Hardy CJD, Levett BA, Jiang J
… +10 more, Core LB, Froud S, Bishop L, Lim D, Durrani F, Volkmer A, Koohi N, Bamiou DE, Marshall CR, Warren JD
Alzheimers Dement
· 2026 May · PMID 42187040
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INTRODUCTION: Central hearing difficulties are a feature of Alzheimer's disease (AD) but not well captured by standard speech perception tests. METHODS: We developed a non-verbal dichotic listening test (NVDLT) based on...INTRODUCTION: Central hearing difficulties are a feature of Alzheimer's disease (AD) but not well captured by standard speech perception tests. METHODS: We developed a non-verbal dichotic listening test (NVDLT) based on everyday sounds, and compared this with a standard verbal dichotic listening test (VDLT) in 36 people with primary progressive aphasia (PPA), 18 with typical AD (tAD), 6 with right temporal-variant frontotemporal dementia (rtvFTD), and 29 cognitively-healthy controls. Daily-life hearing function was assessed using the modified Amsterdam Inventory for Auditory Disability and Handicap (mAIAD). RESULTS: On NVDLT, all dementia groups except rtvFTD performed worse than controls; tAD, logopenic-variant PPA and nonfluent/agrammatic-variant PPA performed worse than rtvFTD. NVDLT performance predicted atrophy in the retrosplenial cortex and hippocampus. NVDLT score discriminated tAD patients from controls with near-perfect accuracy (area under the curve [AUC] = 0.99) and predicted daily-life hearing function (r = 0.57). DISCUSSION: NVDLT performance indexes daily-life hearing function and may aid dementia diagnosis, potentially in culturally-diverse populations.
Wang D, Ta V, Wang H
… +8 more, Ju J, Wang C, Chehadeh C, Torreblanca-Zanca A, Magaña Y, Castle MJ, Wang S, Head BP
Alzheimers Dement
· 2026 May · PMID 42187024
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INTRODUCTION: Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynC...INTRODUCTION: Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy. METHODS: AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43 mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue. RESULTS: SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling. DISCUSSION: These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.
Gianattasio KZ, Steffan M, Reist B
… +2 more, Power MC, Rein DB
Alzheimers Dement
· 2026 May · PMID 42186810
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INTRODUCTION: The Dementia DataHub (DDH) reports U.S. dementia prevalence and incidence from Medicare data. Variation in sensitivity, specificity, and accuracy of diagnoses related to geography and participant characteri...INTRODUCTION: The Dementia DataHub (DDH) reports U.S. dementia prevalence and incidence from Medicare data. Variation in sensitivity, specificity, and accuracy of diagnoses related to geography and participant characteristics complicates the interpretation of these data. METHODS: We evaluated performance of DDH-defined Medicare claims diagnoses against linked Health and Retirement Study (HRS) survey-based dementia classifications. RESULTS: DDH's likely-or-higher dementia definition achieved 50% sensitivity, 97% specificity, and 91% accuracy relative to the HRS classification. Sensitivity, specificity, and accuracy varied across census divisions and by urbanicity. Respondents with dementia missed in claims were younger and healthier than those correctly identified. DISCUSSION: Medicare claims reflecting diagnoses of dementia provide valuable information about who may be receiving dementia treatment and where; however, they often miss cases in ways that differ by geography and patient characteristics. Variation in diagnosis in Medicare claims relative to HRS survey-based dementia classification can be used to improve the value of Medicare diagnoses for surveillance purposes.
Ng YT, Whibley D, Hicken M
… +3 more, Turkelson A, Kratz A, Birditt KS
Alzheimers Dement
· 2026 May · PMID 42186807
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INTRODUCTION: Sleep problems and physical pain are prevalent among dementia caregivers. This study examines daily links between sleep and next-day pain, focusing on differences between Black and White caregivers. METHODS...INTRODUCTION: Sleep problems and physical pain are prevalent among dementia caregivers. This study examines daily links between sleep and next-day pain, focusing on differences between Black and White caregivers. METHODS: Dementia caregivers (N = 210, 34% Black) completed baseline interviews and 5 days of ecological momentary assessments. Each morning, they reported sleep duration and disturbances from the previous night. Pain intensity was reported six times daily and summarized as daily average and time-specific scores. RESULTS: Black caregivers reported shorter sleep duration but lower daily pain than White caregivers. In the full sample, greater sleep disturbances predicted higher morning pain. Longer-than-usual sleep duration predicted lower next-day pain (especially evening pain), observed only among Black caregivers. DISCUSSION: Findings highlight the role of daily sleep patterns in pain. Sleep duration may be a beneficial intervention target for Black caregivers, who reported shorter sleep. Promoting consistent, healthy sleep may help manage pain among dementia caregivers.
Alzheimers Dement
· 2026 May · PMID 42186792
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INTRODUCTION: Alzheimer's disease (AD) research often assumes that familial and sporadic forms share a common pathogenesis. However, the cellular impacts of amyloid precursor protein (APP) mutations compared with age-rel...INTRODUCTION: Alzheimer's disease (AD) research often assumes that familial and sporadic forms share a common pathogenesis. However, the cellular impacts of amyloid precursor protein (APP) mutations compared with age-related overexpression of APP or the deposition of amyloid beta (Aβ) are likely different. METHODS: Using high-density multi-electrode arrays, we compared neural activity in cultured neurons subjected to Aβ exposure or APP overexpression (via lentiviral delivery or genetic models). Effects on neuronal firing, synaptogenesis, axonal branching, and network connectivity were assessed in both developing and mature cultures. RESULTS: APP overexpression reduced individual neuron firing probability and impaired synaptogenesis and axonal branching during development. In contrast, Aβ disrupted synaptic connections in mature cultures and impaired network-level communication without blocking early structural development. DISCUSSION: These findings indicate that APP mis-regulation and Aβ toxicity contribute differently to neuronal behavior. These differences raise questions about the assumptions that familial and sporadic AD are similar if not identical conditions.
DeAngelis R, Burnside L, Donnell DO
… +3 more, Hicken M, Umberson D, Perry B
Alzheimers Dement
· 2026 May · PMID 42186774
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Lack of social connection is a major risk factor for Alzheimer's disease and related dementias, on a par with other common risk factors like physical inactivity and smoking. Yet we still know surprisingly little about ho...Lack of social connection is a major risk factor for Alzheimer's disease and related dementias, on a par with other common risk factors like physical inactivity and smoking. Yet we still know surprisingly little about how social connection affects cognitive health. Our review provides updated guidance for researchers interested in testing new mechanistic models of social connection and cognitive health over the life course. First, we conceptualize social connection and its various components. Second, we provide readers with a supplemental compendium of social connection measures and discuss how to tailor different types of measures to specific research goals. Third, we advance a conceptual model linking social connection to cognitive health across different social, spatial, and temporal contexts, while also considering potential sources of confounding and reciprocal causation. Finally, we outline five priority areas for future research into social connection and cognitive health across the life course.
Cordonier N, Matis S, Teng H
… +5 more, Carrick J, Hwang Y, Ahmed RM, Landin-Romero R, Piguet O
Alzheimers Dement
· 2026 May · PMID 42186116
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INTRODUCTION: Empathy is increasingly recognised as compromised in neurodegenerative disorders. However, its profile and neural bases in the nonfluent (nfvPPA) and logopenic (lvPPA) variants of primary progressive aphasi...INTRODUCTION: Empathy is increasingly recognised as compromised in neurodegenerative disorders. However, its profile and neural bases in the nonfluent (nfvPPA) and logopenic (lvPPA) variants of primary progressive aphasia remain unclear. We aimed to characterize empathy at onset, examine its longitudinal course, and identify neural correlates in nfvPPA and lvPPA. METHODS: Thirty-four nfvPPA, 38 lvPPA, and 45 control subjects completed neuropsychological and MRI assessment, with follow-up up to 9 years. Empathy was measured using the Interpersonal Reactivity Index (Perspective Taking, Empathic Concern). RESULTS: At baseline, both PPA groups showed reduced cognitive empathy but preserved affective empathy. Lower empathy correlated with broader cognitive deficits in nfvPPA and predicted greater caregiver burden. Longitudinally, empathy remained stable in nfvPPA but declined in lvPPA. Brain-behavior analyses implicated temporo-parietal and frontal-insular regions, with progressive frontal atrophy predicting cognitive empathy decline in lvPPA. DISCUSSION: Findings demonstrate early empathy deficits in both variants, distinct trajectories, and syndrome-specific neural substrates, with important clinical implications.
Iqbal S, Olivares CB, Rizzo L
… +20 more, Parker TD, Wong C, Underwood BR, Carpenter J, Dunne R, Raymont V, Reith A, Mummery CJ, Karran EH, Ducotterd F, Wilcock G, Cummings JL, O'Brien JT, Mursaleen L, Schneider LS, Vandenberghe R, Macleod M, Khan Z, Malhotra P, Reeves S
Alzheimers Dement
· 2026 May · PMID 42186115
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INTRODUCTION: There is an urgent need to identify effective, safe, and affordable treatments for Alzheimer's disease (AD). Funded by the UK National Institute for Health and Care Research (NIHR), we developed a systemati...INTRODUCTION: There is an urgent need to identify effective, safe, and affordable treatments for Alzheimer's disease (AD). Funded by the UK National Institute for Health and Care Research (NIHR), we developed a systematic drug prioritization pipeline to identify repurposed drug candidates for inclusion in a planned platform trial for clinical AD. METHODS: The wider AD community was invited to propose compounds using a standardized proposal template. Fourteen proposals were presented to an international expert panel, who independently ranked compounds based on biological plausibility, preclinical efficacy, safety, and trial feasibility. Extended drug summaries were compiled for shortlisted compounds, supported by ReLiSyR, a machine learning-supported systematic review tool. RESULTS: Following review in a second panel meeting, independent re-ranking identified the following compounds: atomoxetine (1st), metformin (2nd), isosorbide mononitrate and levetiracetam (joint 3rd). DISCUSSION: This robust drug prioritization pipeline will speed the identification and progression of promising candidates for therapeutic evaluation.
Fernández RS, Presa J, Acosta I
… +12 more, Salgado AR, Sosa AL, Acosta D, Jimenez-Velazquez IZ, Meier IB, Narayan VA, Guerra M, Salas A, Llibre-Rodriguez JJ, Prina M, Llibre-Guerra JJ, 1066 Dementia Research Group
Alzheimers Dement
· 2026 May · PMID 42174405
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INTRODUCTION: This study examined the latent cognitive structure of the 10/66 Dementia Research Group protocol and assessed its psychometric properties in culturally diverse older adults in Latin America and the Caribbea...INTRODUCTION: This study examined the latent cognitive structure of the 10/66 Dementia Research Group protocol and assessed its psychometric properties in culturally diverse older adults in Latin America and the Caribbean. METHODS: Data from 10,838 adults aged 65+ across five countries were analyzed. Confirmatory factor analyses tested unidimensional and multidimensional models representing major cognitive domains. Model fit, reliability, and a hierarchical second-order structure were examined. Measurement invariance was assessed across normative and non-normative subsamples and gender. RESULTS: A multidimensional structure emerged, comprising memory, orientation, executive functioning, semantic/language, and visuospatial domains, along with a higher-order global cognition factor. Most domains demonstrated adequate fit and acceptable reliability. The second-order model provided the best overall fit. Invariance was supported across all groups tested. DISCUSSION: This study provides the first empirical validation of the 10/66 protocol's latent structure, enabling the derivation of standardized cognitive scores and strengthening its utility for harmonized dementia research in diverse cultural settings.
Alzheimers Dement
· 2026 May · PMID 42174397
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Sleep disturbance is associated with increased risk for cognitive impairment. However, previous research is primarily based on non-Hispanic White individuals, despite higher rates of sleep problems and disorders among Hi...Sleep disturbance is associated with increased risk for cognitive impairment. However, previous research is primarily based on non-Hispanic White individuals, despite higher rates of sleep problems and disorders among Hispanic/Latin American individuals (H/Ls). The present study reviews the current literature on associations between sleep and cognitive function in H/L adults. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we examined literature that (1) examined the association between sleep and cognitive decline in H/Ls, and (2) had a sample with at least 5% H/Ls. We found equivocal evidence of associations between sleep parameters and cognitive performance in H/Ls, with the most compelling evidence supporting a relationship between long sleep and lower cognitive function. Heterogeneity in operationalization and measurement likely contributes to these equivocal findings. Future cross-sectional, experimental, and longitudinal research in H/Ls is needed to address major knowledge gaps.
Gutierrez S, Kunicki ZJ, Strangmann I
… +9 more, Gonzalez AS, Ying G, Mani SS, Torres JM, Weuve J, Terracciano A, Vonk JMJ, Briceño EM, Rentería MA
Alzheimers Dement
· 2026 May · PMID 42174393
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INTRODUCTION: Indigenous adults face educational inequities, but it is unclear how education, literacy, and numeracy contribute to disparities in late-life cognition. METHODS: This study included 1958 adults ages 55+ (me...INTRODUCTION: Indigenous adults face educational inequities, but it is unclear how education, literacy, and numeracy contribute to disparities in late-life cognition. METHODS: This study included 1958 adults ages 55+ (mean 68.1 [8.9 SD] years) from the Mexican Health and Aging Study (MHAS) Ancillary Study on Cognitive Aging (Mex-Cog; 2016). Linear regression models estimated associations between speaking an Indigenous language (vs. not) and cognitive factor scores, adjusting for sociodemographic covariates. Mediation analyses decomposed associations into direct and indirect effects via education, literacy, and numeracy. RESULTS: Eleven percent of participants spoke an Indigenous language, which was associated with lower memory (β [95% confidence interval [CI] = -0.31 [-0.40, -0.21]), language (-0.65 [-0.75, -0.55]), executive function (-0.60 [-0.73, -0.47]), and orientation (-0.31 [-0.44, -0.18]) scores. Education explained 31%-61% of the association, literacy 11%-26%, and numeracy 2%-9%. DISUSSION: High-quality education may help reduce cognitive disparities in Mexico. Future research should address data limitations by collecting measures of Indigeneity beyond language use (e.g., self-identification, colorism).
Bozigar M, Weuve J, Clark SN
… +18 more, Grady ST, Cantuaria ML, Cai YS, Roscoe C, Röösli M, Peters JL, Seto E, Vienneau D, Sørensen M, Neitzel RL, Hastings AL, Luben TJ, Andersen ZJ, Clark C, Hansell AL, Hystad P, Brauer M, Adar SD
Alzheimers Dement
· 2026 May · PMID 42174391
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Noise exposure is increasingly recognized as a modifiable environmental risk factor for Alzheimer's disease and related dementias (ADRD), yet its integration into epidemiologic research remains limited. We reviewed inter...Noise exposure is increasingly recognized as a modifiable environmental risk factor for Alzheimer's disease and related dementias (ADRD), yet its integration into epidemiologic research remains limited. We reviewed international noise mapping resources, exposure metrics, and analytic approaches relevant to ADRD studies. Mechanistic pathways and methodological challenges were synthesized from recent studies via expert knowledge. We present a stepwise framework for integrating noise into ADRD research, detailing metric selection, spatiotemporal assignment, and analytic guardrails. Our review recommends the application of 24-hour average, nighttime, and event-based metrics, and stresses that health effects may occur at low noise levels. We further underscore the importance of accounting for indoor, occupational, and life course exposures. Rigorous noise exposure assessment and transparent reporting will improve comparability and causal inference in ADRD studies. Future research should harmonize exposure metrics, integrate co-exposures (e.g., air pollution), and clarify etiologically relevant windows to strengthen prevention strategies.
Alzheimers Dement
· 2026 May · PMID 42170857
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INTRODUCTION: Opioid use disorder (OUD) may adversely affect brain health, but its role in dementia risk remains poorly understood. METHODS: We investigated associations between OUD and dementia using observational data...INTRODUCTION: Opioid use disorder (OUD) may adversely affect brain health, but its role in dementia risk remains poorly understood. METHODS: We investigated associations between OUD and dementia using observational data from 222,518 participants (European and African ancestry) in the Million Veteran Program and Mendelian randomization (MR) using genome-wide association study summary statistics from 6,066,918 individuals. Polygenic risk score (PRS) analyses were conducted in 229 opioid-naïve Lifebrain consortium participants with longitudinal magnetic resonance imaging data. RESULTS: OUD was associated with increased risk of all-cause dementia (hazard ratio = 1.56, 95% confidence interval [CI]: 1.39 to 1.76), Alzheimer's disease, and vascular dementia. MR supported a potential causal link between genetic liability to OUD and dementia (inverse variance weighted odds ratio = 1.77, 95% CI: 1.43 to 2.19). Genetic variation in the μ-opioid receptor gene was also associated with dementia risk. No PRS associations were found with brain structure. DISCUSSION: These findings suggest a potential causal role for OUD in dementia, implicating μ-opioid receptor pathways in neurodegeneration.
Baniowska MR, Mumford P, Prestia F
… +16 more, Stephan P, Beament M, Birling MC, Lanzillotta C, Ciafardini L, Barone E, Lau G, Chevalier C, Nahy C, Messaddeq N, Lestra T, Wu Y, Nalesso V, Di Domenico F, Wiseman F, Herault Y
Alzheimers Dement
· 2026 May · PMID 42168793
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INTRODUCTION: Down syndrome (DS) is the leading genetic cause of intellectual disability and Alzheimer's disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). The triplication of the APP gene...INTRODUCTION: Down syndrome (DS) is the leading genetic cause of intellectual disability and Alzheimer's disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). The triplication of the APP gene on chromosome 21 drives early amyloid-β (Aβ) accumulation, but other Hsa21 genes also contribute to pathology. Current DSAD models are limited by species-specific Aβ differences. METHODS: We developed and characterized two novel DSAD mouse models with partial humanization of Aβ. RESULTS: These models exhibit early AD features: cognitive deficits, hyperactivity, altered novelty and risk responses, tau hyperphosphorylation, and endolysosomal dysfunction. Amyloid precursor protein (APP) processing shifts toward β-secretase, increasing CTF-β and altering Aβ dynamics. Aβ humanization modulates behavior, improving specific cognitive tasks but enhancing anxiety traits. Myelinosome formation and impaired autophagic flux further align these models with human AD pathology. DISCUSSION: They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.
Alzheimers Dement
· 2026 May · PMID 42168785
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INTRODUCTION: We evaluated associations between an in vivo (magnetic resonance imaging [MRI]) marker of arteriolosclerosis (ARTS) and multimodal neuroimaging and plasma ATN(V) biomarkers. METHODS: Among 238 participants...INTRODUCTION: We evaluated associations between an in vivo (magnetic resonance imaging [MRI]) marker of arteriolosclerosis (ARTS) and multimodal neuroimaging and plasma ATN(V) biomarkers. METHODS: Among 238 participants with both amyloid and tau positron emission tomography (PET) scans within 1 year of MRI, we examined multivariable adjusted models relating ARTS with structural MRI (cortical thickness/volume, white matter hyperintensities [WMH]), diffusion MRI (fractional anisotropy [FA], mean diffusivity [MD], NODDI free water [FW]), cerebral blood flow, plasma biomarkers (p-tau217, Aβ42/40, neurofilament light, glial fibrillary acidic protein [GFAP]), and PET imaging. RESULTS: As expected, ARTS was most strongly linked to age and greater WMH burden and diffusion-based indices of microstructural disruption (FA, MD, and FW). ARTS was elevated in ATN biomarker-positive groups (highest in A+T+N+) and was associated with greater neurodegeneration and higher plasma biomarker levels, GFAP in particular. DISCUSSION: ARTS relates to other markers of vascular brain injury, neurodegeneration, amyloid and tau pathology within the ATN(V) framework, and inflammation.
Lyu X, Brown CA, Duong MT
… +11 more, Fischer EP, McGrew E, Irwin DJ, Dickerson BC, Nasrallah IM, Shinohara RT, Young AL, Yushkevich PA, Das SR, Wolk DA, Alzheimer's Disease Neuroimaging Initiative
Alzheimers Dement
· 2026 May · PMID 42168780
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INTRODUCTION: In Alzheimer's disease (AD), tau-neurodegeneration (T-N) mismatch has been proposed to reflect non-AD processes such as transactive response DNA binding protein 43 kDa and vascular disease. We aimed to char...INTRODUCTION: In Alzheimer's disease (AD), tau-neurodegeneration (T-N) mismatch has been proposed to reflect non-AD processes such as transactive response DNA binding protein 43 kDa and vascular disease. We aimed to characterize the spatiotemporal trajectories of T-N mismatch that may reflect non-AD progression. METHODS: We performed T-N regression on 710 Alzheimer's Disease Neuroimaging Initiative participants using cortical thickness and 18F-flortaucipir uptake across 20 cortical regions. SuStaIn, a data-driven phenotype discovery and staging algorithm, was applied to standardized T-N residuals in canonical (N∼T) and vulnerable (N > T) cases. RESULTS: SuStaIn identified three vulnerable subtypes with distinct N > T progression patterns. The posterior and anterior subtypes displayed different, but progressively diffuse mismatch patterns, while the limbic subtype exhibited temporal-limbic progression. Subtypes and SuStaIn stages were associated with distinct clinical features. Their longitudinal trajectories aligned with SuStaIn inferred progression. DISCUSSION: Findings support that T-N mismatch progression captures specific co-pathological processes.
Gogola A, Minhas D, Lopresti B
… +13 more, Snitz B, Reese AC, Matan C, Wu M, Zeng X, Saeed A, Reis S, Aizenstein H, Ikonomovic MD, Lopez O, Karikari T, Cohen A, Villemagne VL
Alzheimers Dement
· 2026 May · PMID 42168765
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INTRODUCTION: We evaluated the effects of astrogliosis on Alzheimer's disease (AD) pathology, co-pathology, and symptoms. METHODS: Cross-sectional data from 187 non-demented participants were processed to obtain measures...INTRODUCTION: We evaluated the effects of astrogliosis on Alzheimer's disease (AD) pathology, co-pathology, and symptoms. METHODS: Cross-sectional data from 187 non-demented participants were processed to obtain measures of SMBT-1 standard uptake value ration (SUVR), plasma glial fibrillary acidic protein (GFAP), β-amyloid (Aβ), Centiloids (CL), tau (CenTauR), white matter hyperintensities (WMH), hippocampal volume (HV), and cognition. Linear regressions evaluated pairwise associations, linear regression interaction terms indicated moderating association, and causal mediation analysis evaluated mediating associations. RESULTS: Astrogliosis was associated with CL (p < 0.01), neurodegeneration (0.05 < p < 0.1), and global cognition (p < 0.01). Moderation analyses revealed SMBT-1 SUVR had an attenuating interaction with CL in respect to CenTauR (β = -0.13, p = 0.0006) and memory impairment (β = 0.064, p = 0.05). Plasma GFAP had an attenuating interaction with CL in respect to CenTauR (β = -0.19, p = 0.00001). DISCUSSION: Reactive astrogliosis is an early and important player in the AD development pathway by having an early attenuating effect against Aβ. More work is needed to further understand these complex associations.