postoperative changes in cervical hemodynamics and cognitive function in patients with AD.MethodsEighty-three AD patients underwent bilateral cervical LVA. Pre- and postoperative evaluations included Doppler ultrasound of the internal jugular veins and carotid arteries at both hyoid and cricoid levels, along with standardized cognitive and functional tests. Morphologic and hemodynamic changes were analyzed using the Wilcoxon and Spearman analysis.ResultsPostoperatively, significant increases were observed in venous and arterial flow, along with enlargement of internal jugular and carotid cross-sectional areas. Postoperative improvements were observed, with postoperative carotid flow moderately correlated with Mini-Mental State Examination and activities of daily living. Longitudinal follow-up demonstrated sustained neuropsychological improvement up to 9 months, with persistent enhancement of vascular flow in a follow-up subgroup.ConclusionsThe procedure was associated with changes in vascular parameters and clinical outcomes; however, the specific contribution of dcLVA cannot be determined.
Communication strategies for improving readiness for advance care planning in dementia: A systematic review.
Der Nulft VV, Stoppelenburg A, Van Vliet LM … +2 more , Van Der Steen JT, Van Der Linden YM
J Alzheimers Dis · 2026 Jun · PMID 42360075 · Publisher ↗
BackgroundProgressive cognitive decline in Alzheimer's disease and other dementias limits decision-making, emphasizing the need for timely discussions about preferred future care. However, advance care planning (ACP) is...
BackgroundProgressive cognitive decline in Alzheimer's disease and other dementias limits decision-making, emphasizing the need for timely discussions about preferred future care. However, advance care planning (ACP) is often delayed due to limited readiness among people with dementia and their family caregivers.ObjectiveTo identify communication strategies (interventions and communication methods) improving readiness for ACP among people with dementia and their family caregivers.MethodsA mixed-methods systematic review was conducted (PROSPERO: CRD42023480187). PubMed, The Cochrane Library, Embase, PsycINFO, and CINAHL were searched in January 2024, with an update in February 2025 through expert consultation. Eligible articles included people with dementia and their family caregivers, communication strategies, and readiness for ACP. Study selection was performed independently by multiple reviewers using predefined eligibility criteria. Data were synthesized using a data-based convergent approach.ResultsOf 517 identified articles, ten were included: quantitative (n = 5), mixed-methods (n = 3), and qualitative (n = 2). Eight articles described interventions, including ACP discussions, education, and self-paced, stepwise tools. Multi-component interventions combining facilitated discussions and educational components and tools showed improvements in readiness, although some outcomes were variable across subgroups or over time. Two articles explored communication methods, emphasizing the facilitator relationship and approach, timing and continuity of ACP discussions, and conversational techniques to support engagement.ConclusionsMulti-component interventions, tools, and communication methods may enhance readiness for ACP. Findings highlight the importance of tailoring ACP to individual needs and training healthcare professionals in facilitating ACP. Future research should develop a consistent framework of readiness and identify the active "ingredients" of ACP interventions.
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