@article {pmid42928312,
year = {2026},
author = {Konstantopoulou, G and Kyriazi, EE and Felemegkas, P and Alexopoulos, P},
title = {Cognitive-communication features relevant to speech and language therapy in Lewy Body Dementia.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42928312},
issn = {2240-2993},
abstract = {Lewy Body Dementia (LBD) is characterized by fluctuating cognition, executive dysfunction, visuospatial impairment, and parkinsonian features that may jointly affect communication. Despite the clinical importance of these difficulties, direct evidence for speech and language therapy (SLT) in LBD remains limited. This structured narrative review critically synthesizes neuropsychological, linguistic, discourse, motor-speech, and clinically relevant intervention evidence for SLT assessment and management in LBD. Literature published from January 2010 to February 2026 was identified through structured searches of PubMed, Scopus, Web of Science, and PsycINFO, supplemented by reference-list screening. Evidence was organized by directness to LBD, study design, sample characteristics, communication outcomes, and major methodological limitations. The strongest direct evidence indicates that communication difficulties in LBD are heterogeneous and reflect interactions among executive-attentional dysfunction, cognitive fluctuations, visuospatial-perceptual disturbance, pragmatic/discourse impairment, and parkinsonian speech features. Comparative empirical studies suggest relatively greater executive/fluency and prosodic-acoustic involvement in DLB than in Alzheimer's disease, whereas naming and semantic-language impairment may be more pronounced in Alzheimer's disease. Evidence for LBD-specific SLT intervention remains insufficient; therefore, proposed clinical strategies should be regarded as theoretically informed adaptations rather than established LBD treatments. The review proposes a multidimensional cognitive-communication framework while emphasizing the need for repeated, ecologically valid assessment and LBD-specific intervention studies.},
}

@article {pmid42928319,
year = {2026},
author = {Zhang, Z and Cao, H and Baranova, A and Zhang, F},
title = {Evaluating the Impacts of Inflammatory Proteins on the Risk of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42928319},
issn = {1559-1182},
mesh = {*Alzheimer Disease/genetics/blood ; Humans ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; *Inflammation/genetics/blood ; Risk Factors ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/genetics ; *Inflammation Mediators/blood ; },
abstract = {Accumulating evidence suggests that inflammation contributes to the pathogenesis of Alzheimer's disease (AD). However, the relationship between circulating inflammatory proteins and AD remains incompletely understood. Two-sample Mendelian randomization (MR) was used to assess the associations of 91 circulating inflammatory proteins with AD. The discovery stage protein GWAS included 14,824 participants, and the validation stage analysis used UK Biobank data from 54,219 participants. The AD dataset comprised 85,934 cases and 401,577 controls. The inverse variance weighted (IVW) method was the primary approach, complemented by weighted median, MR-Egger, heterogeneity, and pleiotropy analyses. MR estimates from both stages were subsequently combined by meta-analysis, followed by drug-gene interaction analyses. In the discovery stage, four proteins showed nominal associations with AD: AXIN1 (OR = 1.082, P = 0.026), NGF (OR = 1.061, P = 0.048), CXCL11 (OR = 0.952, P = 0.017), and TNFRSF9 (OR = 0.946, P = 0.048). However, none survived FDR correction (FDR = 0.799). In the validation stage, only TNFRSF9 reached nominal significance (OR = 0.870, P = 0.031), which did not survive FDR correction (FDR = 0.125); AXIN1 showed an opposite direction. Meta-analysis provided suggestive pooled estimates for CXCL11 (OR = 0.956, P = 9.34 × 10[-][3]), TNFRSF9 (OR = 0.926, P = 0.034), and NGF (OR = 1.061, P = 0.034), but these should not be regarded as independent confirmation. DGIdb analysis identified interactions between the genes of interest and various drugs or compounds. These findings provide exploratory genetic evidence linking circulating inflammatory proteins to AD, but robust replication was not established after multiple testing correction and requires further validation.},
}

*Alzheimer Disease/genetics/blood
Humans
*Genetic Predisposition to Disease
Genome-Wide Association Study
*Inflammation/genetics/blood
Risk Factors
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide/genetics
*Inflammation Mediators/blood

@article {pmid42928321,
year = {2026},
author = {van der Veere, PJ and Broulíková, HM and Hoogland, J and Handels, R and Vijverberg, EGB and van Harten, AC and Teunissen, CE and Barkhof, F and van de Giessen, E and van der Flier, WM and Berkhof, J},
title = {Developing a microsimulation model of Alzheimer's disease for the evaluation of disease modifying therapies.},
journal = {European journal of epidemiology},
volume = {},
number = {},
pages = {},
pmid = {42928321},
issn = {1573-7284},
support = {73305095007/ZONMW_/ZonMw/Netherlands ; LSHM20106//Health~Holland/ ; 860197//European Commission/ ; 101119596//European Commission/ ; 831434//Horizon 2020/ ; 101034344//EPND/ ; 22HLT07 NEuroBioStand//European Partnership on Metrology/ ; 101156175//Horizon Europe/ ; },
abstract = {Clinical trials of amyloid-targeting therapies (ATTs) for Alzheimer's Disease (AD) showed slowing of decline in continuous cognitive and functional outcomes over eighteen months of follow-up. Existing simulation models used to extrapolate these results do not account for the distinct but correlated trajectories of cognitive and functional decline, limiting their accuracy in evaluating ATT effects on both domains. We developed an AD microsimulation model using an amyloid-positive memory clinic population that can translate slowed cognitive decline into effects on clinical functional independence stages. The model contained stages of mild cognitive impairment (MCI), community dementia, institutionalisation, and death. The transitions from MCI to dementia and from dementia to institutionalisation or death were related to Mini-Mental State Examination (MMSE) measurements through statistical joint models. Model validation showed that observed and predicted cumulative incidence curves overlapped for all stage transitions, indicating an accurate description of time in each stage. An untreated cohort starting with MCI had a mean duration of MCI, mild, moderate and severe community dementia, and institutionalisation of 3.3, 2.3, 1.6, 1.1, and 1.7 years, respectively, totalling 10.0 years. When ATTs slowed MMSE decline by 30% during MCI and mild dementia (community dementia with an MMSE above 20), the duration of MCI and mild dementia was prolonged by 0.4 and 1.0 years, respectively, and institutionalisation was delayed by 1.1 year. The time institutionalised remained similar. Our AD microsimulation model can translate ATT effects on cognition into effects on functional independence and can be used to assess the cost-effectiveness of new therapies.},
}

@article {pmid42928342,
year = {2026},
author = {},
title = {Correction to Alzheimer's & dementia articles.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71906},
pmid = {42928342},
issn = {1552-5279},
}

@article {pmid42928413,
year = {2026},
author = {LeFevre, JD and Vyas, Y and Jefferson, AL},
title = {Vascular drivers of cerebrospinal fluid movement and enlarged perivascular spaces.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71927},
pmid = {42928413},
issn = {1552-5279},
support = {IIRG-08-88733//by Alzheimer's Association/ ; R01-AG034962//by Alzheimer's Association/ ; R01-AG056534//by Alzheimer's Association/ ; R01-NS100980//by Alzheimer's Association/ ; K24-AG046373//by Alzheimer's Association/ ; T32-AG058524//by Alzheimer's Association/ ; F31-AG099738//by Alzheimer's Association/ ; UL1-TR000445//by Alzheimer's Association/ ; UL1-TR002243//by Alzheimer's Association/ ; },
mesh = {Humans ; *Glymphatic System/pathology/physiopathology ; *Cerebrospinal Fluid/physiology ; Animals ; *Cerebral Small Vessel Diseases/pathology ; Alzheimer Disease ; *Brain/blood supply/pathology ; },
abstract = {Perivascular spaces (PVSs) facilitate cerebrospinal fluid flow and waste clearance, which are critical for maintaining brain homeostasis. Enlarged PVSs (ePVSs) are an emerging marker of cerebral small vessel disease and are implicated in protein accumulation, neurodegeneration, and cognitive decline. While prior reviews have described the anatomy and correlates of ePVSs, the vascular mechanisms that drive perivascular fluid dynamics, and how their dysfunction might lead to ePVSs, have not been reviewed. This review examines how vascular mechanisms drive perivascular fluid dynamics and discusses how their impairment may contribute to ePVS formation and their impact on cognition. We propose an integrated vascular-ePVS hypothesis in which early vascular dysfunction may contribute to impaired waste clearance and ePVS burden, potentially linking early-life vascular health with later proteinopathy and cognitive decline. Elucidating the vascular contributions to ePVSs is imperative to identify therapeutic targets to preserve cognition in Alzheimer's disease and related dementias.},
}

Humans
*Glymphatic System/pathology/physiopathology
*Cerebrospinal Fluid/physiology
Animals
*Cerebral Small Vessel Diseases/pathology
Alzheimer Disease
*Brain/blood supply/pathology

@article {pmid42928414,
year = {2026},
author = {Hojjati, SH and Chiang, GC and Wang, XH and Khalafi, M and Shah, S and Zhou, L and Keil, S and Glodzik, L and McIntire, LBJ and Tanzi, E and Feiz, F and Maloney, T and Li, Y and Butler, TA and , },
title = {α-synuclein pathology drives region-specific tau deposition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71932},
pmid = {42928414},
issn = {1552-5279},
support = {1R01AG096446-01/NH/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/metabolism ; *alpha-Synuclein/metabolism ; Female ; Male ; *Lewy Body Disease/pathology/metabolism/diagnostic imaging ; *Brain/pathology/metabolism/diagnostic imaging ; Aged ; Aged, 80 and over ; Positron-Emission Tomography ; *Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) is a common but underdiagnosed neurodegenerative disease associated with α-synuclein pathology. Clinically, DLB is characterized by early motor dysfunction and psychiatric symptoms, in contrast to early memory decline typical of Alzheimer's disease (AD). Lewy body and AD pathology commonly co-occur. It remains unclear how α-synuclein pathology, either alone or in combination with AD pathology, produces clinical features considered distinctive of synucleinopathy.

METHODS: We analyzed 531 Alzheimer's Disease Neuroimaging Initiative participants using neuroimaging to compare tau deposition patterns between α-synuclein-positive and α-synuclein-negative individuals.

RESULTS: α-synuclein-positive individuals showed significantly greater tau deposition in basal ganglia (BG), insula, and medial temporal lobe (MTL). Increased tau burden in these regions correlated with more severe psychiatric symptoms and slower reaction times. These associations were present only in the α-synuclein-positive group.

DISCUSSION: These results suggest that α-synuclein pathology is associated with region-specific tau positron emission tomography abnormalities that map onto core clinical features of synucleinopathy.},
}

Humans
*tau Proteins/metabolism
*alpha-Synuclein/metabolism
Female
Male
*Lewy Body Disease/pathology/metabolism/diagnostic imaging
*Brain/pathology/metabolism/diagnostic imaging
Aged
Aged, 80 and over
Positron-Emission Tomography
*Alzheimer Disease/pathology/metabolism/diagnostic imaging
Magnetic Resonance Imaging

@article {pmid42928420,
year = {2026},
author = {Zammit, MD and Hartley, SL and Christian, BT and Rafii, MS},
title = {Tau extent is associated with lower cognition in Down syndrome-related Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71925},
pmid = {42928420},
issn = {1552-5279},
support = {1R61AG066543-01/AG/NIA NIH HHS/United States ; 1RF1AG094739-01/AG/NIA NIH HHS/United States ; //The Alzheimer's Biomarkers Consortium-Down Syndrome/ ; U01 AG051406//National Institute on Aging and the National Institute for Child Health and Human Development/ ; U01 AG051412//National Institute on Aging and the National Institute for Child Health and Human Development/ ; U19 AG068054//National Institute on Aging and the National Institute for Child Health and Human Development/ ; //Investigation of Co-occurring conditions across the Lifespan to Understand Down syndrome (National Institutes of Health INCLUDE Project)/ ; //National Institutes of Health Programs/ ; P50 AG008702//The Alzheimer's Disease Research Centers Program/ ; P30 AG062421//The Alzheimer's Disease Research Centers Program/ ; P50 AG016573//The Alzheimer's Disease Research Centers Program/ ; P50 AG005133//The Alzheimer's Disease Research Centers Program/ ; P50 AG005681//The Alzheimer's Disease Research Centers Program/ ; P30 AG062715//The Alzheimer's Disease Research Centers Program/ ; P30 AG066519//The Alzheimer's Disease Research Centers Program/ ; P30 AG066468//The Alzheimer's Disease Research Centers Program/ ; P30 AG072973//The Alzheimer's Disease Research Centers Program/ ; P50 HD105353//Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program/ ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //National Institute for Health and Care Research Cambridge Biomedical Research Centre/ ; //Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK/ ; },
mesh = {Humans ; *Down Syndrome/complications/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Female ; *tau Proteins/metabolism ; Male ; *Cognition ; Carbolines ; Middle Aged ; Brain/metabolism/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: [18]F-MK6240 is a second-generation tau positron emission tomography (PET) tracer with high dynamic range able to detect early tau pathology in Alzheimer's disease, however, its binding characteristics have not been evaluated in Down syndrome (DS), which is a population at high risk for early Alzheimer's disease onset. Past Down DS tau PET studies used [18]F-Flortaucipir, which suffers from off-target binding in early-stage regions, limiting pathology confirmation. This study evaluates the binding of [18]F-MK6240 in DS and examines the relationship between tau extent and cognition.

METHODS: Tau Extent was measured in participants from the Trial Ready Cohort-Down Syndrome using [18]F-MK6240 and from the Alzheimer Alzheimer's Biomarker Consortium-Down Syndrome using [18]F-Flortaucipir. Data were compared, harmonized, and explored in relationship to cognitive endpoints with consideration of age, sex, apolipoprotein E (APOE) ε4 status, and level of intellectual disability.

RESULTS: [18]F-MK6240 showed binding in the mesial temporal lobe shortly following the onset of beta-amyloid plaques, similar to our observations with [18]F-Flortaucipir. Increased tau extent correlated with lower episodic memory and overall cognitive performance scores. Age, intellectual disability level, and sex also influenced cognitive scores.

DISCUSSION: This first evaluation of [18]F-MK6240 in DS demonstrates its suitability as a sensitive biomarker for Alzheimer's disease tau pathology. Furthermore, the inverse associations between Tau Extent as measured by both [18]F-MK6240 and [18]F-Flortaucipir and cognitive outcomes highlight the potential of these biomarkers to evaluate signs of early cognitive change, underscoring the urgent need to include this population in early clinical interventions.},
}

Humans
*Down Syndrome/complications/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Positron-Emission Tomography
Female
*tau Proteins/metabolism
Male
*Cognition
Carbolines
Middle Aged
Brain/metabolism/diagnostic imaging
Neuropsychological Tests

@article {pmid42928437,
year = {2026},
author = {Latimer, CS and Walker, RL and Bogdani, M and Keene, CD and Nolan, AL and Child, DD and Mukherjee, S and Choi, SE and Lee, ML and Nakano, C and Ehrlich, K and McEvoy, LK and Crane, PK},
title = {Neuropathologic features of cognitively defined Alzheimer's disease subgroups in the Adult Changes in Thought study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71938},
pmid = {42928437},
issn = {1552-5279},
support = {K08AG065426/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; U19AG066567/AG/NIA NIH HHS/United States ; U01AG006781/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/classification/psychology/complications ; Female ; Male ; Aged ; Aged, 80 and over ; Neuropsychological Tests ; *Brain/pathology ; Hippocampal Sclerosis ; Executive Function ; },
abstract = {BACKGROUND: Individuals with Alzheimer's disease (AD) dementia can be subgrouped based on cognitive performance at diagnosis. We compared neuropathology across cognitively defined AD subgroups in the Adult Changes in Thought study.

METHODS: Scores for memory, executive functioning, language, and visuospatial abilities were derived from the Cognitive Abilities Screening Instrument and a neurocognitive battery. Subgroups were defined by relative performance within domains. Standardized neuropathologic evaluation was performed post mortem. Associations were estimated using ordinal logistic regression, with odds ratios (OR) and 95% confidence intervals (CIs) comparing neuropathology between the AD subgroups and relative to individuals without dementia.

RESULTS: Of 885 participants with post mortem neuropathology, 370 had AD dementia: 54% AD-no domain, 15% AD-memory, 15% AD-visuospatial, 8% AD-language, and 7% AD-executive. Among AD subgroups, associations were detected for limbic-predominant age-related transactive response DNA binding protein 43 kDa encephalopathy neuropathologic change (LATE-NC; P = 0.019) and hippocampal sclerosis (HS; P = 0.006), with highest levels in AD-language (LATE-NC OR 2.37, 95% CI 1.03-5.46 and HS OR 2.19, 95% CI 0.88-5.50) and AD-memory (LATE-NC OR 1.88, 95% CI 1.02-3.46 and HS OR 3.11, 95% CI 1.56-6.20) relative to AD-no domain, and lowest levels in AD-visuospatial. AD-visuospatial tended to have lowest estimated Alzheimer's disease neuropathologic change (ADNC) burden across AD subgroups. Relative to participants without dementia, all AD subgroups expectedly had higher ADNC burden, and several AD subgroups had higher odds of Lewy body pathology (P = 0.017) and gross infarcts (P = 0.004), with broadly similar estimates across multiple AD subgroups.

DISCUSSION: Neuropathologic patterns of ADNC and co-pathologies across AD dementia subgroups suggest cognitive phenotyping may inform clinicopathologic studies of AD dementia.},
}

Humans
*Alzheimer Disease/pathology/classification/psychology/complications
Female
Male
Aged
Aged, 80 and over
Neuropsychological Tests
*Brain/pathology
Hippocampal Sclerosis
Executive Function

@article {pmid42928439,
year = {2026},
author = {Han, SW and Park, YH and Pyun, JM and Hwang, J and Park, JS and Kim, S and Nho, K},
title = {Blood transcriptomic signatures of vascular risk in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71930},
pmid = {42928439},
issn = {1552-5279},
support = {U01AG068057/NH/NIH HHS/United States ; R01AG092591/NH/NIH HHS/United States ; R01AG081951/NH/NIH HHS/United States ; U19AG074879/NH/NIH HHS/United States ; U01AG24904/NH/NIH HHS/United States ; U01AG072177/NH/NIH HHS/United States ; P30AG072976/NH/NIH HHS/United States ; 2020R1C1C1013718//National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00461936//National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT, Republic of Korea/ ; RS-2025-25426019//National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT, Republic of Korea/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/complications ; *Transcriptome/genetics ; Male ; Female ; Aged ; *Cardiovascular Diseases/genetics/blood ; Cohort Studies ; Heart Disease Risk Factors ; Risk Factors ; Gene Expression Profiling ; },
abstract = {INTRODUCTION: Lifestyle and environmental factors contributing to cardiovascular risk are components of the exposome, yet molecular signatures associated with cumulative cardiovascular risk in Alzheimer's disease (AD) remain incompletely understood.

METHODS: We analyzed blood-based transcriptomics data from two independent cohorts: Seoul National University Bundang Hospital (SNUBH; N = 148, Korean) and Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 743, predominantly European ancestry). Framingham cardiovascular risk score (FRS)-associated co-expression network modules were identified, followed by pathway-based enrichment, hub gene-based participant stratification, and bidirectional cross-cohort discovery-replication analyses.

RESULTS: Two co-expression modules were associated with FRS in SNUBH, and six in ADNI. Bidirectional analyses identified two preserved modules with consistent module-FRS associations across cohorts, enriched in pathways implicated in cellular responses to exposure, including RNA-protein homeostasis, mitochondrial function, and hematopoietic processes. Hub genes in the two modules stratified participants into molecularly distinct subgroups concordant with clinical FRS categories.

DISCUSSION: FRS-associated molecular pathways were identified and warrant further investigation as potential targets for risk modification.},
}

Humans
*Alzheimer Disease/genetics/blood/complications
*Transcriptome/genetics
Male
Female
Aged
*Cardiovascular Diseases/genetics/blood
Cohort Studies
Heart Disease Risk Factors
Risk Factors
Gene Expression Profiling

@article {pmid42928702,
year = {2026},
author = {Fontana, IC and Comber, T and Aurora, S and Blackburn, DJ and Buckley, RF and Chow, C and Chow, TW and Croney, R and Crutch, SJ and Holdridge, KC and Hughes, L and Kipps, C and Kohlhaas, S and Llibre-Guerra, J and Malhotra, P and Marshall, CR and McCaughey, S and Oakley, RJ and Raman, R and Ridley, D and Showell, S and Tsai, R and Mummery, CJ},
title = {UK Dementia Trials Network: an expert-informed framework for improving representation in dementia trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71928},
pmid = {42928702},
issn = {1552-5279},
support = {//National Institute for Health and Care Research/ ; //UK Dementia Trials Network/ ; },
mesh = {Humans ; *Dementia/therapy ; United Kingdom ; *Clinical Trials as Topic ; Alzheimer Disease/therapy ; Diversity, Equity, Inclusion ; *Patient Selection ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, yet clinical trials remain unrepresentative of those most affected. Ethnic minoritized groups, socioeconomically deprived communities, adults over 75, and populations in low- and middle-income countries are consistently underrepresented, limiting generalizability and reinforcing health inequities. This white paper draws on an international roundtable on Diversity and Inclusion in Dementia Trials, convened by the UK Dementia Trials Network at the Alzheimer's Association International Conference 2025. We determined that key barriers to research participation included geographic distance, financial burden, restrictive eligibility criteria, invasive procedures, and limited study partner support. We also highlight gaps in ethnic diversity and the inadequate integration of sex and gender considerations in trial design and reporting. Improving representation in AD trials is both a scientific and moral imperative. Achieving this requires coordinated action across community engagement and trust building, data transparency and reporting, global trial access and capacity building, eligibility criteria reform, and financial and logistical support for participants. We propose an expert-informed implementation framework derived from the roundtable that identifies actionable strategies, responsible stakeholders, measurable indicators, and expected implementation outcomes to support translation of our recommendations into practice.},
}

Humans
*Dementia/therapy
United Kingdom
*Clinical Trials as Topic
Alzheimer Disease/therapy
Diversity, Equity, Inclusion
*Patient Selection

@article {pmid42929292,
year = {2026},
author = {Selyutina, OY and Polyakov, NE and Molokoedov, AS and Sidorova, MV and Avdeev, D},
title = {Stereoselectivity of photoinduced interaction of nonsteroidal anti-inflammatory drug S-ketoprofen with (L/D)-Trp-Leu-Pro-Phe peptide in solution studied by NMR, CIDNP and molecular dynamics simulation.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp02914k},
pmid = {42929292},
issn = {1463-9084},
abstract = {The stereoselectivity of chiral drug interactions with enzymatic active sites and cellular receptors is a subject of significant scientific interest. This interest is driven, firstly, by the pronounced differences in the therapeutic activity of drug enantiomers and, secondly, by the emerging role of amino acid chiral inversion in peptides associated with pathologies such as Alzheimer's, Parkinson's, and type II diabetes. To probe the fundamental steps of such biomolecular interactions, electron transfer (ET) serves as a well-defined elementary chemical process. Prior investigations of photoinduced ET in chiral donor-acceptor dyads, incorporating (S)-ketoprofen and (L/D)-tryptophan, have revealed stereoselective and spin-selective phenomena. Extending this work, the present study examines the interaction of (S)-ketoprofen with the L- and D-enantiomers of tryptophan within the tetrapeptide tryptophan-leucine-proline-phenylalanine (WLPF), in homogeneous non-aqueous solutions. Utilizing NMR spectroscopy, chemically induced dynamic nuclear polarization (CIDNP) to detect transient paramagnetic intermediates, and molecular modeling, we have demonstrated that (S)-ketoprofen exhibits stereoselective interaction with the peptide epimers. Furthermore, it was shown that the D-epimer of the peptide has a greater tendency to aggregation than the L-epimer. The stereoselective light-induced formation of the ketoprofen ketyl radicals provides a plausible mechanistic basis for ketoprofen's phototoxic side effects.},
}

@article {pmid42929589,
year = {2026},
author = {Buchthal, K and Kramer, PL and Hubach, D and Bach, G and Wagner, N and Krieger, J and Klöpper, M and Daude, M and Diederich, WE and Volkamer, A},
title = {Subpocket-Aware Fragment-Based Docking Pipeline for Kinase Ligand Design: Methodology and a PKA Case Study.},
journal = {Journal of chemical information and modeling},
volume = {66},
number = {20},
pages = {13397-13412},
doi = {10.1021/acs.jcim.6c01373},
pmid = {42929589},
issn = {1549-960X},
support = {NA//Universit?t des Saarlandes/ ; },
mesh = {Ligands ; *Molecular Docking Simulation ; *Protein Kinase Inhibitors/chemistry/pharmacology/metabolism ; *Drug Design ; *Cyclic AMP-Dependent Protein Kinases/chemistry/metabolism/antagonists & inhibitors ; Humans ; },
abstract = {Protein kinases regulate signal transduction through phosphorylation, and their dysregulation drives diseases like cancer, autoimmune disorders, and Alzheimer's, making them key drug targets. Fragment-based drug design offers a powerful route to kinase inhibitors but often neglects kinase-specific structural insights. While KinFragLib, a library consisting of 7486 fragments derived from kinase-ligand complexes, provides a rich resource, exhaustive recombination of its fragments is computationally demanding. Here, we present an efficient exploration strategy that integrates subpocket-guided fragment growing with template docking to navigate this vast chemical space. Our automated pipeline prioritizes kinase-specific structural information, enabling targeted generation of chemically diverse ligands. Applied to the PKA kinase, the approach produced 33758 candidate molecules with promising docking scores, of which 15 were synthesized. Seven molecules reduced kinase activity by more than 50% at an inhibitor concentration of 100 μM, and five of these compounds also showed promising efficacy at a concentration of 10 μM. The IC50 determination ultimately revealed that five of the molecules were effective in the two- to three-digit nanomolar range. Crystallographic validation confirmed the predicted binding mode of the most potent compound. This methodology demonstrates how structure-informed guidance can transform fragment-based design into a scalable route for discovering novel kinase inhibitors.},
}

Ligands
*Molecular Docking Simulation
*Protein Kinase Inhibitors/chemistry/pharmacology/metabolism
*Drug Design
*Cyclic AMP-Dependent Protein Kinases/chemistry/metabolism/antagonists & inhibitors
Humans

@article {pmid42929812,
year = {2026},
author = {Zhang, N and Freeman, DD and Polster, BM},
title = {BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201839},
pmid = {42929812},
issn = {2073-4409},
support = {R01NS112212/NS/NINDS NIH HHS/United States ; R21NS133527/NS/NINDS NIH HHS/United States ; R21 NS133527 (B.M.P.)./NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *DNA, Mitochondrial/metabolism ; Animals ; *bcl-2-Associated X Protein/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; *Voltage-Dependent Anion Channels/metabolism ; Mitochondria/metabolism ; *Inflammation/metabolism ; },
abstract = {Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.},
}

Humans
*DNA, Mitochondrial/metabolism
Animals
*bcl-2-Associated X Protein/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
*Voltage-Dependent Anion Channels/metabolism
Mitochondria/metabolism
*Inflammation/metabolism

@article {pmid42929814,
year = {2026},
author = {Lin, K and Gu, E and Ackerman, S and Wang, X and Huener, AF and Abou-Seada, I and Li, A and Magnusson, KR and Jin, L},
title = {Differential Genotypic Effects of HSV-1 Infection on Cognitive Function and Pathology in the 5xFAD Mouse Model.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201841},
pmid = {42929814},
issn = {2073-4409},
mesh = {Animals ; *Herpesvirus 1, Human/physiology/genetics/pathogenicity ; Disease Models, Animal ; *Cognition ; *Herpes Simplex/virology/genetics/pathology ; Mice ; *Alzheimer Disease/virology/pathology/genetics ; Mice, Inbred C57BL ; Genotype ; Female ; Brain/virology/pathology ; Heat-Shock Response ; Mice, Transgenic ; Memory ; },
abstract = {Alzheimer's disease (AD) involves several different etiopathogenic mechanisms. A recent infectious theory proposes that pathogens, such as HSV-1, could be the root cause of AD. In this study, we tested this infectious theory in an HSV-1 mouse model using heterozygous 5XFAD mice (Het) carrying 5 AD-linked mutations on a C57BL/6 background and wild-type littermates (WT). We hypothesized that HSV-1 could persist in the latently infected brain and that multiple heat stresses could cause greater HSV-1 persistence, cognitive decline and AD-like pathology. Infected (HSV+) mice and non-infected (HSV-) mice with (HS) or without (NHS) heat stress at 30 and 60 dpi were examined 3 days post-heat stress for each genotype. Impairments in long-term learning were observed in infected mice after 30 dpi, regardless of genotype or heat stress. Heat stress alone impaired memory at 30 dpi across genotypes and cognitive flexibility at 60 dpi in Het mice, but this appeared to be due to the recency of the stress. When another cohort of mice with or without 1-3 heat stresses at 30, 45, and 60 dpi was examined 15 days post-heat stress, long-term learning decline was observed in all latently infected mice, regardless of genotype or heat stress. There was significantly more amyloid plaque staining in the hippocampal CA1 region in Het/HSV+/NHS mice than in Het/HSV-/NHS mice. No amyloid plaque staining was observed in WT mice, regardless of HSV-1 infection or stress. Interestingly, TNF-α transcription was higher in the Het/HSV+ mice than in Het/HSV- mice in the hippocampal region. However, IL-1β transcription was found to be significantly higher in the hippocampal region in WT/HSV+ mice with or without stress than in WT/HSV-/NHS mice. There were more active astrocytes in the CA1 region of the hippocampus of WT/HSV+ mice than in WT/HSV- mice. Active astrocyte staining did not differ significantly between infected and uninfected Het mice. Viral DNA was detected in the brains of recovered Het or WT mice at 90 dpi. HSV-1 reactivation from latency was observed in 50-75% of the explants of the cerebrum and cerebellum at 33 dpi. Therefore, a combination of amyloid plaque accumulation, neuroinflammation and viral persistence may underlie the cognitive declines observed in infected Het and WT mice.},
}

Animals
*Herpesvirus 1, Human/physiology/genetics/pathogenicity
Disease Models, Animal
*Cognition
*Herpes Simplex/virology/genetics/pathology
Mice
*Alzheimer Disease/virology/pathology/genetics
Mice, Inbred C57BL
Genotype
Female
Brain/virology/pathology
Heat-Shock Response
Mice, Transgenic
Memory

@article {pmid42929824,
year = {2026},
author = {Uruk, G and Youssef, H and Gatto, RG and Hossain, N and Bhaskaran, J and Tian, Y and Machulda, MM and Petersen, RC and Whitwell, JL and Reichard, RR and Josephs, KA},
title = {TDP-43 Coincides with Noradrenergic Neurons in Alzheimer's Disease (AD) and Primary Age-Related Tauopathy (PART).},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201850},
pmid = {42929824},
issn = {2073-4409},
support = {9R01AG037491-26/NH/NIH HHS/United States ; 8P30AG062677-28/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Adrenergic Neurons/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Tauopathies/metabolism/pathology ; Male ; Female ; Aged, 80 and over ; Aged ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is a major contributor to cognitive decline in Alzheimer's disease (AD), yet the cellular substrates and circuit-level consequences of its limbic accumulation remain poorly defined. Here, we combined multiplex immunofluorescence with 3D Artificial Intelligence (AI)-based object detection and quantitative colocalization to map phosphorylated TDP-43 (pTDP-43) across neuronal subtypes in the amygdala, hippocampal subfields, and entorhinal cortex (ERC) in human AD, AD with Lewy body disease (AD-LBD), and primary age-related tauopathy (PART). Across 15 deeply phenotyped cases, pTDP-43 showed preferential accumulation in neuromodulatory noradrenergic neurons, with more limited involvement of glutamatergic terminals and cholinergic populations. Noradrenergic neurons marked by dopamine β-hydroxylase (DβH) demonstrated extensive colocalization with pTDP-43 across regions, correlating with APOE genotype, amyloid burden, and tau staging in this cross-sectional cohort, suggesting that neuromodulatory circuits might represent a major convergence point for AD-related molecular stressors. Dopaminergic (tyrosine hydroxylase (TH)) and cholinergic (choline acetyltransferase (ChAT)) neurons showed more restricted but pathology-dependent involvement, with LBD consistently showing lower pTDP-43 burden across multiple transmitter systems. Glutamatergic vesicular glutamate transporter-1 (VGLUT1)-positive neurons and terminals exhibited minimal colocalization except in PART. Principal component (PCA) and hierarchical clustering analyses (HCA) integrating pTDP-43 colocalization with neuropathologic staging metrics (A, B, C, Thal, Braak, LBD) reliably separated PART, AD-TDP, and AD-TDP-LBD groups, with LBD emerging as a dominant modifier of cellular vulnerability. Together, these findings point out that TDP-43 pathology in AD preferentially targets neuromodulatory circuits, is strongly shaped by coexisting synucleinopathy, and provides a cell-type-resolved framework for understanding how TDP-43 contributes to limbic network dysfunction in neurodegeneration.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Adrenergic Neurons/metabolism/pathology
*DNA-Binding Proteins/metabolism
*Tauopathies/metabolism/pathology
Male
Female
Aged, 80 and over
Aged

@article {pmid42929986,
year = {2026},
author = {Mandić-Stojmenović, G and Kostić, V and Marjanović, A and Novaković, I and Aleksić, P and Stojković, T and Stefanova, E},
title = {Genetic Spectrum, Family History and Diagnostic Yield of Targeted Genetic Testing in Early-Onset Alzheimer's Disease and Frontotemporal Dementia: A Serbian Memory Clinic.},
journal = {Diseases (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/diseases14100359},
pmid = {42929986},
issn = {2079-9721},
support = {200110//Ministry of Science, Technological Development, and Innovation/ ; },
abstract = {BACKGROUND/OBJECTIVES: Early-onset dementia (EOD), defined as symptom onset before 65 years of age, is a clinically and genetically heterogeneous group. Alzheimer's disease (AD) and frontotemporal dementia (FTD) are its most common neurodegenerative causes.

METHODS: We investigated the family history, genetic spectrum, and diagnostic yield of targeted genetic testing in a consecutive Serbian cohort of 130 patients with early-onset AD (EOAD) and 78 with early-onset FTD (EOFTD).

RESULTS: Approximately one-third of patients had a positive family history of dementia or another neurodegenerative disorder. Pathogenic or likely pathogenic variants were identified in 3.8% of patients with EOAD, whereas pathogenic or likely pathogenic variants or pathogenic repeat expansions were identified in 9.0% of patients with EOFTD. In EOAD, the diagnostic yield increased to 9.5% in those with a positive family history and, in an exploratory subgroup analysis, was 33.3% in those with symptom onset before 51 years. In EOFTD, the diagnostic yield was 25.0% among those with a positive family history. PSEN1 and APP were the only disease-causing genes identified in EOAD, whereas C9orf72 repeat expansion was the predominant genetic cause of EOFTD, with additional pathogenic variants identified in GRN and VCP.

CONCLUSIONS: These findings support the clinical value of targeted genetic testing guided by family history, age at onset, and clinical phenotype in patients with EOD. Genetically unresolved familial cases may reflect incomplete assessment of known genetic causes, including genes and variant classes not covered by the targeted testing strategy used in this study.},
}

@article {pmid42929995,
year = {2026},
author = {Peregud, D and Pavlova, O and Pavlov, K and Nebogina, K and Zorkina, Y and Abramova, O and Ushakova, V and Ochneva, A and Zubkov, E and Shamakina, I and Andryushchenko, A and Kostyuk, G and Morozova, A and Gurina, O and Chekhonin, V},
title = {Genetic Polymorphisms in SORL1, CLU, BIN1, and VDR Are Associated with Mild Cognitive Impairment and Dementia in a Russian Population.},
journal = {Diseases (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/diseases14100368},
pmid = {42929995},
issn = {2079-9721},
support = {CMGE-2025-0009//Federal Medical Research Centre for Psychiatry and Narcology/ ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia, and genetic factors may influence progression. This study aimed to identify genetic polymorphisms associated with MCI and dementia in a Russian population.

METHODS: A total of 280 participants were enrolled: Controls (n = 84), MCI (n = 94), and Dementia (n = 102). Fifteen single nucleotide polymorphisms in seven candidate genes (TOMM40, SORL1, BIN1, VDR, CLU, CR1, PICALM) were genotyped. Associations were tested using multinomial logistic regression adjusted for age and sex under four genetic models (codominant, dominant, recessive, overdominant). Multiple testing was controlled using the Benjamini-Hochberg false discovery rate (FDR) procedure. Deviation from Hardy-Weinberg equilibrium was observed for three SNPs in the Controls (SORL1 rs1010159, BIN1 rs7561528, rs10200967) and interpreted with caution.

RESULTS: Under the primary FDR correction (60 tests per contrast), only BIN1 polymorphisms remained significantly associated with dementia: rs7561528 (overdominant model: OR = 0.318, 95% CI = 0.162-0.624, p = 0.001, q = 0.0035) and rs10200967 (overdominant model: OR = 0.272, 95% CI = 0.136-0.544, p < 0.001, q < 0.007). Under the more conservative exploratory correction (150 tests), these associations were at the threshold of significance (q = 0.050).

CONCLUSIONS: BIN1 rs7561528 and rs10200967 are associated with reduced odds of dementia in the Russian population. Nominally significant associations with SORL1, CLU, and VDR require replication in larger cohorts. The developed genotyping panel represents a cost-effective research tool for genetic screening; clinical implementation requires validation in larger prospective cohorts.},
}

@article {pmid42930444,
year = {2026},
author = {Alsaigh, H and Alsharief, M and Aljabr, AA and Aljoghaiman, E and Aljofi, FE and Madi, M},
title = {Association Between Periodontal Disease and Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {Dentistry journal},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/dj14100678},
pmid = {42930444},
issn = {2304-6767},
abstract = {Background: Cognitive impairment is an increasing global health burden, and growing evidence suggests that periodontitis may contribute to cognitive decline through chronic inflammation and other oral-systemic pathways. This systematic review aimed to evaluate the association between periodontal disease and cognitive impairment in adults and to contextualize the findings within prior evidence syntheses. In this review, periodontitis is conceptualized as a host-mediated chronic inflammatory burden rather than as a marker of intraoral infection alone. Methods: A PRISMA-based systematic review was conducted using PubMed, Web of Science, and Scopus for observational studies published between 2015 and December 2025. Eligible studies included adults assessed for both periodontal status and cognition using validated clinical, radiographic, and neuropsychological measures. Risk of bias was assessed with the Newcastle-Ottawa Scale, and the certainty of the evidence was judged qualitatively. Database-specific search strategies are provided. Results: Nine studies met the inclusion criteria, including prospective cohort, cross-sectional, and Alzheimer disease cohorts. Across studies, more severe periodontitis was consistently associated with poorer cognitive performance, higher odds of mild cognitive impairment, and faster cognitive decline. In the four studies eligible for quantitative synthesis, the random-effects estimate indicated an approximately twofold overall association estimate (2.12; 95% CI 1.51-2.98), which is best interpreted as a summary association measure rather than a precise risk estimate. In Alzheimer disease cohorts, periodontal inflammation was associated with accelerated deterioration, including a six-fold greater rate of cognitive decline in one study and faster worsening on standardized cognitive scales in another. Risk-of-bias assessment showed three studies at low risk and six at moderate risk, with no study judged high risk. However, the overall certainty of the evidence was considered low because the evidence base was observational, clinically heterogeneous, and vulnerable to residual confounding and possible publication bias; this judgment reflects a qualitative interpretation of the included study designs and their methodological limitations rather than a formal GRADE rating. Conclusions: The current evidence supports a consistent, approximately twofold overall association between periodontal disease and cognitive impairment, broadly in line with prior systematic reviews and meta-analyses, while adding newer cohort and Alzheimer disease data through 2025. The exposure is best understood as a host-mediated periodontal inflammatory burden, and Periodontitis may represent a potentially modifiable contributor to adverse cognitive outcomes, but causal inference and policy-level screening recommendations require stronger interventional and mechanistic evidence. Clinical Relevance: Periodontitis represents a potentially modifiable risk factor for cognitive decline and accelerated deterioration in Alzheimer's disease patients, highlighting the need for interdisciplinary collaboration between dental and medical professionals. Integrating routine periodontal screenings and proactive oral care into the management of aging populations could serve as a valuable, low-risk strategy to help mitigate adverse cognitive outcomes.},
}

@article {pmid42930485,
year = {2026},
author = {Huang, D and Lu, R and Sheng, C and Zheng, J and Wang, Y and Sang, Z},
title = {Therapeutic Potential of Marine Natural Products Against Alzheimer's Disease: Molecular Mechanisms, Druggability Evaluation and Clinical Translation Barriers.},
journal = {Marine drugs},
volume = {24},
number = {10},
pages = {},
doi = {10.3390/md24100356},
pmid = {42930485},
issn = {1660-3397},
support = {22367007//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Biological Products/pharmacology/therapeutic use/chemistry/pharmacokinetics ; Animals ; *Aquatic Organisms/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with complex multifactorial pathological cascades, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, sustained neuroinflammation, oxidative stress, cholinergic dysfunction and gut-brain axis imbalance. Current marketed anti-AD drugs merely relieve symptomatic cognitive impairment without halting or reversing disease progression, highlighting an urgent demand for novel multi-target therapeutic candidates. Marine ecosystems, covering 71% of the Earth's surface, generate structurally unique, low-toxicity secondary metabolites via adaptive metabolic pathways of marine algae, invertebrates and microorganisms, which represent promising lead compounds for developing marine anti-AD therapeutics with synergistic multitarget neuroprotective activities. This systematic review comprehensively summarizes the anti-AD bioactivities and underlying molecular mechanisms of seven major categories of marine natural products, including marine polysaccharides, terpenoids, macrolides, alkaloids, polyphenols and carotenoids, sterols/lipids, and aminosulfonates. We further perform an integrated ADMET druggability assessment of representative marine bioactive molecules to evaluate their blood-brain barrier penetration, oral absorption, physicochemical properties and toxicological risks, identifying homotaurine as the most balanced candidate with favorable central nervous system delivery and safety profiles. We also elaborate the core bottlenecks restricting clinical translation, including insufficient blood-brain barrier permeability and unsatisfactory in vivo pharmacokinetic behaviors of most marine-derived compounds. Finally, we outline future research directions, covering structural modification, nanocarrier delivery, gut-brain axis-targeted intervention and cross-disciplinary translational research. This work aims to provide a comprehensive theoretical reference for the discovery, optimization and clinical transformation of marine anti-Alzheimer drugs, and facilitate high-value exploitation of marine bioactive resources for neurodegenerative disease treatment.},
}

*Alzheimer Disease/drug therapy
Humans
*Biological Products/pharmacology/therapeutic use/chemistry/pharmacokinetics
Animals
*Aquatic Organisms/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Blood-Brain Barrier/metabolism

@article {pmid42930563,
year = {2026},
author = {Burnat, G and Santocki, M and Siekierzycka, A and Płoska, A and Kalinowski, L and Wierońska, JM},
title = {Positive Allosteric Modulation of mGlu and Muscarinic Receptors Differentially Regulate Nitric Oxide-Dependent Signaling in a Scopolamine-Induced Model of Cognitive Impairment.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/medsci14060644},
pmid = {42930563},
issn = {2076-3271},
support = {2019/33/B/NZ7/02699//National Science Centre/ ; 2/566516/SPUB/SP/2023//Ministry of Science and Higher Education/ ; },
mesh = {Animals ; *Nitric Oxide/metabolism ; *Receptors, Metabotropic Glutamate/metabolism ; Signal Transduction/drug effects ; Scopolamine ; Mice ; *Receptors, Muscarinic/metabolism ; Allosteric Regulation/drug effects ; Disease Models, Animal ; Male ; Cyclic GMP/metabolism ; *Cognitive Dysfunction/metabolism/chemically induced/drug therapy ; Humans ; Cell Line ; Astrocytes/metabolism/drug effects ; },
abstract = {Background/Objectives: The aim of the study was to evaluate the effects of positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu2, mGlu5) and muscarinic (M1, M4) receptors on nitric oxide (NO֗)-dependent pathways. Scopolamine-induced cognitive impairment model reflecting cholinergic dysfunction characteristic of Alzheimer's disease was used. Methods: The experiments were performed in vivo in Albino Swiss mice and in vitro in astrocytic cell lines (C8D1A, 1321N1). Chronic (14 days) scopolamine and mGlu2 (LY487379), mGlu5 (CDPPB), M1 (VU0357017), and M4 (VU0152100) PAMs were administered in vivo. In brain tissue samples (frontal cortex or hippocampus) cGMP levels (ELISA), total and protein-specific S-nitrosylation (biotin switch assay), and neuronal (nNOS) or endothelial (eNOS) synthase-dependent (NO֗) release (nanoelectrochemical detection) were measured. In vitro oxidative stress (NBT assay) was performed. Results: Significantly reduced cGMP levels, decreased both nNOS- and eNOS-dependent (NO֗) release, and lowered total protein S-nitrosylation in brain tissue were observed. mGlu2 and mGlu5 PAMs prevented the reduction in nNOS-related (NO֗) release and restored total S-nitrosylation. CDPPB did not protect against eNOS-related impairment. Muscarinic receptors modulators effectively counteracted eNOS dysfunction. All investigated compounds attenuated oxidative stress, with particularly pronounced effects in human astrocytes. Conclusions: mGlu and muscarinic receptor PAMs differentially modulate (NO֗)-related signaling pathways, demonstrating both therapeutic potential and potential safety limitations. None of the tested compounds fully restored neurochemical balance, suggesting that combination strategies (e.g., with (NO֗) donors or modulators of the (NO֗)-cGMP pathway) may represent a promising direction for future Alzheimer's disease treatments.},
}

Animals
*Nitric Oxide/metabolism
*Receptors, Metabotropic Glutamate/metabolism
Signal Transduction/drug effects
Scopolamine
Mice
*Receptors, Muscarinic/metabolism
Allosteric Regulation/drug effects
Disease Models, Animal
Male
Cyclic GMP/metabolism
*Cognitive Dysfunction/metabolism/chemically induced/drug therapy
Humans
Cell Line
Astrocytes/metabolism/drug effects

@article {pmid42930993,
year = {2026},
author = {Simić, S and Łażewska, D and Kalaba, P and Wackerlig-Damle, J and Langer, T},
title = {Biomimetic ADME Profiling of Multifunctional Biphenylalkoxyamine-Related Histamine H3 Receptor Ligands with Anti-Alzheimer Potential.},
journal = {Membranes},
volume = {16},
number = {10},
pages = {},
doi = {10.3390/membranes16100315},
pmid = {42930993},
issn = {2077-0375},
support = {//University of Vienna/ ; },
abstract = {Multifunctional histamine H3 receptor (H3R) ligands with cholinesterase inhibitory activity are being explored as potential Alzheimer's disease therapeutics, but their interactions with biological membranes and associated ADME properties require parallel evaluation. Here, six structurally related alkoxyamine H3R ligands were characterized using an HPLC-based biomimetic workflow centered on immobilized artificial membrane (IAM) chromatography to assess phospholipid affinity, estimate passive blood-brain barrier permeability and human intestinal absorption. IAM measurements were complemented by HSA/AGP plasma protein binding, biomimetic distribution descriptors, plasma stability, chromatographic lipophilicity at pH 7.4 and solubility in JP1 (pH 1.2), JP2 (pH 6.8), and phosphate buffer (pH 7.4). The IAM models classified all six ligands as CNS-positive and predicted high intestinal absorption, while CHIIAM values indicated strong membrane affinity. After 24 h, 77.5-89.5% and 62.2-80.5% parent compound remained in human and rat plasma, respectively. Solubility remained measurable across all three media. Integrated consideration of membrane-related ADME properties and previously reported pharmacology prioritized compounds (6), (5) and (2). Compound (6) showed the strongest overall potency-developability balance, although the biomimetic membrane predictions require confirmation in direct permeability, transporter, and in vivo pharmacokinetic studies.},
}

@article {pmid42931134,
year = {2026},
author = {Papadopoulou, K and Tsokkou, S and Pavlidis, P and Karachrysafi, S and Tseriotis, VS and Kavvadas, D and Kavvada, A and Sardeli, C and Kouvelas, D and Meditskou-Efthymiadou, S and Sioga, A and Papamitsou, T},
title = {Ultrastructural Signatures of Amikacin Neurotoxicity and the Protective Modulation of Memantine in Peripheral Nerves: A Transmission Electron Microscopy Exploration in Wistar Rats.},
journal = {Neurology international},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/neurolint18100180},
pmid = {42931134},
issn = {2035-8385},
abstract = {BACKGROUND/OBJECTIVES: Aminoglycoside antibiotics such as amikacin are indispensable for treating severe Gram-negative infections, but their clinical use is limited by a well-documented toxicity profile that has focused overwhelmingly on ototoxicity and nephrotoxicity, leaving their action on the peripheral nervous system comparatively unexplored. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist used in Alzheimer's disease, has shown protective effects in peripheral-nerve animal models, raising the question of whether it could limit potential amikacin-induced peripheral neurotoxicity.

METHODS: Adult male Wistar rats were allocated to three groups: Group A: control, no drug administration; Group B: amikacin 20 mg/kg/day intraperitoneally for 14 days; and Group C: concurrent administration of amikacin 20 mg/kg/day plus memantine 10 mg/kg/day intraperitoneally for 14 days. Branches of the brachial plexus and the sciatic nerve were harvested and processed for transmission electron microscopy (TEM), and axonal, myelin and Schwann-cell ultrastructure were assessed in a blinded manner.

RESULTS: Group A showed intact axons, compact myelin sheaths and normal Schwann cells. Group B showed pronounced neurotoxic lesions: degeneration of the myelin sheath (splitting, dilation and folding), axoplasmic collapse with swollen organelles, and Schwann cells of abnormal shape. In Group C, memantine markedly attenuated the nerve fiber damage: most axons were preserved, myelin-sheath abnormalities were mild and focal, and numerous normal Schwann cells and unmyelinated nerve fibers were retained.

CONCLUSIONS: Amikacin exerts a distinct, previously under-recognized ultrastructural neurotoxicity on peripheral nerves, and concurrent memantine confers substantial neuroprotection, supporting a potential adjunctive role for NMDA-receptor antagonism during aminoglycoside therapy.},
}

@article {pmid42931140,
year = {2026},
author = {Xu, J and Chang, Y and Liu, D and Chen, C},
title = {INPP5D/SHIP1 in Alzheimer's Disease: Linking Microglial Substrate Handling to Neuroinflammation and Neurovascular Dysfunction.},
journal = {Neurology international},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/neurolint18100186},
pmid = {42931140},
issn = {2035-8385},
support = {82370407//National Natural Science Foundation of China/ ; },
abstract = {INPP5D, which encodes Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), has emerged as an Alzheimer's disease (AD)-associated gene with strong links to microglial biology. As a hematopoietic-enriched lipid phosphatase, SHIP1 converts phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-3,4-bisphosphate, thereby regulating phosphoinositide-dependent receptor signaling, membrane remodeling, phagocytosis, vesicle trafficking, and inflammatory responses. In AD, microglia are chronically exposed to amyloid-β, lipid-rich debris, damaged synapses, complement-tagged structures, and inflammatory mediators. These substrates require coordinated uptake, endolysosomal processing, autophagic adaptation, and controlled inflammatory output. Current data place INPP5D/SHIP1 at a step after receptor engagement, where microglial uptake must be coupled to vesicular routing and lysosomal degradation. When this coupling fails, engulfed amyloid, lipid debris, or synaptic material may accumulate in stressed endolysosomal compartments, promoting defective autophagy, NLRP3 inflammasome activation, and sustained cytokine release. Although current data support a primarily microglial or myeloid-centered role for INPP5D in the brain, altered microglial states may secondarily affect the neurovascular unit through cytokine release, complement activation, oxidative stress, and impaired amyloid or lipid clearance. This review summarizes the molecular function of INPP5D/SHIP1 in AD-related microglial signaling and discusses its implications for phagocytosis, endolysosomal stress, inflammasome activation, therapeutic targeting, and microglia-vascular communication.},
}

@article {pmid42931145,
year = {2026},
author = {Liu, J and Zhu, B and Yu, M and Du, S},
title = {Early Diagnostic Classification of Alzheimer's Disease Using Structural and Resting-State Functional MRI.},
journal = {Neurology international},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/neurolint18100191},
pmid = {42931145},
issn = {2035-8385},
support = {No. YDZJ202601ZYTS071//Jilin Province Science and Technology Department/ ; },
abstract = {Background: Alzheimer's disease (AD) is an irreversible neurodegenerative disorder where early diagnosis at the mild cognitive impairment (MCI) stage is critical for timely intervention. While structural MRI (sMRI) and resting-state functional MRI (rs-fMRI) provide complementary pathological information, clinical translation is limited by high feature heterogeneity and the heavy computational burden of 3D deep learning networks. This study aims to propose a lightweight, hybrid multimodal fusion model to overcome these limitations and improve diagnostic efficiency. Methods: A lightweight MobileViT-XS network was utilized to extract global and local pathological features from gray-matter sMRI images to reduce computational costs. Concurrently, graph theory was applied to rs-fMRI data to construct brain functional networks and calculate global topological properties. Following pretraining, feature-level fusion was performed to integrate sMRI features, rs-fMRI properties, demographic information, and two clinical neuropsychological examinations. Results: The validation results show that the proposed hybrid model achieved high diagnostic performance in the three-class classification task, yielding an accuracy of 0.928 ± 0.010, sensitivity of 0.901 ± 0.014, precision of 0.933 ± 0.014, and an F1 score of 0.911 ± 0.012. On the held-out testing subset of the independently collected dataset after dataset-specific fine-tuning, the proposed model achieved an accuracy of 0.857, with a sensitivity of 0.867, a precision of 0.867, and an F1 score of 0.859. Conclusions: The proposed framework successfully minimizes computational overhead while maintaining high classification accuracy. These findings suggest that the hybrid multimodal fusion model provides a promising computer-aided approach for three-class classification of AD, MCI, and NC.},
}

@article {pmid42931149,
year = {2026},
author = {Shatirishvili, N},
title = {Fluid Biomarkers for the Antemortem Detection of Chronic Traumatic Encephalopathy: A Critical Review.},
journal = {Neurology international},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/neurolint18100195},
pmid = {42931149},
issn = {2035-8385},
abstract = {Chronic traumatic encephalopathy (CTE) is a progressive tauopathy associated with repetitive head impacts (RHIs) and is currently confirmed only at autopsy. The absence of a validated antemortem diagnostic limits individual risk assessment, clinical trial enrollment, and differentiation from disorders such as Alzheimer's disease (AD). This review critically evaluates five candidate fluid biomarkers: phosphorylated tau (p-tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and soluble TREM2 (sTREM2). For each, the review assesses the biological mechanism, CTE/RHI-specific evidence, diagnostic performance, and major confounders. None currently provides CTE-specific discrimination. In the largest cohort, plasma p-tau217 tracked amyloid status rather than CTE pathology. NfL reflects axonal injury but is nonspecific and strongly age-dependent. GFAP is associated with clinical CTE certainty in football and combat-sport cohorts, although not in an independent rugby cohort. S100B responds acutely to head impacts without a persistent cumulative signal. sTREM2 may reflect microglial activation that is bidirectionally related to tau after RHI exposure, but its primary case-control comparison was null. Short study windows may also be poorly matched to CTE's multi-decade latency, and most evidence for p-tau, NfL and GFAP derives from one cohort, with the total tau, extracellular-vesicle and sTREM2 findings from a second. The review therefore emphasizes multi-marker panels, assay standardization, and longitudinal antemortem-to-autopsy cohorts as the validation work required before any fluid biomarker can support antemortem CTE detection.},
}

@article {pmid42931408,
year = {2026},
author = {Tang, J and Balaji, S and Oon, HH},
title = {Off-Target Effects of Recombinant Zoster Vaccine: Clinical Benefits, AS01B Adjuvant Immunobiology, and Observational Evidence.},
journal = {Vaccines},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/vaccines14100879},
pmid = {42931408},
issn = {2076-393X},
abstract = {Background/Objectives: The recombinant zoster vaccine (RZV), Shingrix[®], has shown great efficacy in protecting against herpes zoster. However, emerging evidence suggests that this RZV might provide benefits that extend beyond preventing varicella zoster virus (VZV) reactivation. Specifically, this scoping review explored the literature to investigate the reported non-zoster, off-target effects of the Shingrix[®] RZV, and the possible mechanistic explanations for these effects. Methods: Keyword searches of PubMed database were conducted, along with manual searches of other relevant journals and reference lists of primary articles. Results: Evidence from the included studies demonstrated relationships between administration of RZV vaccination and reduced risk of dementia, Alzheimer's disease and major adverse cardiological events (MACEs), while also conferring geroprotective effects. Mechanistic studies identified two possible causes, namely VZV suppression and AS01B adjuvant immunoregulation. Prevention of herpes zoster resulted in reduced risk of associated cognitive impairment and vasculopathy, reducing incidence of dementia and MACE. AS01B adjuvant was also linked to persistent monocyte reprogramming, and enhanced innate immune response and memory, known as "trained immunity", which provided a plausible explanation for the observed off-target effects. Adverse events because of RZV administration were rare but included Guillain-Barré syndrome (GBS), autoimmune encephalitis and autoimmune flares occurring after vaccination. However, there is insufficient evidence to indicate a causal relationship between RZV administration and these rare immune-mediated adverse effects, and post-marketing surveillance still support a favourable safety profile. Conclusions: Current evidence suggests that RZV administration confers numerous off-target benefits via VZV suppression and the immunomodulatory effects of the AS01B adjuvant. As clinical evidence remains observational, further investigation of the pleiotropic effects of RZV should be carried out to explore its role in reducing all-cause mortality.},
}

@article {pmid42931616,
year = {2026},
author = {Capobianco, M and Zeppieri, M and Nicolosi, SG and Castellino, N and Cappellani, F and Gattazzo, I and Gagliano, C},
title = {Translational Applications of Retinal Biomarkers in Chronic Cardiovascular, Neurological, Metabolic, and Renal Diseases.},
journal = {Vision (Basel, Switzerland)},
volume = {10},
number = {4},
pages = {},
doi = {10.3390/vision10040078},
pmid = {42931616},
issn = {2411-5150},
abstract = {Imaging the retina is a powerful non-invasive probe of systemic vascular, neurological, metabolic, and renal disease, making it a cornerstone of the new field of systemic oculomics. Advanced retinal imaging techniques like optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) provide detailed imaging of structural and microvascular changes potentially associated with systemic disease. Derived from fundus photography, structural imaging, vascular imaging, and artificial intelligence-based image analysis, retinal biomarkers have been associated with cardiovascular and cerebrovascular disease, neurodegenerative disorders, diabetes, chronic kidney disease, and related clinical outcomes. However, the translational maturity of these biomarkers is variable depending on imaging modality, target disease, intended clinical use, and level of validation. Longitudinally, retinal vascular characteristics have been associated with cardiovascular as well as cerebrovascular outcomes. In addition, optical coherence tomography has provided reproducible measures of neuroaxonal injury in selected neurological conditions. This is especially true for multiple sclerosis. The majority of retinal biomarkers in Alzheimer disease, Parkinson disease, chronic kidney disease, and systemic risk prediction remain experimental because of heterogeneous methodologies, insufficient external validation, and insufficient evidence for incremental clinical utility. Diabetes is the most developed translational model with established retinal screening pathways and validated ocular applications of imaging and artificial intelligence, although these cannot be directly extrapolated to systemic diagnosis or treatment guidance. This narrative review assesses retinal biomarkers for cardiovascular, neurological, metabolic, and renal disease with a focus on analytical validity, clinical validity, incremental value, clinical utility, and implementation. The retina is increasingly accepted as a site for discovery of systemic biomarkers and adjunctive risk assessment, although most applications to systemic disease remain to be standardized, validated independently, and studied prospectively before being suitable for routine clinical use.},
}

@article {pmid42931999,
year = {2026},
author = {Di Giesi, ML and Motolese, F and Norata, D and Sapio, E and Selvaggi, SA and Meduri, GM and Capone, F and Pilato, F and Di Lazzaro, V},
title = {A closer look at LATE: a Case Report on a subtly evolving neurodegenerative disorder.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42931999},
issn = {1590-3478},
mesh = {Humans ; Aged ; Positron-Emission Tomography ; *TDP-43 Proteinopathies/diagnosis/diagnostic imaging ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; Disease Progression ; Male ; Magnetic Resonance Imaging ; Alzheimer Disease/diagnosis ; Memory, Episodic ; Neuropsychological Tests ; },
abstract = {OBJECTIVES: Limbic-predominant age-related TDP-43 encephalopathy (LATE) often presents in older adults with a hippocampal-type amnestic syndrome that is clinically indistinguishable from Alzheimer's disease (AD). In the era of anti-amyloid therapies, misdiagnosis carries therapeutic consequences.

METHODS: Single-patient case report. The patient provided written informed consent and all data included in this paper are de-identified.

RESULTS: A 71-year-old with isolated episodic memory impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) AD biomarkers, and [18]F-FDG PET in 2021. Baseline findings showed preserved global cognition, negative AD biomarkers, and mild bilateral medial temporal hypometabolism. Over the subsequent years, episodic memory declined, while daily function and other cognitive domains remained intact. MRI demonstrated bilateral medial temporal atrophy. Repeat CSF examination showed negative AD biomarkers, whereas NfL levels were markedly elevated. On repeat [18]F-FDG PET, bilateral medial temporal hypometabolism progressed, while inferolateral temporal metabolism-usually reduced in AD-remained preserved.

DISCUSSION: The slowly progressing isolated amnestic profile, medial temporal-predominant neurodegeneration, high CSF NfL level, and persistently negative AD biomarkers supported the diagnosis of LATE. LATE should be actively considered in elderly patients with a hippocampal-type amnestic syndrome and negative AD biomarkers. This requires a high index of suspicion, but it is increasingly critical to avoid ineffective therapies and to refine clinical trial selection.},
}

Humans
Aged
Positron-Emission Tomography
*TDP-43 Proteinopathies/diagnosis/diagnostic imaging
*Neurodegenerative Diseases/diagnosis/diagnostic imaging
Disease Progression
Male
Magnetic Resonance Imaging
Alzheimer Disease/diagnosis
Memory, Episodic
Neuropsychological Tests

@article {pmid42932271,
year = {2026},
author = {Fatima, T and Lashari, TA and Moetesum, M and Lashari, SA},
title = {Handwriting-based Alzheimer's disease classification on the DARWIN dataset: Repeated nested validation, task-level reduction, and cross-validated explainability.},
journal = {PloS one},
volume = {21},
number = {10},
pages = {e0361117},
doi = {10.1371/journal.pone.0361117},
pmid = {42932271},
issn = {1932-6203},
mesh = {Humans ; *Handwriting ; *Alzheimer Disease/classification/diagnosis/physiopathology ; ROC Curve ; Random Forest ; Classification Algorithms ; },
abstract = {Online handwriting provides a low-burden source of cognitive-motor measurements, but small datasets can yield optimistic results when preprocessing, task selection, or explanation is not separated from evaluation. We evaluated eight classifiers on the DARWIN dataset (174 participants; 25 tasks; 450 predictors) using ten repetitions of 5-outer/3-inner-fold nested stratified cross-validation. All preprocessing, hyperparameter selection, and calibration were restricted to outer training data. We added a training-derived operating point, fully nested seven-task selection, cross-model subset transfer, foldwise SHAP analysis, and an all-feature SHAP sensitivity analysis. Random Forest had the highest descriptive ROC-AUC (0.938 ± 0.033 across 50 held-out folds). The Friedman omnibus test indicated model differences (p < 0.001), but no one of 28 paired comparisons remained significant after Holm correction. Training-derived thresholds (median 0.461) yielded held-out sensitivity 0.869 and specificity 0.831; these are exploratory operating characteristics, not a clinical cutoff. Nested seven-task selection achieved AUC 0.916 ± 0.037, compared with 0.956 ± 0.030 for all 25 tasks, and selected subsets were unstable (mean Jaccard 0.195). Cross-validated SHAP emphasized temporal variables, although an all-450-feature sensitivity analysis showed that individual ranks depend partly on ANOVA preselection. The study contributes an integrated, leakage-controlled evaluation rather than a new classifier or a validated diagnostic instrument; external prospective validation remains necessary.},
}

Humans
*Handwriting
*Alzheimer Disease/classification/diagnosis/physiopathology
ROC Curve
Random Forest
Classification Algorithms

@article {pmid42932621,
year = {2026},
author = {Ketcham, JD},
title = {Artificial Intelligence as a Return on Investment Multiplier in Health Care.},
journal = {NEJM AI},
volume = {3},
number = {6},
pages = {AIpc2600139},
doi = {10.1056/AIpc2600139},
pmid = {42932621},
issn = {2836-9386},
mesh = {Humans ; *Artificial Intelligence ; Alzheimer Disease/therapy/economics ; *Delivery of Health Care/economics ; Value-Based Health Care ; },
abstract = {AbstractIn heterogeneous clinical populations, the clinical and economic value of therapies depends on how they are allocated. Predictive artificial intelligence (AI) models can improve the precision of treatment allocation beyond what earlier clinical decision support tools could achieve by integrating data across clinical, biomarker, imaging, and administrative domains simultaneously. This capacity can increase the realized value of existing and emerging therapies relative to the status quo by improving two types of treatment decisions: risk-based targeting, which concentrates treatment among patients at higher baseline risk, and response-based targeting, which identifies patients with greater expected treatment benefit. Both mechanisms reduce effective numbers needed to treat (NNT) and improve return on investment (ROI), reducing low-value care and strengthening incentives to develop therapies for well-defined patient subgroups. We illustrate this argument using remote physiological monitoring and Alzheimer's disease - two settings where current deployment heuristics produce high effective NNT and limited ROI, and where improved predictive targeting could materially improve the economic conclusion. Realizing this potential depends on data governance, incentives, and regulatory pathways that support the development, continuous refinement, and clinical integration of predictive models. Framing predictive AI as an ROI multiplier on the therapies it guides has broader consequences for how those therapies are developed, regulated, priced, and covered, and for how predictive AI models themselves should be valued and evaluated.},
}

Humans
*Artificial Intelligence
Alzheimer Disease/therapy/economics
*Delivery of Health Care/economics
Value-Based Health Care

@article {pmid42932815,
year = {2026},
author = {Snell, A and Reutens, D and Du, J and Vegh, V},
title = {Laplace-based cortical thickness without volumetric discretisation.},
journal = {Cerebral cortex (New York, N.Y. : 1991)},
volume = {36},
number = {10},
pages = {},
doi = {10.1093/cercor/bhag179},
pmid = {42932815},
issn = {1460-2199},
support = {//The Australian Research Council/ ; IC170100035//Training Centre for Innovation in Biomedical Imaging Technology/ ; },
mesh = {Humans ; *Cerebral Cortex/diagnostic imaging/pathology ; Magnetic Resonance Imaging/methods ; *Focal Cortical Dysplasia/diagnostic imaging/pathology ; Image Processing, Computer-Assisted/methods ; *Brain Cortical Thickness ; },
abstract = {Laplace-based methods define cortical thickness as the length of a streamline connecting the pial and white surfaces, but existing implementations discretize the volume and lose accuracy in tight folds. Surface-based methods use Euclidean inter-surface distances that cannot enforce orthogonal, non-crossing correspondences. We solve Laplace's equation on the cortical surface itself using a boundary element method, with pial and white surfaces as Dirichlet boundaries and the surrounding edge Neumann boundaries; thickness is the length of a streamline traced along the analytic gradient field. We tested 8044 streamlines across analytical shapes, synthetic gyral patches, and real cortices; reciprocal paths returned within 0.05 mm of their origin, with 95th-percentile asymmetry below 0.68%. On folded patches with known ground truth, length-normalized bias was 0.0003 mm/mm independent of curvature. Streamline validity remained near-complete above a mean triangle shape quality of 0.90 and degraded sharply below 0.80, defining a practical mesh threshold. In three focal cortical dysplasia patients, each imaged at 3 T and 7 T, the method resolved focal thickening at the lesion site, with contralateral cortex mapped alongside as a visual reference. Vertex-wise comparison against FreeSurfer on identical surfaces showed differences scaling with local curvature. The observed bias is over an order of magnitude below preclinical Alzheimer's thinning rates.},
}

Humans
*Cerebral Cortex/diagnostic imaging/pathology
Magnetic Resonance Imaging/methods
*Focal Cortical Dysplasia/diagnostic imaging/pathology
Image Processing, Computer-Assisted/methods
*Brain Cortical Thickness

@article {pmid42933039,
year = {2026},
author = {Nazari, M and Rabiee, N},
title = {Exosome-amyloid interplay: Mechanisms, pathological roles, and materials-driven opportunities.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {270},
number = {},
pages = {116274},
doi = {10.1016/j.colsurfb.2026.116274},
pmid = {42933039},
issn = {1873-4367},
abstract = {Amyloid aggregation is a defining molecular feature of several neurodegenerative disorders, particularly Alzheimer's disease (AD), in which amyloid-β (Aβ) peptides assemble into heterogeneous oligomeric and fibrillar states. Extracellular vesicles (EVs) can interact with these assemblies, but their biological effects are context dependent: selected EV populations can sequester or promote clearance of toxic species, whereas other vesicles can support seeding, transport, or impaired clearance. This review adopts current EV terminology by reserving exosome for vesicles whose endosomal origin is demonstrated and using small EV (sEV) when biogenesis is not established. We critically examine the physicochemical determinants of EV-amyloid interactions, including membrane lipid composition, ceramide and cholesterol, cellular prion protein (PrPᶜ), Aβ isoform and assembly state, vesicle-to-Aβ ratio, recipient-cell competence, inflammation, and clearance capacity. We distinguish evidence from patient-cohort biomarker associations, mechanistic cell studies, animal-model causality, proof-of-concept engineering, and hypothesis-generating concepts. Patient studies reporting associations between circulating EV-associated Aβ42 and brain amyloid burden are discussed as promising but not yet sufficient to establish superiority over validated plasma biomarkers. Materials-enabled EV enrichment, microfluidics, surface-enhanced Raman spectroscopy, and engineered vesicle systems are evaluated alongside limitations in isolation, normalization, biodistribution, immunogenicity, manufacturing, and external clinical validation. This evidence-weighted framework positions EVs as context-sensitive components of proteinopathy and as investigational diagnostic or delivery platforms whose translation requires standardized characterization and independent validation.},
}

@article {pmid42933063,
year = {2026},
author = {Hu, C and Li, J and Jiang, L and Zhou, Y and Deng, Y and Pan, Q and Wang, S and Yang, W and Zhang, L and Chao, F and Luo, Y and Tang, J and Xiao, Q and Liang, X and Qi, Y and Tang, Y and Zhou, C},
title = {Overexpression of hippocampal AdipoR1 ameliorates cognitive dysfunction in APP/PS1 mice through inhibiting NLRP3-Mediated neuronal pyroptosis.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {24},
number = {1},
pages = {e01093},
doi = {10.1016/j.neurot.2026.e01093},
pmid = {42933063},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive dysfunction. Substantial loss of hippocampal neurons is closely associated with irreversible cognitive decline; however, the underlying mechanisms have not yet been fully elucidated. In this study, conditionally overexpressing adiponectin receptor 1 (AdipoR1) in the hippocampus of APP/PS1 transgenic AD mice, we found that it significantly improved learning and memory abilities and effectively mitigated the abnormal loss of hippocampal neurons and dendritic spines. AdipoR1 overexpression primarily maintained neuronal numbers through reducing neuronal death rather than promoting neurogenesis, and this protective effect is closely linked to the inhibition of the neuronal NLRP3 inflammasome, leading to a marked reduction in pyroptosis levels within the hippocampus. Our results demonstrated, for the first time, that AdipoR1 exerted a crucial neuroprotective role in AD pathology through modulating the NLRP3-mediated neuroinflammatory pathway, which might offer new insights into the mechanisms of neuronal loss in AD and suggest that the AdipoR1-NLRP3 signaling axis may serve as a potential therapeutic target for early intervention in AD.},
}

@article {pmid42933077,
year = {2026},
author = {Alshammari, F and M Al-Kuraishy, H and M Abdelaziz, A and Alruwaili, M and Batiha, GE},
title = {Immunopharmacology of proton pump inhibitors in Alzheimer's Disease: An evidence-weighted mechanistic review of Neuroinflammation, neuroprotection, and neurodegeneration.},
journal = {International immunopharmacology},
volume = {191},
number = {Pt 1},
pages = {117618},
doi = {10.1016/j.intimp.2026.117618},
pmid = {42933077},
issn = {1878-1705},
abstract = {Proton pump inhibitors (PPIs) are among the most widely prescribed drugs worldwide, and their relationship with Alzheimer's disease (AD) remains clinically uncertain because epidemiological and mechanistic evidence conflict. This evidence-weighted mechanistic review critically synthesizes PPI immunopharmacology in AD and grades the strength of mechanistic and human evidence while explicitly considering bias and confounding. Mechanistic evidence indicates context-dependent dual actions. Putative neuroprotective pathways include suppression of microglial/astrocytic inflammation via STAT3 inhibition, liver X receptor-mediated Aβ clearance, antioxidant effects, cholinesterase inhibition, and possible autophagy induction. Conversely, harmful pathways include inverse γ-secretase modulation increasing Aβ1-42, V-ATPase inhibition impairing microglial lysosomal Aβ degradation, choline acetyltransferase inhibition, vitamin B12 deficiency with hyperhomocysteinemia, and indirect gut dysbiosis/endothelial dysfunction. Epidemiological findings are inconsistent and limited by protopathic bias, residual confounding, exposure and outcome misclassification, inadequate APOE ε4/CYP2C19 stratification, and heterogeneity in PPI agent, dose, and duration. Experimental evidence suggests that some PPIs can modulate AD-relevant pathways in opposing directions, but the human relevance, direction of the net effect, and any causal role in AD remain unestablished. Putative modifiers such as PPI type, dose, duration, and genetic susceptibility are hypothesized rather than demonstrated. Rigorous prospective, agent-specific studies incorporating pharmacokinetic and, where feasible, genetic stratification are needed. Clinically, general medication-safety measures, judicious prescribing, periodic review/deprescribing where appropriate, and nutritional monitoring in at-risk long-term users are reasonable independent of any assumed AD effect; current evidence does not support PPI changes specifically to modify dementia risk.},
}

@article {pmid42933097,
year = {2026},
author = {Rose, SE and Wang, A and Hesson, J and Tan, A and Sharp-Milgrom, M and Johnson, CSC and Regier, MC and Frankowski, H and Smith, AC and Keene, CD and Garden, GA and Crane, PK and Blue, E and Jayadev, S and Mathieu, J and Young, JE},
title = {Generation of autopsy-derived human iPSC lines from 24 sporadic Alzheimer's disease and control donors characterized for polygenic AD risk.},
journal = {Stem cell research},
volume = {97},
number = {},
pages = {104120},
doi = {10.1016/j.scr.2026.104120},
pmid = {42933097},
issn = {1876-7753},
abstract = {We developed 24 new human induced pluripotent stem cell (hiPSC) lines from postmortem donors with a range of sporadic Alzheimer's disease (AD) neuropathology and comorbid aging-related neurodegenerative disorders from prospective cohort studies in Seattle, WA. Leptomeningeal tissue was collected at the time of brain removal and primary fibroblast cultures derived as the parent cell source for reprogramming. Extensive clinical, genetic, and neuropathologic data are available for each brain donor, including genotyping for polygenic Alzheimer's disease risk through the endolysosomal pathway. These hiPSC lines will advance our understanding of the cellular mechanisms involved in AD pathogenesis, particularly the underlying genetic contributions to the disease, and serve as a screening tool for drug development.},
}

@article {pmid42933203,
year = {2026},
author = {Rogan, M and Blinc, L and Rejc, L and Martek, BA and Vezonik, U and Babnik, I and Mukaetov, B and Rajković, AB and Meden, A and Pfabe, J and Rupnik, MS and Jaklin, M and Bresjanac, M and Gobec, S and Knez, D and Kladnik, J and Košmrlj, J},
title = {Novel NIR DDNP-type solvatochromic and fluorogenic probes for amyloid β detection.},
journal = {Bioorganic chemistry},
volume = {184},
number = {},
pages = {110655},
doi = {10.1016/j.bioorg.2026.110655},
pmid = {42933203},
issn = {1090-2120},
abstract = {Selective near-infrared fluorescent probes for amyloid β aggregates are of considerable interest as molecular imaging tools for the diagnosis and study of Alzheimer's disease. Herein, we describe the rational design and synthesis of DDNP-type donor-π-acceptor fluorophores incorporating a fixed N,N-dimethylamino donor group, while systematically modifying seven aromatic π-bridges and four electron-withdrawing acceptor groups to investigate structure-property relationships. The library of 26 probes is a result of multi-step synthetic routes and exhibits pronounced solvatochromic behaviour together with strong fluorogenic responses. Compounds' photophysical properties, including absorption and emission maxima, Stokes shifts, and quantum yields, are systematically evaluated in five solvents of varying polarity. The study reveals clear structure-property relationships, demonstrating the influence of π-bridge length and electron-acceptor strength on the optical characteristics, including near-infrared emission. Selected fluorophores are further assessed for their affinity towards amyloid β fibrils through a combination of in vitro experiments and in silico molecular docking studies. Among the compounds investigated, the N,N-dimethylamino-stilbene-malononitrile derivative emerges as the lead candidate, showing an optimal balance of favourable photophysical properties and strong amyloid β binding affinity. Subsequent evaluation using brain tissue obtained post mortem from a patient with Alzheimer's disease demonstrates selective staining of amyloid β plaques with minimal background fluorescence.},
}

@article {pmid42933647,
year = {2026},
author = {Koh, YM and Yang, JJ and Cai, Q and Yoo, MJ and Jo, A and Hong, YR and Zeidan, RS and Cacciatore, S and Anton, S and Leeuwenburgh, C and Yoon, HS},
title = {Higher Serum α-Tocopherol Is Associated with Lower Cancer Mortality and Higher γ-Tocopherol with Lower Alzheimer's Disease Mortality in Older U.S. Adults.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101901},
doi = {10.1016/j.tjnut.2026.101901},
pmid = {42933647},
issn = {1541-6100},
abstract = {BACKGROUND: Despite shared antioxidant properties, α- and γ-tocopherol exhibit different associations with health indicators. Currently, their associations with cause-specific mortality remain unclear, particularly among older U.S. adults, in whom tocopherol status may be especially relevant to aging-related disease risk.

OBJECTIVES: We investigated the associations between serum α- and γ-tocopherol concentrations and cause-specific mortality using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006.

METHODS: We analyzed 6,025 adults aged ≥60 years with serum α- and γ-tocopherol data. All-cause and cause-specific mortality were ascertained through linkage to the National Death Index. Cox proportional models were used to estimate hazard ratios (HRs) and 95% CIs, adjusting for serum cholesterol, sociodemographics, lifestyle factors, and comorbid conditions.

RESULTS: Over a mean follow-up of 12.1 years, 3,745 deaths occurred. Higher serum α-tocopherol concentrations were independently associated with lower all-cause and cancer mortality: individuals in the highest quartile vs. lowest quartile showed 16% lower all-cause mortality (HR [95% CI] = 0.84 [0.73-0.97]) and 35% lower cancer mortality (0.65 [0.48-0.86]). The inverse association with cancer mortality was more pronounced among those with a history of cancer than among those without (0.42 [0.25-0.72] vs. 0.79 [0.53-1.18], respectively; p-interaction = 0.029). Conversely, γ-tocopherol was positively associated with all-cause and cancer mortality in models adjusted for demographic variables only; however, these associations were no longer present after full adjustment. Of note, higher γ-tocopherol levels were associated with a 37% reduction in Alzheimer's disease mortality (0.63 [0.40-0.99]), irrespective of baseline risk factors.

CONCLUSION: Higher circulating α-tocopherol levels were independently associated with reduced all-cause and cancer mortality, whereas higher γ-tocopherol levels were associated with lower Alzheimer's mortality in older adults. These findings suggest that tocopherol status may represent a potentially modifiable target for aging-related mortality, warranting further studies to explore underlying mechanisms and causal relationships.},
}

@article {pmid42933736,
year = {2026},
author = {Chakraborty, W and Anand, A and Kumar, S and Roy, KK},
title = {Circadian aging and neurodegeneration: the emerging role of the melatonin-cortisol axis in brain homeostasis, disease progression, and precision chronomedicine.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101292},
doi = {10.1016/j.yfrne.2026.101292},
pmid = {42933736},
issn = {1095-6808},
abstract = {Circadian aging may promote neurodegenerative illnesses by dysregulating the melatonin-cortisol axis. Low nighttime melatonin synthesis, blunted cortisol circadian cycles, abnormal clock-gene oscillation patterns, and sleep-wake architecture undermine central and peripheral circadian equilibrium with age. Neuroendocrine alterations produce oxidative stress, mitochondrial failure, pervasive neuroinflammation (CNS immune function loss), and proteostasis. Increasing Alzheimer's, Parkinson's, ALS, Huntington's, frontotemporal dementia, Lewy body disease, PTSD, and vascular cognitive impairment due to impaired glymphatic axonal clearance/blood-brain barrier dysregulation/synaptic degeneration/pathoproteopathic protein We examine how clock genes, melatonin signaling, hypothalamic-pituitary-adrenal axis administration, microglia reactivity, and immune-mediated metabolic dysregulation affect dementia. New endocrine, transcriptomic, multi-omics, and wearable-derived digital biomarkers, chronopharmacology (including melatonin receptor agonists), bright-light therapy, time-restricted eating with exercise chronotherapy guidance/synchronization, sleep optimization, and gut microbiota modulation This study addressed inter-individual circadian variability, genetic susceptibility to therapy timing, biomarker standardization, and clinical trial design. The melatonin-cortisol axis may identify and treat age-related neurodegenerative diseases with tailored treatment.},
}

@article {pmid42933739,
year = {2026},
author = {Tian, Y and Guo, J and Lin, X and Zhang, F and Xie, J and Hou, X and Deng, J and Hao, E and Du, Z},
title = {Mechanisms of Traditional Chinese Medicine-Derived Active Components in the Treatment of Alzheimer's Disease: A Comprehensive Review.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122574},
doi = {10.1016/j.jep.2026.122574},
pmid = {42933739},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and multifactorial pathology. Because AD involves interacting pathological processes, the limited efficacy of conventional single-target therapies has increased interest in traditional Chinese medicine (TCM) and other natural medicines with multi-target pharmacological actions. TCM-derived active components originate from medicinal materials used in traditional practice and are evaluated using modern pharmacological approaches. Their source medicines have diverse traditional-use backgrounds. Some have historical associations with memory or cognitive symptoms, whereas many others were traditionally used for broader deficiency, phlegm, blood-stasis, heat, or related syndromic patterns. These records provide ethnopharmacological context for the source medicines but should not be taken as historical evidence for the anti-AD activity of their isolated constituents.

AIM OF THE REVIEW: This review synthesizes current evidence on the mechanisms of TCM-derived bioactive components in AD while incorporating relevant traditional-use information on their source medicines. Particular attention is given to their multi-target actions and emerging mechanisms involving ferroptosis, mitophagy, and the gut-brain axis.

MATERIALS AND METHODS: Mechanistic literature published between January 2019 and November 2025 was retrieved from Ovid MEDLINE, PubMed, ScienceDirect, and Web of Science. Ovid MEDLINE and PubMed were searched separately to maximize retrieval across indexed and additional PubMed records, with overlapping records removed during deduplication. Traditional-use information was evaluated separately for the source medicines. A targeted search of PubMed and ClinicalTrials.gov was also conducted to assess human interventional evidence for compounds covered in the review, with trial-registration information updated through August 2026.

RESULTS: Current preclinical findings suggest that TCM active components may produce coordinated preclinical pharmacological effects through multiple pathways, including the inhibition of β-amyloid (Aβ) production and deposition, regulation of tau aggregation and phosphorylation, alleviation of neuroinflammation and oxidative stress, improvement of mitophagy and iron metabolism disorders, and modulation of gut microbiota homeostasis. Among these components, saponins show broad mechanistic coverage. Flavonoids, polysaccharides, and other bioactive substances have likewise shown anti-inflammatory and antioxidant activities, together with protective effects on synaptic function, in preclinical models. These mechanistic findings were derived predominantly from cellular and animal studies, with computational analyses providing mainly hypothesis-generating support. Human evidence was available for only a small subset of compounds and was not uniformly positive. Huperzine A has progressed to controlled clinical testing but has shown mixed efficacy findings; resveratrol demonstrated CNS exposure and biomarker activity without consistent cognitive benefit; curcumin did not show efficacy in a placebo-controlled AD trial; and favorable signals from ginseng studies were limited by open-label designs and the use of whole preparations rather than isolated ginsenosides.

CONCLUSIONS: The available evidence supports broad preclinical activity of TCM-derived components across several interconnected AD-related processes, but the strength of mechanistic support varies markedly among compounds and pathways. Human translation remains limited and inconsistent, and current clinical data do not establish disease-modifying efficacy for the compounds reviewed. Further development should therefore be guided by the main uncertainty surrounding each candidate-whether mechanistic causality, reproducibility, systemic or CNS exposure, preparation standardization, or clinical efficacy-rather than by a fixed sequence of technologies.},
}

@article {pmid42933985,
year = {2026},
author = {Chiu, JH and Zemke, NR and Gao, X and Garduño, M and Yang, B and Oakes, ML and Bartosik, WM and Wong, K and Pezo-Valderrama, P and Xie, Y and Urra, C and Macias-Velasco, JF and Tomlinson, C and Cogram, P and Xu, X and Ren, B},
title = {Chromosome-scale genome assembly and annotation of Octodon degus.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.281858.126},
pmid = {42933985},
issn = {1549-5469},
abstract = {High-quality reference genomes are essential for comparative and functional genomics yet remain unavailable for many emerging model organisms. Here, we report OctDeg2.0, a chromosome-level genome assembly and annotation of the degu (Octodon degus), generated using PacBio HiFi long-read sequencing and Hi-C scaffolding from a single male individual. Octodon degus is of growing interest as a natural animal model for aging and Alzheimer's disease research. The 3.4 billion base-pair assembly comprises 28 autosomes and both sex chromosomes, with markedly improved contiguity and completeness over the prior short-read assembly while maintaining high base accuracy. The new assembly provides substantially enhanced gene annotation, clearer resolution of chromatin architecture and cis-regulatory element landscapes, with much improved characterization of repetitive and structurally complex regions, including centromeres and segmental duplications. We present a streamlined and reproducible pipeline for high-resolution de novo genome assembly and gene annotation applicable to other emerging model organisms. This work establishes a robust genomic resource for studying molecular and cellular mechanisms in health and disease in Octodon degus.},
}

@article {pmid42927207,
year = {2026},
author = {Cella, A and Mure, LS},
title = {Intrinsically photosensitive retinal ganglion cells: Context-Dependent resilience and vulnerability.},
journal = {Neurobiology of sleep and circadian rhythms},
volume = {21},
number = {},
pages = {100153},
pmid = {42927207},
issn = {2451-9944},
abstract = {Retinal ganglion cells (RGCs) exhibit marked heterogeneity in their susceptibility to injury and disease. Intrinsically photosensitive retinal ganglion cells (ipRGCs), a small subset of melanopsin-expressing RGCs involved in non-image-forming visual functions, have emerged as a particularly informative example. In multiple experimental models, ipRGCs show relative resistance to acute insults such as optic nerve injury, excitotoxicity, and mitochondrial dysfuinction. In contrast, functional alterations and degeneration have been reported in aging and in neurodegenerative conditions including Alzheimer's and Parkinson's disease. This apparent discrepancy suggests that ipRGC survival may depend on the nature and duration of the underlying stress. In this review, we summarize current evidence on ipRGC resilience and vulnerability across a range of experimental and pathological contexts. We discuss candidate mechanisms that may contribute to these responses, including sustained activity, calcium handling, metabolic specialization, neurochemical interactions, and gene expression programs. We also consider the role of subtype-specific diversity within the ipRGC population in shaping these outcomes. Finally, we examine the potential of ipRGCs as biomarkers of disease and as a source of insight for neuroprotective strategies. Together, these observations support the view that ipRGC behaviour reflects an interaction between intrinsic cellular properties and the context in which they are engaged.},
}

@article {pmid42927299,
year = {2026},
author = {Gil, N and Naik, P and Koran, ME and Silverman, D and Kako, B and Chen, J},
title = {PET-based molecular imaging in neurodegeneration and dementia: current and emerging radiotracers.},
journal = {Radiology advances},
volume = {3},
number = {5},
pages = {umag046},
pmid = {42927299},
issn = {2976-9337},
abstract = {Positron emission tomography (PET)-based molecular imaging is a clinically important tool for the evaluation of dementia and other neurodegenerative disorders, using radiotracers that target specific molecular and pathophysiological processes. Fluorodeoxyglucose brain PET has historically supported neurodegenerative disorder evaluation through detection of characteristic patterns of regional glucose hypometabolism. In recent years, the molecular imaging of protein aggregates has taken on an increasingly important role. This is evident with the widespread clinical adoption of amyloid PET and early use of tau PET to provide diagnostic and prognostic information for patients with suspected Alzheimer's disease. Additional classes of radiotracers relevant to neurodegenerative diseases are under active investigation, including those targeting neuroinflammation, synaptic density, and α-synuclein aggregates. We review the major classes of PET radiotracers for neurodegenerative diseases, describing their molecular mechanisms, diagnostic performance, and their current and emerging clinical roles in dementia evaluation. Case examples for clinically used tracers illustrate imaging features relevant to diagnosis and characterization of prognosis and treatment effect. Finally, we discuss early developments and current challenges in the development of theranostic approaches and novel radiotracers for neurodegenerative diseases.},
}

@article {pmid42927368,
year = {2026},
author = {Kandilas, A and Samolis, A and Kalamatianos, T and Margaritis, I and Tsakotos, G and Triantafyllou, G and Piagkou, M},
title = {Network Neuroanatomy of Self-Awareness: A Narrative Review of Self-Referential Processing, Metacognition, and Embodiment.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116848},
pmid = {42927368},
issn = {2168-8184},
abstract = {Self-awareness encompasses the capacity to recognize and evaluate information about oneself, including mental states, actions, autobiographical history, and bodily experience. Although closely related to consciousness, autobiographical memory, metacognition, clinical insight, anosognosia, and bodily self-consciousness, these constructs are not interchangeable. This focused narrative review synthesizes human neuroanatomical and neuroimaging evidence identified through a targeted PubMed/MEDLINE search covering January 1997 to August 15, 2026, supplemented by reference-chain searching. To improve methodological transparency, the revised review specifies eligibility principles, the narrative synthesis strategy, and reproducible domain-specific Boolean search strings; because the article is a narrative rather than a systematic review, no protocol registration, PRISMA screening flow, formal study-level risk-of-bias assessment, or quantitative pooling was undertaken. The evidence is organized into four interacting domains: self-referential representation, autobiographical continuity, metacognitive monitoring, and embodied self-processing. Cortical midline and default mode regions are prominent in self-referential evaluation; medial temporal systems support autobiographical information; anterior and lateral prefrontal and frontoparietal regions contribute to monitoring and updating; and temporoparietal, precuneal, insular, and sensorimotor regions contribute to bodily self-processing. Importantly, these macroscopic territories overlap and contain functionally heterogeneous subregions, so the proposed mappings represent network-weighted tendencies rather than one-to-one anatomical assignments. Clinical findings further show that anosognosia in Alzheimer's disease, impaired insight in schizophrenia, altered self-experience in depersonalization-derealization disorder, and awareness deficits after acquired brain injury (ABI) involve different combinations of these processes. We therefore propose a representation-memory-monitoring-embodiment framework as a heuristic neuroanatomical synthesis, not a diagnostic or treatment model. Its value lies in separating constructs often grouped under the term self-awareness and in generating testable hypotheses for longitudinal multimodal imaging, lesion mapping, causal studies, and construct-matched interventions.},
}

@article {pmid42927744,
year = {2026},
author = {Mishchenko, TA and Grechukhina, AA and Kulikov, SS and Olajide, OJ and Mitroshina, EV and Krysko, DV and Vedunova, MV},
title = {When the Brain Signals Danger: Roles of Calreticulin and HMGB1 in Cell Death Mechanisms in Neurooncology and Neurodegeneration.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {10},
pages = {1822-1841},
doi = {10.1134/S0006297926601565},
pmid = {42927744},
issn = {1608-3040},
mesh = {Humans ; *HMGB1 Protein/metabolism ; *Calreticulin/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Cell Death ; Signal Transduction ; Alarmins/metabolism ; },
abstract = {Contrary to the classical paradigm of brain immune privilege, damage-associated molecular patterns (DAMPs) act as key mediators in the dialogue between CNS cells and the immune system, determining pathways of immune response development. This review examines the role of key DAMPs - calreticulin (CRT) and high-mobility group box 1 protein (HMGB1) - in the functioning of CNS under normal conditions and during the development of neuropathologies, particularly oncological and neurodegenerative processes. Under normal conditions, CRT and HMGB1 ensure functioning of the brain, acting as necessary effectors of neurogenesis and homeostatic plasticity. In neurooncology, exposure of CRT on the surface of dying cells and release of HMGB1 serve as powerful adjuvant signals for antigen-presenting cells, inducing immunogenic cell death (ICD). Particular attention is given to the mechanisms of passive HMGB1 release during various types of regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis), as well as to the role of redox modifications of the protein, which determine its pro-inflammatory, immunogenic, or tolerogenic properties. In neurodegeneration (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), excessive DAMP release exacerbates the development of chronic neuroinflammation, disrupts integrity of the blood-brain barrier (BBB), and forms a vicious cycle of pathological changes. Detection of CRT and HMGB1 in biological fluids or brain tissues has important prognostic potential, and regulation of their signaling pathways opens promising approaches for overcoming tumor resistance or inhibiting progressive neurodegenerative changes in the brain.},
}

Humans
*HMGB1 Protein/metabolism
*Calreticulin/metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
Cell Death
Signal Transduction
Alarmins/metabolism

@article {pmid42927749,
year = {2026},
author = {Nikulin, SV and Hushpulian, DM and Zakharyants, AA and Thomas, B and Kazakov, SV and Gazaryan, IG},
title = {Erebosis: An Emerging Concept of a New Type of Regulated Cell Death.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {10},
pages = {1907-1921},
doi = {10.1134/S0006297926602935},
pmid = {42927749},
issn = {1608-3040},
mesh = {Animals ; Humans ; *Drosophila melanogaster/metabolism/cytology ; *Regulated Cell Death ; Drosophila Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; Heme/metabolism ; Cell Death ; },
abstract = {This review briefly describes the discovery of a morphologically distinct form of regulated cell death in Drosophila, termed erebosis, which is characterized by organelle loss, nuclear flattening, and intracellular accumulation of Ance. The latter serves as a biomarker of this type of cell death but does not act as its trigger. Erebosis can be induced by amino acid deprivation accompanied by the reduced cytoplasmic viscosity, and its development is also associated with the increased heme oxygenase activity and decreased intracellular heme levels. We hypothesize that the heme-sensing protein E75 in Drosophila melanogaster, a homolog of mammalian REV-ERB proteins involved in circadian regulation, may provide a link between erebosis and renewal of enterocytes from the intestinal stem cells. Finally, we discuss the differences between erebosis and other forms of regulated cell death, as well as detection of ACE2 in the brains of mice in different models of Alzheimer's disease.},
}

Animals
Humans
*Drosophila melanogaster/metabolism/cytology
*Regulated Cell Death
Drosophila Proteins/metabolism
Alzheimer Disease/metabolism/pathology
Heme/metabolism
Cell Death

@article {pmid42927808,
year = {2026},
author = {Ribeiro-Rodrigues, L and Griškova-Bulanova, I and Diógenes, MJ and Xapelli, S},
title = {The dual role of BDNF in epilepsy: insights from calpain-mediated TrkB-FL cleavage.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109702},
doi = {10.1016/j.phrs.2026.109702},
pmid = {42927808},
issn = {1096-1186},
abstract = {Despite the efficacy of current antiseizure medications in managing seizures, approximately one-third of patients develop refractory epilepsy, highlighting an urgent need to uncover the molecular mechanisms driving epileptogenesis. This process emerges from a complex interplay of molecular alterations, involving changes in neuronal signaling pathways. Among these, brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, the full-length tropomyosin receptor kinase B (TrkB-FL), are heavily implicated in epilepsy pathophysiology. While traditionally recognized for promoting synaptic plasticity, BDNF signaling can become maladaptive in pathological states. Consequently, BDNF exhibits a paradoxical dual role in epilepsy, acting as a proepileptogenic factor in the acute phase, while exerting antiepileptic effects during the chronic phase. Recently, a calpain-dependent proteolytic mechanism mediating TrkB-FL cleavage, previously described in Alzheimer's disease (AD) and cerebral ischemia, has been shown to occur during epileptogenesis. Elevated levels of the intracellular cleavage product of TrkB-FL, TrkB-ICD, have been observed in the hippocampus of patients with refractory epilepsy, establishing its clinical relevance. In vitro, TrkB-ICD overexpression depolarizes neuronal membranes, increases miniature excitatory postsynaptic current frequency, and alters the transcription of genes related to synaptic transmission and plasticity. In vivo, its overexpression induces long-term memory impairment, a common comorbidity in epilepsy. Moreover, in experimental epilepsy models, TrkB-ICD protein levels correlate with seizure frequency during the acute phase (status epilepticus) and remain elevated during the chronic phase (established epilepsy). These findings highlight TrkB-FL cleavage and TrkB-ICD formation as molecular determinants in epileptogenesis, providing a biological rationale for the contrasting effects of BDNF. Inhibiting this cleavage, using tools like cell-penetrating peptides, represents a promising therapeutic avenue. As the field moves forward, elucidating the precise functions, regulation, and translational potential of the TrkB-FL proteolysis and TrkB-ICD formation may yield innovative, disease-modifying strategies for epilepsy, moving beyond the symptomatic suppression offered by conventional antiseizure drugs.},
}

@article {pmid42927826,
year = {2026},
author = {Shi, H and Ke, Z and Wang, B and Zhang, X and Gui, Y and Zhang, H and Liang, R},
title = {Targeting insulin resistance with exercise mimetics: A potential therapeutic strategy for Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116091},
doi = {10.1016/j.expneurol.2026.116091},
pmid = {42927826},
issn = {1090-2430},
abstract = {Insulin resistance (IR) has emerged as a key pathological mechanism underlying Alzheimer's disease (AD). This resistance accelerates AD progression by promoting amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Although regular physical exercise can slow cognitive decline in AD by improving insulin sensitivity through multiple pathways, many patients experience progressive physical decline. This reduces adherence to exercise programs and limits their long-term effectiveness. Exercise mimetics have therefore attracted attention. These bioactive agents can reproduce or enhance selected health benefits of exercise by targeting exercise-related molecular signaling pathways, without requiring direct physical exertion. This review summarizes the mechanisms by which exercise mimetics improve AD pathology through the regulation of IR. It also provides a theoretical basis for the development of targeted exercise mimetics.},
}

@article {pmid42925933,
year = {2026},
author = {Wang, T and Ji, Y and Liu, S and Wu, H and Gu, L and Guo, M and Wang, P and Xu, G},
title = {Multimodal evidence associated with 20Hz rTMS in AD: neuroaxonal injury reduction, neural oscillatory rebalancing, and multilayer network integration.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116536},
doi = {10.1016/j.bbr.2026.116536},
pmid = {42925933},
issn = {1872-7549},
abstract = {High-frequency repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to enhance cognitive function in patients with Alzheimer's disease (AD), but the neurobiological mechanisms associated with neuroaxonal injury, neural oscillatory dynamics, and large-scale network reorganization remain unclear. In this study, we first conducted a randomized, sham-controlled trial with 16 patients with AD to evaluate the efficacy of DLPFC-targeted rTMS, followed by a single-arm multimodal cohort study of 30 patients to explore potential neurobiological mechanisms through cognitive assessments, blood biomarkers, EEG oscillatory activity, and multiplex brain network analysis. In Stage 1, the sham group showed no significant pre-post changes in MMSE or MoCA scores (MMSE: Z = -0.738, Cohen's r = 0.26; MoCA: Z =-0.853, Cohen's r = 0.30). The active rTMS group showed improvements in MMSE (Z = -2.124, Cohen's r = 0.75) and MoCA (Z = -2.108, Cohen's r = 0.75). In stage 2, rTMS was associated with improvements in MMSE (Z = -2.863, Cohen's r = 0.523) and MoCA (t = -6.137, Cohen's r = 0.752) scores. Biomarker analyses indicated a significant decrease in NfL concentrations (Z=-2.371, Cohen's r=0.484). EEG recordings revealed a decrease in delta power in the left temporal lobe (t=2.158, Cohen's r=0.372) and increases in beta power in the right parietal lobe and gamma power in the temporal lobe (beta: Z=-2.088, Cohen's r=0.381; gamma: Z=-2.129, Cohen's r=0.389). Network analysis showed reduced modularity and enhanced global efficiency across theta, alpha, and beta bands, accompanied by increased degree of overlap in frontal, parietal, and occipital regions. Importantly, MoCA improvement correlated with gamma-band global efficiency (R=0.389, P=0.034) and multilayer clustering coefficients in the left frontal and right occipital regions (R=0.478, P=0.008; R=0.398, P=0.029). Overall, rTMS exposure was associated with cognitive improvements in patients with AD, together with changes in neurodegeneration-related biomarkers and EEG network organization. These findings suggest that cognitive changes following rTMS may be associated with oscillatory modulation and large-scale network remodeling. TRIAL REGISTRATION: Registration number: ChiCTR2500095949; Registration Date: 2025-01-15.},
}

@article {pmid42926064,
year = {2026},
author = {Marick, A and Hemachandra Reddy, P and Manna, PR},
title = {Restoration of StAR-governed neurosteroids with all-trans retinoic acid in alleviating cognitive deficits in a humanized amyloid-β knock-in mouse model of late-onset Alzheimer's disease: New insights into therapeutics.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106280},
doi = {10.1016/j.neuint.2026.106280},
pmid = {42926064},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder of the elderly characterized by cognitive decline that involves diverse pathological processes. Aging, modulating neuronal instability, is the primary risk factor AD, resulting in dementia, for which a crucial neuropathological feature is the accumulation of amyloid-β (Aβ) plaques wherein suppression of neurosteroids plays important roles. Neurosteroidogenesis gradually decreases during aging, and the regulation of neurosteroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. We demonstrate that treatment with all-trans retinoic acid (atRA, 20 mg/kg, 12-weeks) in humanized Aβ knock-in (hAbKI) mice (11-month old) resulted in increases in hippocampal StAR and sex neurosteroid (estradiol-17β/(E2) in females and testosterone in males) levels, when compared with controls. Elevated StAR and sex neurosteroid levels were associated with reductions in not only Aβ accumulation but also toxic soluble Aβ1-40 and Aβ1-42 peptides in both sexes, emphasizing an inverse correlation between neurosteroidogenesis and AD pathogenesis. Notably, atRA was capable of ameliorating cognitive impairments in both female and male hAbKI mice, as evaluated by Morris Water Maze analyses. These findings provide insights into the mechanistic events by which atRA restores neurosteroid instability, reduces neurotoxicity, and alleviates cognitive impairments in sex-specific hAbKI mice, demonstrating that retinoid therapy could serve as a novel target for the management of AD-related dementia for healthy aging.},
}

@article {pmid42926367,
year = {2026},
author = {Kowash, Z and Lim, J and Annalora, AJ and Wang, H and Cui, JY},
title = {Triple-Omics Analysis Unveiled the Neuroprotective Mechanisms of Akkermansia muciniphila in an Environmental Exposure-Linked Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755812},
pmid = {42926367},
issn = {2692-8205},
abstract = {UNLABELLED: Cadmium (Cd) is an emerging environmental risk factor for cognitive decline and Alzheimer's disease, and few interventions limit its effects on the brain. Akkermansia muciniphila , a human gut commensal, is neuroprotective through mechanisms that remain unclear. Building on our finding that A. muciniphila prevented Cd-induced memory deficits without reducing brain Cd burden (Wang et al., 2026a), we tested whether it reprograms Cd-disrupted hippocampal RNA regulation. Male C57BL/6J mice received A. muciniphila (1×10[9] CFU, oral gavage, 5 days/week) before and throughout 9 weeks of 3 mg/L CdCl2 exposure; hippocampi were analyzed by RNA-seq, m[6]A epitranscriptomic profiling, and rMATS-based alternative-splicing analysis. Cd disrupted hippocampal neuropeptide signaling, neuronal excitability, and synaptic plasticity. Co-exposure with A. muciniphila reversed signatures enriched for Nrf2-centered cytoprotective signaling and opposed m[6]A and splicing changes across more than a thousand genes, largely without changes in total mRNA abundance. Restored events converged on machinery governing local translation, calcium-dependent plasticity, and synaptic transmission. Projected onto predicted protein structures, most introduced a premature termination codon predicted to trigger nonsense-mediated decay or edited short loop and linker segments rather than rebuilding folded domains, regulation largely invisible to gene-level expression analysis. Among these, paired events amplifying semaphorin-plexin signaling, an axis linked to oligodendrocyte injury and memory consolidation, were reversed. These findings identify restoration of hippocampal transcript fate and splice-isoform selection as a mechanism potentially underlying A. muciniphila -mediated protection against Cd neurotoxicity, and establish post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity.

IMPACT STATEMENT: Cadmium is a widespread environmental contaminant associated with cognitive decline and Alzheimer's disease, and few interventions are available to limit its effects on the brain. This study shows that supplementation with the gut commensal Akkermansia muciniphila reverses Cd-induced changes in hippocampal m⁶A methylation and splice-isoform selection, largely without altering total transcript abundance. These results identify post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity, and show that conventional gene-expression analysis alone would miss most of the protective response.},
}

@article {pmid42926376,
year = {2026},
author = {Hillman, N and Chen, AA and Hu, F and Vandekar, SN and Melhem, R and Beason-Held, LL and Satterthwaite, TD and Davatzikos, C and Shou, H and Shinohara, RT and , },
title = {Imputation-Based Harmonization Mitigates Site Effects Without Data Leakage in Machine Learning Studies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.755204},
pmid = {42926376},
issn = {2692-8205},
abstract = {Neuroimaging studies that pool data across clinical sites often suffer from site effects - variability in imaging measures that arises from technical heterogeneity across sites as opposed to true biological signal. While numerous harmonization methods have been proposed to remove site effects from imaging features, less attention has been placed on how to incorporate harmonization models into common machine-learning pipelines. We demonstrate that current approaches for integration either suffer from data leakage, fail to fully remove site effects from the target data, or attenuate true biological associations during the harmonization process. To address these issues, we propose Multiple Imputation for Removing Technical Heterogeneity (MIRTH), which uses imputed outcomes to harmonize the test data. We benchmark MIRTH's performance using both simulated and real-world volumetric data from the Alzheimer's Disease Neuroimaging Initiative and the Baltimore Longitudinal Study of Aging, demonstrating that MIRTH can achieve high predictive accuracy while avoiding inflated performance when the outcome is imbalanced across clinical sites.},
}

@article {pmid42926382,
year = {2026},
author = {Moallem, EZ and Bruntz, RC and Cox, MF and Bytyqi, L and Roberts, TK and Patel, SP and Macheda, T and Roberts, KN and Higgins, EK and Sun, RC and Gentry, MS and Sullivan, PG and Johnson, LA and Bachstetter, AD},
title = {Closed-head injury produces a delayed, region-specific defect in glucose-carbon routing at the pyruvate branchpoint in APP/PS1 KI mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.29.755475},
pmid = {42926382},
issn = {2692-8205},
abstract = {Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), and both conditions are associated with impaired glucose metabolism and mitochondrial dysfunction. We previously reported time-dependent mitochondrial dysfunction following closed-head injury (CHI) in amyloid precursor protein/presenilin 1 (APP/PS1) knock-in (KI) mice, but whether glucose-derived carbon labeling showed a corresponding temporal pattern remained unknown. We hypothesized that early deficits would involve tricarboxylic acid (TCA)-cycle metabolites, whereas chronic changes persisted upstream at the pyruvate-lactate branchpoint. Here, oral uniformly [13] C-labeled glucose ([U- [13] C]-glucose) tracing and gas chromatography-mass spectrometry (GC-MS)-based isotopologue analysis were used to quantify first-turn glucose-derived carbon fate in cortex and hippocampus. To distinguish the effects of age at injury from those of post-injury interval, mice were analyzed 1 month after injury either at 7 or 12 months of age or 8 months after injury at 12 months of age. The most pronounced alterations occurred 8 months after CHI, when KI mice exhibited increased pyruvate and lactate labeling in the cortex and broader increases in glycolytic labeling in the hippocampus. These findings suggest that in APP/PS1 KI mice, chronic closed-head injury produced a delayed shift in glucose-derived carbon labeling centered on glycolytic and pyruvate/lactate nodes, with loss of hippocampal precursor-product coupling but without broad reduction of first-turn TCA-linked labeling.},
}

@article {pmid42926390,
year = {2026},
author = {Deng, Q and Chen, C and Zikopoulos, B and Yazdanbakhsh, A},
title = {Biophysical modeling of excitation/inhibition imbalance in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755800},
pmid = {42926390},
issn = {2692-8205},
abstract = {INTRODUCTION: Alzheimer's disease (AD) involves early sensory and perceptual changes that can precede memory decline. We developed a two-layer rate-based neural model of early and higher visual areas with feedforward, feedback, and recurrent connections to examine how excitatory/inhibitory (E/I) balance shapes visual motion perception in AD.

METHODS: Using Motion-Induced Position Shift and Altered Motion Repulsion stimuli, we factorially manipulated excitatory (E) and inhibitory (I) subfield power and connectivity to examine their effects on illusion representation across visual layers.

RESULTS: Increased E, decreased I, and increased E/I reduced illusion representation, consistent with reduced illusion susceptibility in AD, whereas the converse increased illusion representation, reflecting neurotypical processing. Higher-level layer 2 representations were more resistant to E/I perturbations than lower-level layer 1. Illusion representation was less affected by E/I increases in intra-areal (recurrent) connectivity than in inter-areal (feedforward/feedback) connectivity.

DISCUSSION: This mechanistic framework links E/I balance and connectivity to altered visual motion illusion representations in AD and suggests that E/I and connectivity measures may provide probes of early AD neurobiology. The framework may also generalize beyond vision.},
}

@article {pmid42926395,
year = {2026},
author = {Huang, M and Lövestam, S and Cheam, KAX and Ghetti, B and McEwan, WA and Scheres, SHW and Goedert, M},
title = {Templated paired helical filament formation and tau fold-dependent inclusion morphologies in primary neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755038},
pmid = {42926395},
issn = {2692-8205},
abstract = {UNLABELLED: Neurodegenerative tauopathies are characterized by the abnormal assembly of tau into amyloid filaments with distinct, disease-specific folds. These filaments are proposed to spread in a prion-like manner, thus underlying the progression of pathology in diseased brains. A prediction of this hypothesis is that tau filaments will induce progeny filaments identical to the input seed material, yet cellular models of templated tau assembly have failed to fully recapitulate brain-derived filament structures. Here, we show that mixed primary mouse cortical neurons overexpressing full-length human tau via adeno-associated virus transduction propagate Alzheimer's disease paired helical filaments upon exposure to human brain-derived seeds. Using minimal tags and core mutations, we were able to unambiguously differentiate induced aggregates from the original seeds. Super-resolution microscopy and live-cell imaging revealed progressive inclusion formation in neurons. Moreover, seeding primary neurons with brain extracts from individuals with Pick's disease, corticobasal degeneration and progressive supranuclear palsy induced the formation of morphologically distinct inclusions. Together, these findings establish that primary neurons provide an environment for the faithful propagation of paired helical filaments and show that tau filament folds dictate higher-order inclusion morphologies within neurons.

SIGNIFICANCE STATEMENT: Neurodegenerative tauopathies are characterized by the assembly of tau protein into disease-specific amyloid folds. While prion-like propagation is hypothesized to drive disease progression, cell models have previously failed to fully replicate human-brain derived filament structures. Here we show that primary mouse neurons support the templated propagation of human Alzheimer's disease paired helical filaments. By incorporating a disease-causing mutation (V337M) into the amyloid core, we unambiguously resolved cryo-EM structures of the induced assemblies. Moreover, by using super-resolution light microscopy, we show that seeds from tauopathies induced the formation of morphologically distinct intraneuronal inclusions. These findings describe a system for dissecting the cellular factors that govern tau fold propagation and for understanding how distinct filament structures dictate phenotypic differences across tauopathies.},
}

@article {pmid42926415,
year = {2026},
author = {Farina, R and Wang, Y and Gabitto, MI and Agrawal, A and Mena, GE},
title = {Multi-Trajectory Pseudotime Inference via Permutation Factorizations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.27.728207},
pmid = {42926415},
issn = {2692-8205},
abstract = {Inferring disease progression from cross-sectional data typically relies on placing individuals along a single latent pseudotemporal axis. However, diseases often exhibit different biomarkers that evolve with different dynamics, making a single shared trajectory insufficient and often leading to biased or inconsistent orderings. We propose a probabilistic framework that maintains a shared global ordering of individuals while allowing clusters of features to follow distinct monotone trajectories along this ordering. Rather than assigning individuals to separate progressions, our approach captures heterogeneity through cluster-specific temporal responses defined with respect to a common latent sequence of individuals. Our key observation is that monotone transformations of a common progression preserve the ordering of individuals, so multiple pseudotimes factorize into a single latent permutation over individuals and cluster-specific monotonic functions, enabling flexible yet comparable representations of biomarker dynamics. We jointly infer donor ordering, biomarker clusters, and trajectories within a unified Bayesian framework, using stochastic variational inference over permutations. Across two major neuropathological datasets in Alzheimer's disease, our method recovers biologically meaningful feature clusters and improves overall alignment with established staging measures compared to single-trajectory baselines. These results show that modeling heterogeneous dynamics relative to a shared progression yields more accurate and interpretable reconstructions of disease progression from cross-sectional data.},
}

@article {pmid42926432,
year = {2026},
author = {Liu, H and Tong, M and Fang, S and Mormino, EC and Sperling, RA and Aisen, P and Buckley, RF and Crane, PK and Hohman, TJ and Saykin, AJ and Yan, J and , },
title = {Continuous amyloid staging complements global amyloid burden in early Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.03.756367},
pmid = {42926432},
issn = {2692-8205},
abstract = {INTRODUCTION: Early Alzheimer's disease (AD) staging remains challenging because clinical categories and global amyloid PET measures provide only coarse characterization of disease progression. We developed a continuous amyloid staging score from regional amyloid PET to complement global amyloid burden.

METHODS: Using longitudinal florbetapir PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we trained an end-to-end deep learning model to directly estimate a continuous amyloid staging score. We evaluated longitudinal consistency, its relationship with global amyloid burden, regional contributors to early-stage variation, and whether the staging score stratified subsequent memory decline among participants matched for baseline global amyloid burden. Cognitive analyses were replicated in A4+LEARN.

RESULTS: The staging score better preserved longitudinal visit order than existing amyloid staging approaches. During early disease stages, it captured regional amyloid variation despite relatively stable global amyloid burden. Among participants with similar baseline global amyloid burden, higher staging scores were associated with faster subsequent memory decline in both ADNI and A4+LEARN.

DISCUSSION: A continuous amyloid staging score complements global amyloid burden for early AD staging and cognitive risk stratification.},
}

@article {pmid42926465,
year = {2026},
author = {Ji, C and Zhu, Y and Erdjument-Bromage, H and Song, SC and Chang, N and Liu, AR and Lee, AR and DeGulis, O and Schoppik, D and Neubert, TA and Ryoo, HD and Sigurdsson, EM},
title = {Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.756807},
pmid = {42926465},
issn = {2692-8205},
abstract = {UNLABELLED: Pathological tau disrupts neuronal activity and brain function in Alzheimer's disease and other tauopathies. However, the underlying mechanisms for neuronal network dysfunction remain largely unknown. Using human inducible pluripotent stem cell (iPSC) - derived neurons, we show that the familial MAPT P301L mutation leads to neuronal network hyperexcitability. Imbalanced excitation and inhibition were attributable to neuronal subtype-specific tau pathology that was associated with different alterations of tau interactomes in excitatory versus inhibitory neurons. Suppressing enhanced excitatory synaptic transmission or blocking Ca [2+] influx resulting from enhanced P301L tau/AHNAK interaction in inhibitory neurons rescued the neuronal network hyperexcitability. This study expands our understanding on how disease-causing tau mutations alter the excitatory/inhibitory balance, leading to network dysfunction in human neurons.

HIGHLIGHTS: The FTD-causing P301L tau mutation leads to neuronal network hyperexcitability.P301L tau causes hyperactivity of excitatory neurons while hypoactivity of inhibitory neurons.Tau and P301L tau interactomes differ in excitatory vs. inhibitory neurons.Enhanced excitatory synaptic transmission and P301L tau/AHNAK interaction in inhibitory neurons contribute to neuronal network hyperexcitability.},
}

@article {pmid42926485,
year = {2026},
author = {Suh, Y and Wang, H and Li, L and Gu, H and Johnson-Martinez, J and Magis, AT and Gibbons, SM and Cui, JY},
title = {The microbial soy metabolite S-equol mitigates cadmium neurotoxicity in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.01.756095},
pmid = {42926485},
issn = {2692-8205},
abstract = {Environmental exposures are major but understudied determinants of chronic disease. Cadmium is a pervasive toxic metal encountered through diet and tobacco smoke that has been associated with cognitive impairment and Alzheimer's disease mortality, yet strategies to mitigate its neurotoxicity remain limited. S-equol is a gut microbial metabolite of soy daidzein that crosses the blood brain barrier and preferentially activates estrogen receptor beta. Here, we show that cadmium disrupts an axis linking the equol producing gut bacterium Adlercreutzia equolifaciens to circulating S-equol and hippocampal estrogen receptor expression in mice, that S-equol attenuates cadmium-induced cytotoxicity and restores neuronal, glutamatergic and synaptic transcriptional programs in mouse neural progenitor cells, and that circulating S-equol in older humans is lower in apolipoprotein E4 carriers and covaries with body mass index, identifying S-equol as a microbiome-derived, host-modulated candidate countermeasure against cadmium neurotoxicity.},
}

@article {pmid42926510,
year = {2026},
author = {Huang, LY and Zeng, V and Raymond, N and Stiltner, B and Molho, W and Cao, Y and Bannai, D and Ying, D and Oss, E and Dhunna, DP and Patel, P and Adesokan, A and Hricay, M and Lyons, V and Tolentino, N and Keshavan, MS and Fried, P and Jammoul, M and Kuegler, D and Estrada, S and Reuter, M and Lizano, P},
title = {A large, comprehensive labeled MRI dataset of the human lateral ventricle choroid plexus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757728},
pmid = {42926510},
issn = {2692-8205},
abstract = {The choroid plexus (ChP) is a highly vascularized structure located in the brain ventricles that plays important roles in multiple central nervous system functions. ChP enlargement has been implicated in many neuropsychiatric conditions such as multiple sclerosis, depression, schizophrenia, and Alzheimer's disease. However, limitation in the accuracy of the current segmentation tools highlight the need for more reliable methods to quantify ChP volume in healthy and clinical human populations. The shape and size of the ChP vary drastically from person to person, and currently there are no large ChP datasets which allow comprehensive training of segmentation models. Here we introduce DataPlex, a collection of 700 structural MRI brain images where the lateral ventricle ChP has been manually labeled and checked by expert human raters. DataPlex is balanced and representative across a wide range of scanning parameters, demographics, and clinical profiles, and subject-level information will be available for each labeled image. DataPlex will be open source to support the creation of reliable segmentation tools for the human lateral ventricle ChP.},
}

@article {pmid42926600,
year = {2026},
author = {Landon, B and Abraham Daniel, A and Fischer, T and Phillips, NR and Barber, RC and Reynolds, AW and , },
title = {A Multiethnic Analysis of DNA Methylation Reveals Links Between Alzheimer's Disease and Metabolic Comorbidities.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364777},
pmid = {42926600},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading contributor to dementia burden, and the risk of developing it is impacted by a multitude of factors. Among these factors are metabolic conditions like type-2 diabetes (T2D) and metabolic syndrome (MetS), along with ethnicity, which interacts both with AD and the metabolic comorbidities. Previous studies have established associations between methylation patterns at specific CpG sites and risk for AD, T2D and MetS individually, but the underlying etiology that is responsible for interactions between metabolic conditions and AD risk remains unresolved.

OBJECTIVE: We aimed to examine methylation patterns among Mexican American (MA) and Non-Hispanic White (NHW) individuals in the context of AD, alongside T2D and MetS, to identify CpG sites associated with disease-specific and interaction-dependent methylation effects related to those comorbidities.

METHODS: DNA methylation data from 551 patients of MA or NHW ancestry who were enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC) were available for analysis. Participants were stratified into groups by AD/T2D status or AD/MetS score and Beta-values from the Illumina MethylationEPIC chip array were obtained for each patient. Differential methylation status was analyzed using the lumi and cate packages in R.

RESULTS: Five CpG sites had statistically significant differential methylation patterns, including two (cg06322660 and cg25514677) which exhibited significant interactions between AD and T2D status or AD and MetS score respectively, with cg06322660 being significant in the NHW cohort and cg25514677 being significant in the MA cohort. The association at cg25514677 was replicated in an independent MA cohort.

CONCLUSIONS: The two sites associated with interactions between AD and a metabolic condition could explain the influence that those conditions have on the risk for AD and are prime candidates for future study.},
}

@article {pmid42926604,
year = {2026},
author = {Chen, Y and Boon, BDC and Engelberg-Cook, E and Zhu, L and Rothberg, D and Rozemuller, A and Grinberg, LT and Ushizima, D},
title = {Generalizing Amyloid β Pathology from Postmortem Human Brains with Vision Foundation Models for Lesion Quantification.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364184},
pmid = {42926604},
abstract = {BACKGROUND: Traditional neuropathological assessment of Alzheimer's disease (AD) relies on manual, semi-quantitative scoring of amyloid-beta (Aβ) burden. This approach is limited by high inter-rater variability and often qualitative, failing to capture subtle, continuous pathology changes. While 11C-PiB PET neuroimaging provides non-invasive longitudinal monitoring, it has a limited dynamic range and lacks the sub-millimeter spatial resolution necessary to track localized microvascular and parenchymal Aβ trajectories.

METHODS: We introduce ViTamyloid, a generalizable modular computational pathology pipeline for high-throughput Aβ segmentation and classification in postmortem tissue. In Stage 1, a pathologist-supervised hybrid framework combining an EfficientNet-B4 encoder with a Residual U-Net decoder, complement with a localization-aware Faster R-CNN detector, to generate binary segmentation masks and isolated lesion candidates. In Stage 2, classification model powered by a frozen, high-resolution UNI2-h computational pathology foundation backbone and a ViT-Adapter, classifies candidates into a fine-grained four-class taxonomy: classic cored plaques (CCP), coarse-grained plaques (CGP), capillary cerebral amyloid angiopathy (CAA Type 1), and parenchymal/leptomeningeal CAA (CAA Type 2). We bench-marked out-of-distribution (OOD) robustness on external datasets from different brain banks, and validated clinical scalability across 1,646 whole-slide images from three brain banks.

RESULTS: The ViTamyloid classifier achieved strong feature-separation metrics, yielding area under the receiver operating characteristic curve (AUROC) and precision-recall curve (AUPRC) values of 0.994/0.958 for CCP, 0.989/0.945 for CGP, 0.992/0.977 for CAA Type 1, and 0.997/0.978 for CAA Type 2. More importantly, ViTamyloid consistently outperforms other pipelines' models and frozen features in all external datasets with different antibodies, and scanner settings, and image quality.

CONCLUSION: By replacing empirical, from-scratch architectures with a generalizable foundation model adapter framework, ViTamyloid provides a highly sensitive scalable digital pathomics toolkit. This pipeline expose continuous microscopic neuropathological dynamics beyond the spatial and sensitivity plateaus of in vivo neuroimaging, offering objective, quantitative endpoints for Alzheimer's disease clinical trials and disease subtyping.},
}

@article {pmid42926614,
year = {2026},
author = {Sharma, RU and Tolosa-Tort, P and Okorie, M and Chatterjee, A and Jonson, C and Yaffe, K and Belloy, ME and Andrews, SJ and , },
title = {Sex differences in genetic liability to modifiable Alzheimer's disease risk factors.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.01.26364536},
pmid = {42926614},
abstract = {INTRODUCTION: Alzheimer's disease (AD) shows sex differences in risk, clinical progression, and biomarker profiles, but whether inherited genetic liability to modifiable risk factors contributes differently to AD susceptibility in females and males remains unclear. We evaluated whether genetic relationships between several modifiable dementia risk factors and AD differ between females and males.

METHODS: We integrated polygenic risk scores (PRSs) for modifiable risk factors, genome-wide genetic correlation, and two-sample Mendelian randomization (MR) analyses. PRS associations with AD diagnosis were evaluated in the Alzheimer's Disease Genetics Consortium (n=27,751) and with AD plasma biomarkers in the Health and Aging Brain Study-Health Disparities (n=2,307-2,737, depending on the biomarker). Primary analyses evaluated female- and male-specific associations and compared sex-specific estimates.

RESULTS: Educational attainment and physical activity PRSs were associated with AD in both sexes. PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction. Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males. Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction. In HABS-HD, type 2 diabetes PRS was associated with higher NfL, BMI PRS with higher pTau 181 , and the composite PRS with higher NfL among males after FDR correction.

DISCUSSION: Evidence that modifiable dementia risk factors relate differently to AD by sex was limited and depended on the genetic measure examined. Sex differences in genome-wide genetic overlap were not consistently reflected in PRS or MR, indicating that shared genetic architecture does not necessarily translate into sex-specific inherited liability or causal effects.

RESEARCH IN CONTEXT: Systematic review: We reviewed the published literature on modifiable dementia risk factors, Alzheimer's disease (AD) genetics, and sex differences using PubMed and relevant reference lists. Previous studies support genetic relationships between several modifiable risk factors and AD, but systematic comparisons of female- and male-specific relationships across complementary genetic approaches remain limited.Interpretatio: The strongest evidence of sex heterogeneity for modifiable risk factors and AD was observed in their shared genetic architectures, with FDR-significant female-male differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. PRS and Mendelian randomization analyses provided less evidence of formal sex heterogeneity, suggesting that sex differences in shared genetic architecture do not necessarily imply sex-specific causal effects.Future directions: Larger sex-stratified and ancestry-diverse GWAS integrated with longitudinal exposure and biomarker data are needed to determine whether these signals reflect sex-dependent biological mechanisms and whether they have implications for dementia prevention.Highlights: - Sex differences in AD-related genetic architecture were concentrated in behavioral, lipid, and vascular traits.- Genetic correlations with AD differed between females and males for social isolation, physical activity, LDL cholesterol, and pulse pressure.- PRS analyses implicated educational attainment and physical activity in AD in both sexes, but no PRS sex difference survived FDR correction.- MR identified associations within sex strata but provided little robust evidence of sex-specific causal effects.},
}

@article {pmid42926616,
year = {2026},
author = {Dai, Q and Murphy, M and Lyu, J and Tang, S and Hu, J and Tasaki, S and Wang, Y and Bennett, DA and Menon, V and De Jager, PL and Buchman, AS and Epstein, MP and Yang, J},
title = {Cell-Cell Communication Patterns in Alzheimer's Disease Differ by Cortical Layer.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364776},
pmid = {42926616},
abstract = {INTRODUCTION: Existing cell-cell communication (CCC) studies of Alzheimer's disease dementia (ADD) using cortical snRNAseq data do not account for the distinct cell-type and gene-expression profiles within cortical layers. Cortical-layer-aware CCC analysis may clarify biological mechanisms associated with ADD and mild cognitive impairment (MCI).

METHODS: We applied our recent analytical tool STACCato to identify CCC events associated with ADD and MCI within cortical layers, using a large-scale prefrontal cortex snRNAseq dataset (∼1.4M nuclei, n=395) with cortical layers annotated from reference spatial transcriptomics data.

RESULTS: We identified ADD/MCI-related CCC events with distinct patterns within cortical layers, including ADD-related interactions involving the known AD risk genes APOE and APP that were detected only in microglia in layer 5, and those with opposite effects of ADD and MCI in layers 5 and 6.

DISCUSSION: Our findings on cortical-layer-aware ADD/MCI-related CCC events underscore the importance of spatially-aware genomics studies of AD.},
}

@article {pmid42926649,
year = {2026},
author = {Matthey, N and Palani, RS and Liu, J and Bahri, S and Silvers, R and Michael, B and Gershenfeld, N and Linse, S and Griffin, RG},
title = {1H, 13C, and 15N chemical shift assignments of monomorphic Aβ1-40 at 100 kHz MAS in a diamond rotor.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11089530/v1},
pmid = {42926649},
issn = {2693-5015},
abstract = {Amyloid-β (Aβ) fibrils are the principal component of the senile plaques that characterize Alzheimer's disease, and fibrils formed from the Aβ 1-40 alloform are strongly polymorphic, which has long complicated their structural characterization. We recently reported a reproducible, unseeded, monomorphic Aβ 1-40 fibril grown at neutral pH from supersaturated monomer, together with its atomic-resolution structure and its [13] C and [15] N chemical shift assignments (PDB 12GB; BMRB 31300). Here we extend that reference to [1] H. From a 3D [1] H-detected hCCH (RFDR) experiment and a 2D hNH experiment recorded at 18.8 T and ω r /2π = 100 kHz on approximately 0.5 mg of hydrated fibrils packed in a home-built 0.7 mm single-crystal diamond rotor, we assign 123 [1] H resonances, corresponding close to 90% of the distinct [1] H sites of the rigid core (residues Q15→V40), together with sixteen [1] H of the dynamic N-terminal segment. The [1] H-detected data additionally yield six previously unassigned [13] C and three previously unassigned [15] N resonances, predominantly in aromatic side chains and in the mobile N-terminus, and nine [1] H- [13] C and twenty [1] H- [15] N inter-residue contacts that are consistent with the published structure. These assignments provide a residue-level reference for fingerprinting Aβ 1-40 polymorphs and for mapping the binding of antibodies, chaperones and small molecules to this fibril.},
}

@article {pmid42926663,
year = {2026},
author = {Kotredes, KP and Pandey, RS and Reagan, AM and Sarica, Z and O'Rourke, R and Herrick, S and Davis, A and Garceau, D and Sasner, M and Carter, GW and Howell, GR},
title = {MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11166891/v1},
pmid = {42926663},
issn = {2693-5015},
abstract = {Background Late-onset Alzheimer's disease (LOAD) comprises more than 95% of all AD cases. Transgenic, overexpression animal models have off-target side effects, do not effectively produce the heterogeneity observed clinically in LOAD patients, and are therefore not best suited for preclinical therapeutic development. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) Consortium was established to develop novel mouse strains to model human-relevant genetic and environmental risk factors for LOAD. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in the MTHFR gene, notably 677C > T , are associated with ADRD, and we have previously shown the Mthfr [677C>T] mouse model phenocopies humans carrying the variant and develops cerebrovascular deficits. Methods To examine the contributions of Mthfr [677C>T] in the context of late-onset Alzheimer's disease (LOAD), MODEL-AD created a novel mouse strain on the C57BL/6J (B6) background that was homozygous for Mthfr [677C>T] , in combination with humanized Aβ , APOEe4 , and Trem2*R47H (referred to as LOAD2.Mthfr [677C>T]) . Mice were assessed over multiple ages for disease-relevant phenotypes. Regular behavior measurements and biometric samples were collected longitudinally to 24 months of age. Blood and brain tissue were collected for transcriptomics, proteomics, human disease correlation, and neuropathology. Results Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr [677C>T] mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients. Conclusions These data further support the use of the LOAD2.Mthfr [677C>T] mouse model to study aspects of ADRD such as cerebrovascular compromise.},
}

@article {pmid42926671,
year = {2026},
author = {Rutherford, S and Zahid, Z and Welsh, RC and Avena-Koenigsberger, A and Hammers, DB and Koppelmans, V and Mejia, AF and Initiative, ADN},
title = {A Pipeline for ADNI Resting-State Functional MRI Processing and Quality Control.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11132707/v1},
pmid = {42926671},
issn = {2693-5015},
abstract = {The Alzheimer's Disease Neuroimaging Initiative (ADNI) provides a comprehensive multimodal neuroimaging resource for studying aging and Alzheimer's disease (AD). However, its resting-state functional MRI (rs-fMRI) data remain underutilized, in part due to challenges with data processing driven by considerable variability in acquisition protocols, inconsistent organization, missing or incomplete imaging sessions, and frequency of data quality issues due to participant motion and aging-related factors. To facilitate widespread use of ADNI rs-fMRI data, we developed an open-source pipeline encompassing the download and organization of imaging and clinical data, conversion to Brain Imaging Data Structure (BIDS), preprocessing with fMRIPrep, and automated quality control (QC). Our QC considers acquisition parameters and 16 structural and functional MRIQC image-quality metrics, flagging scans that fall outside acceptable ranges based on expert input and robust outlier detection techniques. Processed imaging sessions are matched to temporally aligned clinical assessments to produce an analysis-ready dataset. Applying the pipeline to more than 2,800 sessions from ADNI GO, ADNI 2, and ADNI 3 yielded 2,086 quality-checked functional and structural MRI sessions from 935 unique participants. Exclusions occurred at every processing stage and were driven primarily by BIDS conversion errors, image quality flags, and preprocessing- or motion-related failures. The open-source pipeline described in this work produces one of the largest pre-processed, quality controlled, and analysis-ready functional and structural MRI datasets yet available for studying aging and AD. It lowers barriers to large-cohort and longitudinal neuroimaging research and supports large-scale neuroimaging biomarker discovery in AD.},
}

@article {pmid42926678,
year = {2026},
author = {Elia, A and Vazquez-Torres, R and Carey, A and Wolf, M and Gade, VR and Alves, M and Fossati, S},
title = {Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757731},
pmid = {42926678},
issn = {2692-8205},
abstract = {FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid-β (Aβ) pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrase (CAs) as a promising, previously untapped therapeutic target for AD and vascular contribution to dementia. We have recently shown that Aβ aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects. In this study, we present the first in-depth examination of CAI therapy (acetazolamide-ATZ) in Tg2576 mice, a well-established model of AD and CAA. We confirm that progressive cardiac fibrosis and Aβ deposition in 13-month-old mice severely impair the cardiac neuro-signaling system, marked by a drastic decrease in BDNF and reductions in adrenergic fibers and regenerating nerve endings (TH and GAP-43 markers), leading to significant declines in ejection fraction and fractional shortening compared to age-matched WT littermates. Critically, this study demonstrates that long-term ATZ treatment in Tg2576 mice significantly reduces cardiac Aβ burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography. These in vivo findings were corroborated in human cardiomyocytes, in which CA inhibition reduced human Aβ40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing Aβ-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576-AD model. Given the established benefits of CAIs on cerebrovascular function and cognition, our findings further support advancing repurposing efforts into clinical trials. CAIs such as ATZ could offer a dual-action therapy approach, addressing both the central nervous system and cardiac pathologies associated with AD and, potentially, the systemic effects of amyloidosis.},
}

@article {pmid42926699,
year = {2026},
author = {Shi, R and Choity, LT and Farinas, MF and Zeng, X and Emanuel, JE and Saeed, A and Reis, SE and Lopez, OL and Kamboh, IM and Cohen, AD and Gildengers, AG and Wilckens, KA and Karikari, TK},
title = {Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.26364972},
pmid = {42926699},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder strongly influenced by genetic factors, with apolipoprotein E (APOE) ε4 allele being the most established risk variant. Although DNA-based genotyping remains standard, plasma proteotyping may provide scalable, isoform-specific alternatives. Here, we aimed to investigate the clinical utility of APOE proteotyping as a surrogate for genotyping in different clinical and research cohorts.

METHODS: Plasma APOE4 protein were quantified using the NULISAseq CNS panel across four cohorts (ADRC, HeartSCORE, LATTICE, and ALPS). DNA-based APOE genotyping was the reference standard. Proteotyping thresholds for APOE ε4 carrier status and copy number were derived in ADRC and externally validated in the other cohorts. Logistic, proportional-odds, and Cox proportional-hazards models compared genotype- and proteotype-defined groups in relation to amyloid positivity, cross-sectional CDR global scores, and time to CDR-SB worsening, respectively.

RESULTS: Plasma APOE4 accurately classified APOE ε4 carrier status in ADRC (AUC=0.977, 95%CI 0.967-0.985; threshold 5.78 NULISA protein quantification [NPQ] value) and achieved near-perfect external validation in HeartSCORE, LATTICE, and ALPS (all AUCs=1.000, 95%CI 1.000-1.000). Plasma APOE4 also well-differentiated heterozygous from homozygous ε4 carriers (ADRC AUC=0.879, 95%CI 0.834-0.921; threshold 12.23 NPQ value). Genotype- and proteotype-defined ε4 carrier status showed similar associations with amyloid positivity (OR=4.40 vs 4.45), higher CDR global scores (OR=1.50 for both), and CDR-SB worsening (HR=1.22 for both).

DISCUSSION: Plasma APOE4 proteotyping accurately distinguished genotype-defined APOE ε4 carrier status and copy number while demonstrating AD-related associations comparable to DNA genotyping.},
}

@article {pmid42926738,
year = {2026},
author = {Dashnaw, CM and Rastogi, S and Morgan, N and Memon, I and Jaczynska, K and Nguyen, BA and Saelices, L and White, CL and Shahmoradian, S and Joachimiak, LA},
title = {Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757173},
pmid = {42926738},
issn = {2692-8205},
abstract = {Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.},
}

@article {pmid42926775,
year = {2026},
author = {Tan, G and Demarest, P and Kardashina, T and Adams, J and Willie, JT and Roland, J and Gorlewicz, JL and Brunner, P and Leuthardt, EC},
title = {Vibrotactile transcutaneous auricular vagus nerve stimulation (taVNS) during working memory: convergent electrophysiological evidence for cortical efficiency.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.756069},
pmid = {42926775},
issn = {2692-8205},
abstract = {BACKGROUND: Working memory, the cognitive ability to maintain and manipulate a finite amount of information, is fundamental in reasoning, learning, and decision-making. Working memory erodes in conditions from Alzheimer's disease to stroke to healthy aging. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising neuromodulation method for improving working memory. By stimulating the auricular branch of the vagus nerve, taVNS is thought to engage ascending arousal systems such as the locus coeruleus-norepinephrine (LC-NE) system. However, the physiological link between LC-NE system modulation via taVNS and improved working memory remains largely unknown. This mechanistic gap limits the rational optimization of the stimulation protocol and the identification of the cognitive functions and patient populations that are likely to benefit.

OBJECTIVE: We test two competing hypotheses for how taVNS may improve working memory: sensory amplification or enhancement of cortical efficiency. The sensory-amplification hypothesis predicts increased cortical responses to stimuli, whereas the cortical-efficiency hypothesis predicts reduced cortical responses.

METHODS: Twenty healthy adults completed N-back working memory tasks during three counterbalanced sessions: baseline, active vibrotactile taVNS (vtaVNS), and sham stimulation, while we simultaneously recorded electroencephalography, electrocardiography, eye-tracking, and behavioral responses. To study the effect of vtaVNS on neuronal activity, we also recruited 20 patients with epilepsy undergoing invasive monitoring. Of these, 19 fully completed the spatial working-memory task. We quantified cortical responses to visual stimuli using event-related potentials (ERPs) in scalp EEG and high-gamma activity in intracranial local field potentials. To examine prediction of the cortical-efficiency hypothesis, we further explored the effect of vtaVNS on distance to criticality and heartbeat-evoked potentials.

RESULTS: Active vtaVNS reduced both scalp-recorded visual ERP and high-gamma response in temporal cortices, relative to sham stimulation. Moreover, smaller visual event-related potentials were associated with successful encoding during the most demanding working-memory condition (i.e., 4-back task). Exploratory analyses showed that vtaVNS shifted cortical dynamics closer to criticality.

CONCLUSION: Our results converge on the conclusion that vtaVNS does not uniformly amplify cortical responses to external stimuli. Instead, vtaVNS enhances cortical efficiency, supporting more effective allocation of cognitive resources between exteroceptive and mnemonic processes. These findings provide a framework for predicting when taVNS will be most beneficial and for optimizing stimulation protocols across cognitive and clinical applications.

HIGHLIGHTS: Consistent visual event-related potential in human subjects during an N-back working memory taskVibrotactile taVNS reduced stimulus-evoked cortical responses in both scalp EEG and intracranial high-gamma activity (70-150 Hz).Reduced visual event-related potentials are associated with successful encoding in the 4-back task.Vibrotactile taVNS shifted cortical dynamics toward a near-critical regime.},
}

@article {pmid42926800,
year = {2026},
author = {Zhang, A and Shen, W and Yan, S and Chen, J and Liu, X and Zou, J and Li, S and Hu, S and Liu, Y and Pan, C and Lan, Z and Peng, G and Zhang, Q and Peng, W and Ahmadizar, F and Zhang, J and , },
title = {Cross-Tissue Inflammatory Convergence Supports a Putative Muscle-Brain Axis in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.751107},
pmid = {42926800},
issn = {2692-8205},
abstract = {BACKGROUND: Reduced muscle strength is associated with cognitive decline and Alzheimer's disease (AD), suggesting that skeletal-muscle aging and AD-related neurodegeneration may share biological mechanisms. Vascular dysfunction, immune activation, and extracellular-matrix remodeling have been implicated in both tissues, but the extent of shared cellular and molecular programs remains unclear. We investigated cross-tissue transcriptional programs in aging skeletal muscle and AD-related brain tissue and evaluated whether related signals are detectable in peripheral blood.

METHODS: We analyzed independent, unpaired human transcriptomic datasets from skeletal muscle (23 donors), the SEA-AD middle temporal gyrus atlas (84 donors), and peripheral blood. Donor-aware models identified age-associated changes in muscle and transcriptomic changes across continuous pseudoprogression score (CPS) in brain. Cross-tissue comparisons focused on 30 brain donors within an early CPS window. Shared tissue-derived programs were assessed in peripheral blood mononuclear cells and independently tested in frailty bulk-blood and Alzheimer's Disease Neuroimaging Initiative (ADNI) whole-blood datasets. CellOracle simulations were used to prioritize candidate transcriptional regulators.

RESULTS: Aging muscle showed increased inflammatory, extracellular-matrix, and stromal communication programs. During early AD-related brain progression, vascular and immune populations showed increasing inflammatory and matrix-associated activity together with shifts in intercellular communication. Cross-tissue analysis identified six concordantly enriched pathways comprising 109 leading-edge genes in endothelial populations and four pathways comprising 51 genes in myeloid populations. Related peripheral-blood signatures varied across cohorts and cell types. However, in independent frailty and ADNI mild cognitive impairment and AD datasets, 23 of 30 predefined tissue-derived pathway-subset tests showed significant positive enrichment after false-discovery-rate correction, whereas individual gene-level bulk-blood associations did not survive correction. CellOracle analyses prioritized ETS2 and BHLHE40 as exploratory endothelial regulators whose simulated perturbation consistently reduced selected shared program scores across tissues.

CONCLUSIONS: Aging skeletal muscle and AD-related brain tissue exhibit convergent endothelial and myeloid inflammatory programs, with related pathway-level signals detectable in peripheral blood. These cross-tissue programs and candidate endothelial regulators provide testable hypotheses for mechanisms linking systemic aging, muscle dysfunction, and AD-related neurodegeneration.},
}

@article {pmid42926809,
year = {2026},
author = {Shi, R and Zeng, X and Farinas, MF and Nafash, MN and Smirnov, DS and Kamboh, MI and Snitz, BE and Kofler, JK and Cohen, AD and Pascoal, TA and Ikonomovic, MD and Zetterberg, H and Lopez, OL and Karikari, TK},
title = {Plasma eMTBR-tau as a robust biomarker for Alzheimer's disease tangle pathology up to 10 years before death.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.29.26363951},
pmid = {42926809},
abstract = {Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimer's disease prognosis, diagnosis and monitoring. Here, we show that a blood-based immunoassay for an endogenously-cleaved "eMTBR-tau" fragment of tau protein is strongly associated with autopsy-diagnosed Alzheimer neuropathologic change (ADNC) and predominantly reflects the burden and anatomical progression of tangle pathology but not amyloid plaque load despite being most elevated in amyloid-positive symptomatic individuals. Plasma eMTBR-tau was significantly more accurate than plasma p-tau217 in classifying Braak staging and ADNC statuses at autopsy. Importantly, neuropathologic classification by plasma eMTBR-tau remained high (AUC=0.91-0.95) even when increasing intervals between blood collection and death up to a decade, while maintaining superior sensitivity and specificity over p-tau217. Higher baseline plasma eMTBR-tau was associated with worse cognition cross-sectionally and longitudinally predicted faster worsening. These results were replicated in a living cohort with in vivo tangle and plaque neuroimaging. Plasma eMTBR-tau concordance with tau neuroimaging was up to 94%, suggesting surrogacy. Together, plasma eMTBR-tau captures biological signatures of Braak staging and ADNC over a prolonged pre-mortem window, highlighting potential for early disease detection, biological staging, prognosis and therapeutic development.},
}

@article {pmid42926826,
year = {2026},
author = {Costa, AP and Karim, HT and Farinas, MF and Nicholson, N and Geissinger, MM and Zeng, X and Tudorascu, DL and Butters, MA and Karikari, TK and Andreescu, C},
title = {Association between plasma brain-derived p-tau variants and anxiety phenotypes in older adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.02.26364610},
pmid = {42926826},
abstract = {OBJECTIVES: To determine whether distinct anxiety phenotypes (rumination, global anxiety and worry; RAW) are associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease (AD) in older adults.

DESIGN: Cross-sectional observational study.

METHODS: Participants were 89 older adults aged ≥50 years (mean age 64.3±8.8 years) enrolled in the RAW Brain study (R01 MH108509) in Pittsburgh, Pennsylvania. Anxiety phenotypes were assessed using the Penn State Worry Questionnaire (PWSQ≥50), Rumination Subscale from the Response Style Questionnaire (RSQ>50), and Hamilton Anxiety Rating Scale (HARS>17). Participants were classified as High-RAW if they exceeded established severity thresholds on ≥1 domain; continuous anxiety scores were used for primary analyses. Plasma BD-tau, BD-p-tau181, BD-p-tau217, and BD-p-tau231, and matched non-BD versions were quantified using the NULISAseq™ CNS Panel. Associations between anxiety phenotypes and tau biomarkers were examined using multivariable linear regression adjusted for age, sex, and APOE4 status, with Benjamini-Hochberg false discovery rate correction.

RESULTS: Greater global anxiety was associated with higher plasma BD-p-tau181 (β=0.308, 95% CI [0.003,0.048], p=0.047). This association was also observed categorically (adjusted Cohen's d=0.462, p=0.049). Worry and rumination were not associated with BD-p-tau181, and no anxiety phenotypes were associated with BD-tau, BD-p-tau217, BD-p-tau231, or corresponding non-BD alternatives.

CONCLUSIONS: Greater late-life global anxiety, but not worry or rumination, was selectively associated with higher plasma BD-p-tau181. These findings extend epidemiologic evidence linking anxiety to AD risk by identifying a biologically specific blood-based correlate linking anxiety with AD-related p-tau biology. Longitudinal studies incorporating amyloid and tau biomarker confirmation are needed to determine whether anxiety precedes, accompanies, or results from early AD pathophysiology.

HIGHLIGHTS: 1) What is the primary question addressed by this study? -The question addressed by the study must limited to only one sentence. Is late-life anxiety, including rumination, global anxiety, and worry, associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease in older adults? 2) What is the main finding of this study? -The finding must be limited to two sentences. Greater global anxiety, but not worry or rumination, was associated with higher plasma BD-p-tau181 after adjustment for age, sex, and APOE4 status. No associations were observed with other BD-tau variants or with non-BD-tau versions. 3) What is the meaning of the finding? -The meaning of the finding must be limited to one sentence. These findings suggest that global anxiety may be linked to early Alzheimer's disease-related tau biology and support further longitudinal investigation of anxiety as a potential marker of preclinical disease.},
}

@article {pmid42926842,
year = {2026},
author = {Lee, YR and Zeng, X and Farinas, MF and Lopresti, BJ and Habte, RF and Wilckens, KA and Karikari, TK},
title = {Analytical performance of a delayed-centrifugation blood collection tube for remote blood biomarker assessment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364780},
pmid = {42926842},
abstract = {Current biobanking guidelines require in-person blood collection and immediate processing for Alzheimer's disease (AD) biomarker assessment. We recently reported that the P100 blood collection tubes containing protease inhibitors improve protein biomarker stability over delayed centrifugation periods. However, whether this comparability extends beyond a small set of biomarkers to the broad panels enabled by high-plex platforms has not been established. Here, we performed a head-to-head comparison of 127 neurodegeneration-related biomarkers in paired P100 vs. standard ethylenediaminetetraacetic acid (EDTA) plasma samples from n = 43 community-dwelling older adult participants using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) proteomic technology. The NULISA assay demonstrated excellent technical reproducibility (intra- and inter-plate coefficients of variation [CVs] <10%). Biomarker levels in P100 and EDTA tubes were strongly correlated, with mean and median Spearman coefficients exceeding ρ = 0.8. Six conventional AD biomarkers showed strong P100-EDTA correlations (ρ > 0.8) with minimal mean differences and no significant proportional bias in Bland-Altman analysis, including plasma Aβ42, GFAP, MAPT, NEFL, p-tau181, and p-tau231, while p-tau217 showed a P100-EDTA correlation of ρ = 0.57. Two biomarker ratios (Aβ42/Aβ40 and p-tau217/Aβ42) also showed minimal bias with no proportional bias detected. Receiver operating characteristic analysis using amyloid status, assessed with positron emission tomography in a subset of participants, showed comparable classification performance between the two tube types, with classification concordance up to 92% and no significant DeLong differences for most (80%) biomarkers. These findings indicate that, on the NULISA platform, P100 tubes yield analytical and classification performance comparable to conventional EDTA tubes, supporting their use for blood-based neurodegeneration biomarker research where immediate sample processing is not feasible.},
}

@article {pmid42926851,
year = {2026},
author = {Koenders, CL and Chiu, R and Medeiros-Furquim, T and Bergink, S},
title = {Astrocytic timekeepers and their influence on brain waste clearance in Alzheimer's disease.},
journal = {Neurobiology of sleep and circadian rhythms},
volume = {21},
number = {},
pages = {100155},
doi = {10.1016/j.nbscr.2026.100155},
pmid = {42926851},
issn = {2451-9944},
abstract = {Alzheimer's disease is associated with disruptions in circadian rhythmicity, yet the underlying mechanisms remain only partially understood. Developing insights suggest that astrocytes possess their own intrinsic circadian clocks, influencing multiple functions in brain homeostasis. Given the central role of astrocytes in brain waste clearance, this review investigates how the astrocytic clock mediates brain waste clearance and contributes to Alzheimer's disease pathology. By reviewing recent findings on extracellular clearance, cellular protein homeostasis, cellular detoxification/redox defence and neurotransmitter homeostasis, this review bridges research on astrocytic clock disruption with altered brain waste clearance dynamics. It further highlights the relevance of these alterations to Alzheimer's disease pathology. Interestingly, some clock-gene disruptions are associated with markers suggestive of increased autophagic activity and glymphatic-related gene expression, which may represent a compensatory response to circadian clock alteration. However, whether these changes translate into improved functional clearance in vivo, and whether they meaningfully affect Alzheimer's disease progression, remains uncertain. In contrast, similar clock-gene alterations generally impair blood-brain barrier integrity, glutamate clearance and antioxidant response, decreasing waste clearance capacity. These findings suggest a possible bidirectional relationship, in which some pathways may partially compensate for impairments in others. However, it remains unclear to what extent an imbalance in these pathways contributes to the development and/or progression of Alzheimer's disease. Altogether, the astrocytic circadian clock is positioned as an important regulator of brain waste clearance and warrants future mechanistic and therapeutic investigation.},
}

@article {pmid42926864,
year = {2026},
author = {Gautier, A and Zheng, L and Schreurs, BG},
title = {Forecasting Alzheimer's disease progression using non-imaging clinical features and XGBoost.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364229},
pmid = {42926864},
abstract = {UNLABELLED: Identifying progressive dementia during its prodromal stage is a challenging yet critical task for healthcare providers. Traditional clinical assessments are often not sensitive enough to detect warning signs of cognitive decline. Machine learning (ML) methods have shown promise in modeling clinical trajectories associated with neurodegenerative disorders such as Alzheimer's disease (AD). Validation of these models' forecasting abilities, however, is widely lacking in the literature. To address this gap, we established a longitudinal cohort from the National Alzheimer's Coordinating Center (n = 15,727) comprising individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI) at baseline. Cognitive status and clinical observations collected over up to 10 visits were used to train several ML classifiers. We employed the gradient-boosted tree ensemble method XGBoost with a custom feature-engineering pipeline. On non-imputed data, our models achieved an AUC-ROC of 0.9447 [0.9417-0.9476] and PR-AUC of 0.8554 [0.8497-0.8611] for the CN→MCI task, and an AUC-ROC of 0.9059 [0.8983-0.9134] and PR-AUC of 0.9214 [0.9156-0.9272] for the MCI→AD task. In a lead-time forecasting analysis spanning mean follow-up periods of 56.1 months (range, 9.1-214.1) for CN→MCI and 42.7 months (range, 9.1-126.1) for MCI→AD, the non-imputed models detected future progression before diagnosis in 29.58% [28.29%-30.87%] of CN→MCI progressors and 22.41% [21.36%-23.46%] of MCI→AD progressors. Among these individuals, the mean lead time was 33.04 months [32.52-33.56] and 17.95 months [17.71-18.19], respectively. False alarm rates among non-progressors were 12.6% [11.5%-13.7%] and 20.0% [18.4%-21.6%], respectively. These findings suggest that longitudinal machine learning models can identify future cognitive decline before diagnosis, indicating clinical utility for early dementia risk stratification.

AUTHOR SUMMARY: Alzheimer's disease (AD) is a progressive and currently incurable neurodegenerative disorder that remains highly difficult to diagnose during its early stages. While modern early-stage dementia research relies on advanced neuroimaging, the high cost of these tests excludes many vulnerable communities. We designed our study to advance scalable, low-cost diagnostic alternatives that can identify individuals at significant risk of cognitive decline, ensuring faster access to emerging therapies.We examined trajectories of cognitive decline in 15,727 adults (mean age = 71.45 years, SD = 9.06) who had between 2 and 10 follow-up visits. Using 37 demographic, behavioral, clinical, and genetic variables, we modeled cognitively stable and declining trajectories using the XGBoost algorithm. Additionally, we evaluated the models' ability to forecast future diagnoses and the impact of longitudinal imputation.Our models performed well in both classification tasks (AUC-ROC ≥ 0.90).Imputation did not substantively alter the classifiers' performance. In forecasting diagnosis conversion, the models raised alarms before the recorded conversion visit in a subset of progressors, with non-imputed models yielding longer net lead times than imputed models in AD forecasting. This work describes a strategy for handling mixed-length temporal dimensions in longitudinal cohorts and evaluates its prognostic ability.},
}

@article {pmid42926876,
year = {2026},
author = {Zeng, X and Abrahamson, EE and Balogun, WG and Kofler, J and Paljug, WR and Pivtoraiko, VN and Ikonomovic, MD and Karikari, TK},
title = {Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.04.26361149},
pmid = {42926876},
abstract = {Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau proteins are a hallmark neuropathology of Alzheimer's disease. However, the molecular basis underlying their spatial heterogeneity and biochemical complexity remain unclear. To address this, we performed mass spectrometry-based proteomic profiling of two neocortical regions with different susceptibilities to NFT pathology-the inferior temporal (IT) and middle frontal (MF) cortices-from 27 autopsy cases stratified by Braak NFT stage (Low 0-II, n=8; Mid III-IV, n=11; High V-VI, n=8). Brain homogenates were sequentially fractionated using buffers of increasing solubility (TBS, Na2CO3, and Urea), followed by trypsin digestion and analysis by nanoLC-MS/MS with data-independent acquisition. Proteins were identified using PEAKS Studio 12 and linear mixed-effects models were applied to assess Braak stage-associated and region-specific changes in protein abundance and solubility. A total of 5,573 protein groups were identified, including 452 differentially expressed proteins (DEPs), 183 bidirectional expression proteins (BEPs), and 693 differentially soluble proteins (DSPs) associated with NFT pathology. These proteins were enriched in pathways related to cytoskeletal organization, synaptic transmission, metabolism, vesicular trafficking, and proteostasis. Marked regional differences were observed, with limited overlap between IT and MF across DEPs, BEPs, and DSPs. Protein change in MF was dynamic with a higher number of BEPs and suggested active cytoskeletal remodeling, whereas IT showed fewer BEPs and evidence of structural disruption, including alterations in intermediate filament components, consistent with vulnerability of IT and possible compensatory/plasticity changes in MF cortex. MF cortex had the greatest downregulation of DEPs between Low and Mid Braak stages, while the transition from Mid to High Braak stage showed upregulation of most of DEPs in both regions. In addition, widespread changes in protein solubility were observed, particularly decreased solubility at later Braak stages, implicating disruption of proteostasis. Together, these findings highlight region- and stage-dependent proteomic alterations associated with tau pathology and underscore their relevance for understanding disease mechanisms and informing biomarker development.},
}

@article {pmid42926894,
year = {2026},
author = {Roussos, P and Choi, Y and Bendl, J and Hoffman, G and Vicari, J and M, PN and Kosoy, R and Wang, X and Kinrot, S and Yang, H and Girdhar, K and Lee, D and Fullard, J and Dong, P},
title = {Cell-type-resolved mRNA 3'-end remodeling in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11143166/v1},
pmid = {42926894},
issn = {2693-5015},
abstract = {Alternative polyadenylation diversifies messenger RNAs by altering coding sequences and 3' untranslated regions, but its organization across human brain cell types and disruption in neurodegeneration remain poorly understood. By analyzing 3'-capture single-nucleus RNA sequencing data of 6.3 million nuclei from the prefrontal cortex of 1,494 human donors, we defined 108,768 polyadenylation sites across 25,274 genes, most of which were absent from the GENCODE polyadenylation-site annotation. Polyadenylation-site usage was strongly cell-type-specific and revealed regulatory differences not captured by gene expression. With increasing Alzheimer's disease clinicopathological severity, excitatory neurons, oligodendrocytes and immune cells showed increased distal-site preference, including reduced relative usage of intronic sites and increased distal 3' untranslated region usage in synaptic and RNA-processing genes. External single-nucleus data supported neuronal and oligodendrocyte patterns, while complementary analyses of purified microglia supported selected immune-cell findings. Integrative analyses of cleavage and polyadenylation factor expression, co-regulated usage networks, sequence motifs and published perturbations prioritized the cleavage factor Im complex as a candidate regulator. These findings identify cell-type-specific messenger RNA 3'-end remodeling as a reproducible dimension of Alzheimer's disease molecular pathology that is only partly captured by gene-level analyses.},
}

@article {pmid42926906,
year = {2026},
author = {Campbell, A and Becker, L and Kreimer, S and Gonzales, M and Raedschelders, K and Eyk, JV},
title = {Scalable Hydrogel Nanoparticle Enrichment for Enhanced Mass Spectrometry-based Proteomic Analysis of Plasma or Volumetric Dried Blood Samples.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11053241/v1},
pmid = {42926906},
issn = {2693-5015},
abstract = {Discovery-based proteomics for translational research requires workflows that reveal deep proteomes with a high degree of analytical precision, are scalable across large sample cohorts, and that can be adapted to different sample matrices. In our work, these sample matrices often extend beyond plasma to include volumetric dried blood samples (VDBS) that offer a minimally invasive alternative to standard venipuncture and enable remote, self-directed sampling. We describe the development and validation of a one-day, 96-well plate-based workflow built on the Ceres Nanotrap Protein Enrichment Affinity (PEAK) nanoparticle platform, optimized independently for both plasma and VDBS ahead of liquid chromatography-tandem mass spectrometry (LC-MS/MS). We benchmarked a tube-based Ceres workflow against both a Seer-encrichment and an unenriched SP3 workflow, assessed its suitability for VDBS, and translated this workflow to a plate-based protocol with a 2-hour digestion. The adapted workflow demonstrated robust reproducibility for both matrices: plasma yielded 4,937 unique proteins with a median inter-day CV of 11% whereas VDBS yielded 3,613 proteins with a median inter-day CV of 19%. Plasma and VDBS proteomes were highly concordant, with 75% of shared proteins quantified within one order of magnitude between matrices. We preliminarily evaluated the biological utility of this platform against a curated panel of 20 Alzheimer's Disease-associated proteins. Our results reveal the Ceres PEAK platform as a flexible, laboratory-adaptable workflow capable of deep and reproducible proteomic profiling of both plasma and VDBS.},
}

@article {pmid42926943,
year = {2026},
author = {Srikanth, M and Jiang, S and Wellman, SM and Sarkar, S and Lorman, DE and Lantin, T and Runyan, AM and Kumar, M and Sydney, E and Figueroa, HY and Yang, M and Wang, Q and Myeku, N},
title = {Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11129729/v1},
pmid = {42926943},
issn = {2693-5015},
abstract = {Background Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether this response protects proteostasis or amplifies neuroinflammation remains unresolved. Microglia must engage, internalize and degrade pathological protein cargo, yet uptake alone may not indicate successful clearance. We investigated how loss of inducible immunoproteasome function affects AD-related protein pathology and microglial processing of pathological cargo. Methods We crossed L7M1 mice, which lack the immunoproteasome catalytic subunits β2i/MECL-1/PSMB10 and β5i/LMP7/PSMB8, with PS19 tauopathy mice and APP/human tau double-knock-in mice. Tau and amyloid pathology, glial reactivity, constitutive proteasome activity and behavior were evaluated in vivo. Microglial uptake and processing of tau aggregate-bearing material were examined using primary microglial cultures, live-cell imaging and longitudinal in vivo two-photon microscopy. Mouse single-nucleus RNA sequencing and reanalysis of two human single-nucleus transcriptomic datasets were used to define associated cellular programs. Isolated brain mitochondrial respiration was also assessed. Results Immunoproteasome deficiency increased phospho-tau burden and microglial reactivity in PS19 mice and exacerbated tau and amyloid-β pathology in APP/human tau double-knock-in mice. These pathological changes occurred without detectable suppression of constitutive 26S proteasome activity. Although immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material, live-cell imaging showed inefficient resolution of internalized cargo. Longitudinal two-photon imaging similarly demonstrated retention or accumulation of microglia-associated tau in immunoproteasome-deficient mice, identifying a post-engulfment degradative defect in vivo. Single-nucleus transcriptomics revealed a remodeled P2ry12low/Trem2high microglial state accompanied by altered phagolysosomal cargo-processing and mitochondrial programs. In two human datasets, lower microglial immunoproteasome expression was associated with cargo-processing gene-program changes that overlapped with those observed in immunoproteasome-deficient mouse microglia. Despite transcriptional suppression of mitochondrial programs, no detectable impairment of isolated brain mitochondrial respiration was observed. Conclusions These findings support immunoproteasome biogenesis as a protective glial stress response that facilitates post-engulfment processing of pathological cargo and restrains tau and amyloid accumulation in AD-relevant brain environments. They further distinguish microglial engagement and uptake from successful intracellular resolution, identifying immunoproteasome function as an important component of aggregate clearance in AD.},
}

@article {pmid42926960,
year = {2026},
author = {Quiring, M and Shuai, Y and Zhao, W and Alitin, JPM and Kapoor, A and Engstrom, AC and Joyce, JL and Iyengar, P and Lohman, T and Lashin, B and Gaubert, A and Shenasa, F and Contreras, L and Law, KW and Ferrer, F and Wang, DJJ and Head, E and Malhas, R and Rodgers, K and Han, SD and Thayer, JF and Bondi, MW and Mather, M and Nation, DA},
title = {Locus coeruleus intensity as a marker of early-stage Alzheimer's disease: associations with plasma pTau 217 and memory.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.26364896},
pmid = {42926960},
abstract = {INTRODUCTION: The locus coeruleus (LC) is one of the earliest sites of Alzheimer's disease (AD) pathophysiological changes. LC magnetic resonance imaging (MRI) intensity may reflect effects of AD pathophysiology on the LC, providing a biomarker of early-stage AD. This study examined relationships among MRI-derived LC intensity, plasma phosphorylated tau 217 (pTau 217), and memory in older adults without dementia.

METHODS: Independently living adults aged 59-89 years (N = 163) underwent neuropsychological assessment and T1-weighted fast spin-echo MRI. We quantified a bilateral LC contrast ratio relative to a pontine reference region, averaged across axial slices. Plasma pTau 217 was measured using the Quanterix ALZpath p-Tau217 Advantage PLUS assay. For a subset (n = 127), a memory composite score was calculated.

RESULTS: After adjustment for age, sex, and APOE ɛ4 status, lower LC intensity was associated with higher plasma pTau 217 concentrations (β = -0.17, P = .02). Each 1- SD decrease in LC intensity was associated with 53% higher odds of pTau 217 positivity (P = .03). In models additionally adjusted for education, a significant LC × pTau 217 interaction for memory (β = -0.18, P = .009) indicated that lower LC intensity was associated with worse memory at low (P = .01), but not high (P = .64) pTau 217 levels.

DISCUSSION: These findings support MRI-derived LC intensity as a marker of early AD-related processes and suggest that LC intensity may provide complementary information not captured by plasma pTau 217 alone. Longitudinal studies are warranted to determine how these relationships change across the early stages of AD.},
}

@article {pmid42926980,
year = {2026},
author = {Britt, KC and Harb, A and Bailey, B and Saffold, B and Luo, X and Brown, RT and Huang, B},
title = {Navigating Life After Dementia Diagnosis: Questions, Challenges, and Support Needs Among Dementia Dyads.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.26364992},
pmid = {42926980},
abstract = {BACKGROUND: Older adults living with mild cognitive impairment (MCI) or Alzheimer's disease and related dementias (AD/ADRD) and their care partners face substantial daily challenges that evolve with disease progression and extend far beyond the clinical setting, including symptom management, care coordination, healthcare navigation, and planning for future care needs. Understanding these challenges is essential for developing innovative solutions to provide ongoing and targeted support. In this study, we explored questions, challenges, and support needs dementia dyads experienced following diagnosis to inform the development of an artificial intelligence (AI)-based chatbot designed to provide ongoing support for dementia dyads.

METHODS: We recruited 11 community-dwelling dyads comprising persons living with MCI or mild AD/ADRD and their care partners, one additional care partner, and 12 dementia care experts from academic medical centers, clinics, and aging organizations in the U.S. We conducted semi-structured interviews and analyzed them using conventional content analysis.

RESULTS: Participants described interconnected questions, challenges, and support needs that evolved while navigating life with MCI or AD/ADRD. Questions centered around day-to-day care management, medical concerns, behavioral symptom management, diagnosis and prognosis, safety, and resources and services. Challenges included care partner overwhelm, limited dementia knowledge, condition-related uncertainty, healthcare system navigation difficulties, financial constraints, and technology-related barriers. Participants identified needs for ongoing education, personalized care planning, resource navigation, logistical support and follow-up, culturally responsive care, and social and emotional support.

CONCLUSIONS: Dementia dyads experience substantial informational, emotional, and practical support needs in the early stages of MCI and AD/ADRD. Findings suggest that post-diagnostic support should extend beyond information provision alone to provide ongoing, personalized, and practical guidance that helps dyads navigate changing needs, resources, and everyday dementia care. These findings are informing the development of an AI-based chatbot intended to complement existing dementia care by extending access to education, practical guidance, and resource navigation between clinical encounters.},
}

@article {pmid42927022,
year = {2026},
author = {Jin, Z and Xu, K and Qi, M and Zhu, Q and Yang, B and Ferrada, GA and Fu, JS and Scovronick, N and Chang, HH and Alonso, A and Steenland, K and Liu, Y},
title = {Carbonaceous Components Underlying Wildfire Smoke PM 2.5 -Associated Alzheimer's Disease and Related Dementias in Older US Adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.26364863},
pmid = {42927022},
abstract = {Wildfire smoke exposure is increasing across the U.S., but the long-term neurological effects of smoke-specific fine particulate matter (PM 2.5) and its carbonaceous components remain uncertain. Using Medicare data from 2002 through 2019, we examined incident Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) among 39,678,630 fee-for-service Medicare beneficiaries followed from 2005 through 2019. We identified 3,501,414 incident AD cases over 258.5 million person-years and 8,377,416 incident ADRD cases over 248.6 million person-years. We linked the cohort with annual, high-resolution estimates of smoke and non-smoke PM 2.5 mass and carbonaceous components (elemental and organic carbon) and fitted stratified Cox proportional hazards models. Per 1 µg/m [3] increase, smoke PM 2.5 was associated with incident AD (hazard ratio [HR], 1.015, 95% confidence interval [CI], 1.005-1.026) and ADRD (1.029 [1.024-1.035]). Smoke carbonaceous fraction was also associated with AD (1.063 [1.042-1.085]) and ADRD (1.090 [1.077-1.103]). Within the ADRD endpoint, smoke-related associations exceeded their corresponding non-smoke associations on a per-unit-mass basis. Per interquartile range, associations were smaller for smoke PM 2.5 (AD, 1.005 [1.002-1.008]; ADRD, 1.009 [1.008-1.011]) than for non-smoke PM 2.5 (AD, 1.086 [1.079-1.094]; ADRD, 1.048 [1.043-1.053]). Associations varied across geographic, racial, socioeconomic, and clinical subgroups. Long-term wildfire smoke exposure, particularly its carbonaceous fraction, was associated with higher incidence of AD and ADRD among older U.S. adults. The associations correspond to 2,284 and 11,142 incident cases per year of AD and ADRD attributable to smoke PM 2.5 among older Medicare beneficiaries, with the carbonaceous fraction accounting for most of this burden. These findings support the use of source-resolved and composition-specific smoke metrics in dementia research and wildfire-smoke health-impact assessments.},
}

@article {pmid42927039,
year = {2026},
author = {Mouton, CP and Pappadis, M and Schlag, K and Westra, J and Kuo, YF and Raji, M and Wood, L and Temple, J},
title = {ELDER MISTREATMENT: A ROAD TO A NEW RISK ALGORITHM USING ICD-10 DATA.},
journal = {Transactions of the American Clinical and Climatological Association},
volume = {136},
number = {},
pages = {98-116},
pmid = {42927039},
issn = {0065-7778},
abstract = {Elder mistreatment (EM)-a growing public health problem in the United States-is associated with poor quality of life, accelerated disability, and premature death. EM remains underrecognized and underreported, with the diagnosis frequently being made at a late stage when the afflicted older adults have experienced prolonged suffering including emotional, physical, and financial abuse. One way to increase early EM recognition and timely management is through the development and implementation of predictive algorithms that can help alert clinicians to the need for additional screening. In earlier work, using International Classification of Diseases, Tenth Revision (ICD-10) diagnostics codes, we were able to develop a logistic regression approach to determine an EM predictive algorithm with an area under the curve (AUC) of 0.73, a sensitivity of 80%, and specificity of 47%. Subsequently, this model was applied to a vulnerable group of older adults-those with Alzheimer's disease and related dementias (ADRD). In this cohort, we found illiteracy to be the strongest predictor associated with EM. These EM predictive algorithms can be useful in the creation of electronic health record (EHR) reminders to prompt clinicians to suspect EM and implement appropriate follow-up care plans.},
}

@article {pmid42927045,
year = {2026},
author = {Wang, Y and Zhan, W and Wu, Z and Zhang, Y and Ma, Z and Ding, X},
title = {Updating deficits in subjective cognitive decline: A differential pattern of executive dysfunction across clinical stages.},
journal = {International journal of clinical and health psychology : IJCHP},
volume = {26},
number = {3},
pages = {100728},
doi = {10.1016/j.ijchp.2026.100728},
pmid = {42927045},
issn = {2174-0852},
abstract = {Identifying objective cognitive markers in the preclinical stage of Alzheimer's disease (AD), particularly in Subjective Cognitive Decline (SCD), is critical for early intervention. While executive function comprises three core components (inhibition, updating/switching), their impairment trajectory during the SCD-to-Mild Cognitive Impairment (MCI) progression remains unclear. This study aims to systematically compare these components among Cognitively Normal (NC), SCD, and MCI individuals to determine the earliest sensitive cognitive indicators of AD pathology. Community-dwelling adults aged ≥50 years were classified into NC, SCD, and MCI groups based on comprehensive screening (MoCA, SCD-Q, CDR, ADL). All participants completed standardized computerized tasks assessing inhibition (Oddball, Stop Signal Task), updating (spatial 1-back, VWM task), and switching (task-cue paradigm). One-way ANOVA with post-hoc tests compared group differences in accuracy and reaction time. SCD showed no difference from NC in inhibition but intermediate switch costs; crucially, SCD's spatial 1-back performance was significantly worse than NC and comparable to MCI, indicating early MCI-level updating deficits. Visuospatial storage capacity showed gradual impairment. Updating ability (visuospatial working memory) is the earliest and stably impaired indicator in SCD, serving as a sensitive marker for ultra-early AD screening. These findings suggest that updating ability, particularly visuospatial working memory, is the earliest and most stable impaired executive component, making it a sensitive behavioral marker for identifying high-risk SCD and enabling ultra-early AD screening. In contrast, significant impairments in inhibition and switching are delayed or progressive. This provides new scientific evidence for early assessment and targeted cognitive intervention.},
}

@article {pmid42927060,
year = {2026},
author = {Tanwar, S and Bhatt, LK},
title = {Flavokawain A: a multi-targeted kava chalcone with diverse therapeutic potential.},
journal = {3 Biotech},
volume = {16},
number = {11},
pages = {476},
doi = {10.1007/s13205-026-05100-7},
pmid = {42927060},
issn = {2190-572X},
abstract = {Piper methysticum G. Forst., commonly known as Kava, is a culturally significant shrub native to the Pacific islands, including Fiji, Vanuatu, and Tonga. Flavokawain A is one of the primary non-kavalactone constituents found within its rhizomes. This review aims to provide a comprehensive and critical evaluation of the current state of research on Flavokawain A. Specifically, it aims to elucidate the diverse molecular mechanisms and signaling networks that drive its pharmacological effects, while assessing its viability as a multi-targeted therapeutic candidate for diverse diseases. Flavokawain A exhibits profound therapeutic potential across a spectrum of pathological conditions, including malignancy, chronic inflammation, myocardial infarction, and neurodegenerative disorders such as Alzheimer's disease. Evidence from in silico, in vitro and in vivo models suggests that Flavokawain A's efficacy is rooted in its ability to modulate key signaling hubs, notably the TGF-β1, NF-κB, PI3K/AKT, and Nrf2 pathways, as well as regulatory proteins like PRMT5, CDK2, and SKP2. These multi-target interactions underpin Flavokawain A's potent antioxidant, anti-apoptotic, and anti-inflammatory properties, positioning it as a promising candidate for multifactorial disease management. FKA represents a versatile, multi-targeted potential therapeutic scaffold with a robust pharmacological profile. Its demonstrated anti-fibrotic, anti-inflammatory, and anti-proliferative activities across diverse disease models underscore its clinical potential. However, bridging the gap from bench to bedside requires rigorous translational studies and clinical trials to validate its safety, bioavailability, and therapeutic efficacy in human populations.},
}

@article {pmid42919989,
year = {2026},
author = {Rossini, E and Garibaldi, M and Hanna, MG and Pitceathly, RDS and Pizzamiglio, C},
title = {Mitochondrial dysfunction in neurology: biomarkers and clinical implications.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42919989},
issn = {1759-4766},
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.},
}

@article {pmid42920192,
year = {2026},
author = {Ralph, LT and Salter, EW and Tidball, P and Park, B and Choi, SL and Zhang, L and Tian, M and Kadia, A and Jin, F and Bradley, CA and Fraser, PE and Schmitt-Ulms, G and Gertsenstein, M and Nutter, LMJ and Georgiou, J and Collingridge, GL},
title = {Antithetical roles of tau in hippocampal long-term synaptic depression in rats versus mice.},
journal = {Molecular brain},
volume = {19},
number = {1},
pages = {},
pmid = {42920192},
issn = {1756-6606},
support = {PJT 173497//CIHR Project Grant/ ; #154276//CIHR (Canadian Institutes of Health Research) Foundation Grant/ ; },
mesh = {Animals ; *tau Proteins/metabolism/deficiency ; *Hippocampus/metabolism/physiology ; *Long-Term Synaptic Depression/physiology ; Mice, Knockout ; Schaffer Collaterals ; Male ; Mice, Inbred C57BL ; Rats ; Synapses/metabolism ; Mice ; },
abstract = {Synaptic dysfunction is a primary feature of tauopathies, a group of major neurodegenerative diseases that includes Alzheimer's disease. However, the normal synaptic functions of tau are poorly understood. Since rats provide advantages over mice for understanding human tau, such as expressing six tau isoforms and showing more robust signs of tau pathology, as well as offering a richer behavioural repertoire, we developed a tau knockout (Mapt KO) rat line. We primarily investigated the impact of tau elimination on long-term synaptic depression (LTD)-a form of synaptic weakening that tau mediates in mice. Low-frequency stimulation of hippocampal Schaffer collateral-CA1 synapses revealed a robust enhancement of LTD in Mapt KO rats relative to WT littermates. In contrast, in interleaved experiments, Mapt KO mice exhibited reduced LTD compared to WT littermates, in line with previous reports. Together, our findings demonstrate a species-dependent role for endogenous tau in regulating hippocampal LTD, promoting it in mice yet constraining it in rats. Therefore, the functions of tau are not necessarily conserved in rodents, underscoring the importance of animal model choice.},
}

Animals
*tau Proteins/metabolism/deficiency
*Hippocampus/metabolism/physiology
*Long-Term Synaptic Depression/physiology
Mice, Knockout
Schaffer Collaterals
Male
Mice, Inbred C57BL
Rats
Synapses/metabolism
Mice

@article {pmid42920245,
year = {2026},
author = {Ekanayake, A and Hwang, S and Peiris, S and Elyan, R and Mustafa, G and Tulchinsky, M and Wang, J and Eslinger, P and Yang, Q and Karunanayaka, P},
title = {An exploratory synthetic MRI-derived FLAIR-DIR contrast in olfactory-limbic regions in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498397},
doi = {10.1177/13872877261498397},
pmid = {42920245},
issn = {1875-8908},
abstract = {BackgroundOdor identification impairment is an early feature of Alzheimer's disease and predicts memory decline, but its microstructural basis remains unclear.ObjectiveTo evaluate FD, a semi-quantitative synthetic magnetic resonance imaging (MRI)-derived Fluid-Attenuated Inversion Recovery (FLAIR)-Double Inversion Recovery (DIR) contrast, against myelin volume fraction (MVF) in olfactory-limbic brain regions of patients diagnosed with mild cognitive impairment (MCI).MethodsSixteen healthy controls (HC) and 17 individuals diagnosed with MCI completed olfactory and cognitive testing and underwent 3T MRI using a QALAS sequence. MVF maps were generated and FD was computed as (FLAIR - DIR)/FLAIR. Group differences were examined in olfactory-limbic gray matter and associated white-matter tracts, and voxel-wise regression assessed FD-odor identification associations, including models adjusted for voxel-wise MVF. Region of interest and voxel-wise analyses were exploratory and largely uncorrected for multiple comparisons.ResultsCompared with HC, MCI showed lower FD across olfactory-limbic gray matter and white-matter pathways, including hippocampus, amygdala, orbitofrontal cortex, thalamus and corpus callosum, whereas MVF differences were more limited. Better odor identification was associated with higher FD in hippocampal/parahippocampal regions and insula, persisting after MVF adjustment. MVF showed positive associations in the right parahippocampal gyrus, left thalamus and genu of the corpus callosum. In an exploratory secondary analysis reported in the Supplemental Material, FD-based classification exceeded chance but was not separable from age alone.ConclusionsFD is a semi-quantitative relaxation-contrast metric showing regional patterns partially distinct from MVF. These exploratory findings require replication in larger, demographically matched, biomarker-confirmed cohorts before FD can be regarded as a marker of early olfactory-limbic microstructural change in MCI.},
}

@article {pmid42920246,
year = {2026},
author = {Duboisdindien, G and Durieux, N and Kieu, M and Cattini, J},
title = {Discourse-based assessment in clinical context for persons with Alzheimer's disease: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497928},
doi = {10.1177/13872877261497928},
pmid = {42920246},
issn = {1875-8908},
abstract = {BackgroundDiscourse assessment captures communicative abilities integrating linguistic, cognitive, and pragmatic processes and is widely used to characterize communication changes in Alzheimer's disease (AD).ObjectiveTo identify and map clinically applicable methods and linguistic measures for assessing discourse changes in persons with AD.MethodsThis scoping review followed JBI methodology and PRISMA-ScR guidelines. Observational studies assessing spoken discourse in persons with AD compared with normocognitive controls were identified through systematic searches of MEDLINE, PsycINFO, Linguistics and Language Behavior Abstracts, and Scopus. Studies based exclusively on automated language-processing approaches were excluded to maintain a focus on clinically applicable assessment. English or French-language studies were included. To assess inter-rater reliability, data from 17/76 studies (22.4%) in the broader review were independently extracted by two reviewers, with high agreement; remaining studies were extracted by one reviewer, with uncertainties resolved collectively. Extracted data included elicitation tasks, coding procedures, linguistic domains, and outcome measures and were summarized descriptively.ResultsFifty-nine papers were included. Picture description predominated, followed by conversational and narrative formats. Across papers, 291 distinct linguistic measures were identified. Discourse/pragmatic measures constituted the largest domain and had the greatest number of reported statistically significant findings. Fluency measures were also frequently associated with statistically significant differences, whereas morphosyntactic measures showed fewer such findings.ConclusionsSubstantial variability in elicitation procedures, operational definitions, and linguistic measures limits cross-study comparability. Methodological harmonization and further evaluation of the psychometric and clinical properties of discourse measures are needed to support evidence-based clinical assessment.},
}

@article {pmid42920248,
year = {2026},
author = {Duboisdindien, G and Durieux, N and Kieu, M and Cattini, J},
title = {Discourse-based assessment in clinical context for persons with mild cognitive impairment: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261499243},
doi = {10.1177/13872877261499243},
pmid = {42920248},
issn = {1875-8908},
abstract = {BackgroundDiscourse assessment may capture subtle communication changes in persons with mild cognitive impairment (MCI) that are not readily detected by standardized test batteries.ObjectiveTo identify and map clinically applicable methods and linguistic measures for assessing discourse changes in persons with MCI.MethodsThis scoping review followed JBI methodology and PRISMA-ScR reporting guidance. Observational studies assessed spoken discourse in persons with MCI, including comparisons with normocognitive controls or persons with Alzheimer's disease (AD). Studies published in English or French were identified through systematic searches of MEDLINE, PsycINFO, Linguistics and Language Behavior Abstracts, and Scopus, updated in January 2025. Studies based exclusively on automated language-processing approaches were excluded. Data from 17 of the 76 studies in the broader review program (22.4%) underwent independent double extraction, with high inter-rater agreement. Data from the remaining studies were extracted by one reviewer, with uncertainties resolved collectively. Findings were summarized descriptively.ResultsSeventeen studies were included. Narrative and descriptive tasks predominated. Across studies, 119 distinct linguistic measures were identified across six domains. Only implausible or irrelevant details showed statistically significant MCI-control differences consistently across independent studies. No measure showed this pattern for MCI-AD comparisons. Most other measures were reported in single studies or yielded inconsistent findings across tasks and samples.ConclusionsHeterogeneity in elicitation procedures, operational definitions, and linguistic measures limits comparability across studies. Methodological harmonization and further evaluation of psychometric properties and clinical feasibility are needed to support evidence-based discourse assessment by speech-language pathologists.},
}

@article {pmid42920249,
year = {2026},
author = {Elmaleh, D and Gupta, A and Brazier, D and Garofano, W and Conti, PS},
title = {A phase III trial of ALZT-OP1 (cromolyn + ibuprofen) in early Alzheimer's disease: Primary results and exploratory analyses by APOE4 genotype.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498247},
doi = {10.1177/13872877261498247},
pmid = {42920249},
issn = {1875-8908},
abstract = {BackgroundThis study tested ALZT-OP1 (inhaled cromolyn 17.1 mg and oral ibuprofen 10 mg) in early Alzheimer's disease (AD).ObjectiveTo evaluate the efficacy and safety of ALZT-OP1 in early AD.MethodsCognite was a Phase III, double-blind, placebo-controlled, four-arm factorial trial in 619 participants with early AD (cerebrospinal fluid [CSF] amyloid-β42 (Aβ42) 180-690 pg/mL; Clinical Dementia Rating-Global 0.5). Randomization was 1:1:1:1 to cromolyn, ibuprofen, combination therapy, or placebo for 72 weeks. The primary endpoint was change from baseline to Week 72 in Clinical Dementia Rating-Sum of Boxes (CDR-SB), comparing combination versus each monotherapy. Secondary and exploratory endpoints included comparisons with placebo, subgroup analyses by apolipoprotein E4 (APOE4) status, Mini-Mental State Examination scores, CSF biomarkers, and safety.ResultsIn the modified intent-to-treat population (n = 594), the primary endpoint was not met. No statistically significant difference was found between combination and cromolyn (difference 0.16, 95% CI -0.58 to 0.90; p = 0.675) or ibuprofen (0.40, 95% CI -0.32 to 1.13; p = 0.276). APOE4 non-carriers receiving combination therapy showed a numerical benefit versus placebo (least-squares mean difference -0.96; 95% CI -2.00 to 0.08; p = 0.069), although this was not statistically significant. ALZT-OP1 was safe and well tolerated.ConclusionsALZT-OP1 did not demonstrate efficacy in an unselected early AD population. The numerical benefit observed in APOE4 non-carriers warrants prospective evaluation in a genotype-stratified trial. ALZT-OP1 was safe and well tolerated over 72 weeks, and the study provides insights for future AD trial design.The study is registered at ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT02547818; NCT02547818).},
}

@article {pmid42920252,
year = {2026},
author = {Tian, D and Shi, T and Xu, S and Lan, J and Zhao, M and Wu, H and Yang, J and Wang, Z and Wang, J},
title = {A putative iron-related evolving framework in Alzheimer's disease: From iron dyshomeostasis and ferro-aging to ferroptosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261501439},
doi = {10.1177/13872877261501439},
pmid = {42920252},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) ranks as a prototypical age-related neurodegenerative disorder. Emerging evidence indicates that disrupted brain iron metabolism and ferroptosis act as critical upstream drivers of AD pathological progression. AD exhibits core hallmarks of ferroptosis, including iron overload, lipid peroxidation, elevated reactive oxygen species, and impaired antioxidant enzyme activity. These abnormalities interact synergistically with amyloid-β plaques and tau pathology. Iron accumulation during aging and damage-associated molecular patterns released concomitantly with ferroptosis drive susceptible microglia toward M1-like polarization, propagate chronic neuroinflammation, and fuel the vicious cycle of AD pathology. Targeting ferroptotic pathways represents a promising strategy to alleviate cognitive impairment in AD. Ferro-aging ranks as a recently identified form of programmed cellular senescence marked by iron dependency, ACSL4 regulation, and lipid peroxidation-driven damage. Although ferro-aging has only been preliminarily validated in aging models, its molecular signatures, regulatory axes, and phenotypic outcomes align remarkably well with the progression of brain aging and AD. It thus emerges as a potentially pivotal hub linking physiological aging to iron-associated pathology in AD. We systematically summarize the physiological regulation of brain iron homeostasis and core ferroptotic pathways disrupted in AD. We further integrate current evidence to explore how ferro-aging may contribute to AD pathogenesis, proposing a mechanistic framework in which: iron dyshomeostasis initiates damage, ferro-aging drives chronic progression, and ferroptosis mediates acute injury. Finally, we review intervention strategies targeting iron-related pathology, providing theoretical insights for understanding the aging-dependent nature of AD and developing novel therapeutic approaches.},
}

@article {pmid42920257,
year = {2026},
author = {Chuang, TC and Liang, CK and Chou, MY and Chan, YH and Wang, HP and Wang, YC and Hsu, YH and Lin, YT},
title = {Changes in gray matter volume associated with gait speed and muscle mass in older adults with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500490},
doi = {10.1177/13872877261500490},
pmid = {42920257},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) is an early stage of cognitive decline between normal aging and dementia. Gait speed, a key marker of physical function, has been associated with both cognitive decline and brain atrophy. Sarcopenia, characterized by age-related loss of muscle mass and function, has also been linked to structural brain changes.ObjectiveTo investigate the associations between sarcopenia, its individual components and regional gray matter volume (GMV) in older adults with MCI.MethodsThis cross-sectional study included 234 older adults with MCI. Sarcopenia, gait speed, handgrip strength, and appendicular skeletal muscle mass index (ASMI) were assessed according to the 2019 Asian Working Group for Sarcopenia criteria. Brain T1-weighted magnetic resonance imaging was analyzed using voxel-based morphometry. Voxel-wise group comparisons were performed to identify GMV differences after adjustment age, sex, comorbidity, depressive symptoms, nutritional status, and total intracranial volume.ResultsSlower gait speed was significantly associated with lower GMV in the bilateral putamen and left superior frontal cortex. Lower ASMI was associated with higher GMV in the left inferior temporal cortex. No significant GMV differences were found by sarcopenia status or handgrip strength.ConclusionsSlower gait speed is associated with reduced GMV in motor-related brain regions, indicating early brain structural changes in older adults with MCI. Although lower ASMI was associated with higher GMV, this finding should be interpreted cautiously. These findings highlight the complex interactions between physical function and brain structure, emphasizing gait speed as a potential indicator of brain health in older adults with MCI.},
}

@article {pmid42920259,
year = {2026},
author = {Tian, H and Zhang, J and Zuo, H and Liu, Y and Kim, ID and Gui, Y},
title = {Cerebrospinal fluid cell-free DNA methylation captures disease-specific biology in tauopathies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500498},
doi = {10.1177/13872877261500498},
pmid = {42920259},
issn = {1875-8908},
abstract = {BackgroundDifferentiating tau-related dementias remains challenging, particularly during early disease stages when clinical symptoms overlap. Existing biomarkers mainly reflect downstream pathology and provide limited insight into disease-specific molecular processes.ObjectiveWe examined whether cerebrospinal fluid (CSF)-derived cell-free DNA (cfDNA) methylation could distinguish Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), and progressive supranuclear palsy (PSP).MethodsPromoter methylation of 20 genes associated with AD risk, neuroinflammation, cellular senescence, and glymphatic or lymphatic regulation was analyzed in CSF and matched plasma cfDNA from controls (n = 15), AD (n = 21), bvFTD (n = 14), and PSP (n = 17). cfDNA concentration and fragmentomic profiles were assessed. Diagnostic performance was evaluated using logistic regression and receiver operating characteristic (ROC) analysis. Findings were validated in an independent cohort.ResultsCSF cfDNA concentrations were increased in AD, whereas fragment size distributions were similar across diagnostic groups. Disease-associated methylation signatures were prominent in CSF but weak or absent in plasma. AD demonstrated widespread hypomethylation of inflammatory and senescence-associated genes together with hypermethylation of glymphatic and lymphatic regulators. bvFTD showed intermediate glial- and stress-related methylation changes, while PSP retained relatively preserved inflammatory and clearance-associated profiles. CSF methylation panels consistently outperformed plasma-derived markers for disease classification. ROC analyses demonstrated strong discrimination for AD, with AUC values reaching 0.84-0.85, while plasma-based markers showed limited diagnostic utility.ConclusionsCSF cfDNA methylation captures disease-specific epigenetic states linked to core pathogenic pathways in tau-related dementias. This approach may provide a biologically informative and clinically useful platform for molecular classification and diagnostic stratification.},
}

@article {pmid42920264,
year = {2026},
author = {Passmore, SR and Gooding, DC and Medina, MN and Ocoko, F and Bouges, S and Randolph, M and Smith, T and Carter, FP and Zuelsdorff, M and Nirschl, J and Gleason, CE},
title = {Decision-making in biospecimen and biomarker research among African American participants: Procedure-specific perspectives including on the uniqueness of brain donation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500123},
doi = {10.1177/13872877261500123},
pmid = {42920264},
issn = {1875-8908},
abstract = {BackgroundAfrican Americans are disproportionately affected by Alzheimer's disease (AD) but remain significantly underrepresented in research. While previous studies often assess these barriers to such research engagement using hypothetical scenarios, there is a need to focus on in vivo decision-making processesObjectiveTo identify the specific facilitators and barriers influencing African American participants' decisions to engage in or decline four types of biospecimen data collection: biomarker collection via MRI, PET, or lumbar puncture (LP), and brain donation.MethodsSemi-structured interviews were conducted with 41 participants (68.2% female; age range 58-84; average 68) recruited from the African Americans Fighting Alzheimer's in Midlife Study who had made the decision for or against these four types of research. A descriptive content analysis identified specific factors that influenced decision-making.ResultsAcceptability levels varied by procedure: MRI (80.5%) and PET scans (63.4%) were the most accepted, whereas LP (36.6%) and brain donation (34.1%) were the least. Common motivations included personal family experience with AD and a desire to benefit the African American community. Barriers for LP and MRI included perceived physical risk and claustrophobia, respectively. Brain donation emerged as a unique, family-centered decision rather than an individual one. A high percentage of participants (34%) remained undecided about brain donation due to concerns about family burden during end-of-life transitions and a lack of procedural information.ConclusionsThis examination of real-life research decisions confirmed prior findings and highlighted opportunities to improve outreach to African American community members, particularly regarding brain donation, which may require unique approaches.},
}

@article {pmid42920267,
year = {2026},
author = {Case, K and Halliwell, C and Clay, T and Ding, Y and Colon, K and Callen, E},
title = {A scoping literature review: Identifying the comorbidities of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500119},
doi = {10.1177/13872877261500119},
pmid = {42920267},
issn = {1875-8908},
abstract = {BackgroundThere are many co-occurring conditions of Alzheimer's disease (AD).ObjectiveThis scoping literature review aims to identify the comorbidities of AD found in the literature.MethodsWe conducted an extensive scoping search using PubMed for January 1, 2015 to June 10, 2025, yielding 461 articles. 39 articles met inclusion criteria. Descriptive statistics were completed on the extracted information.ResultsThe conditions identified encompass the body's major organ systems, with diabetes and hypertension appearing the most.ConclusionsThis scoping review highlights the large number of comorbidities associated with AD.},
}

@article {pmid42920272,
year = {2026},
author = {Minucchi, E and Di Gerlando, R and Dragoni, F and Imbimbo, C and Zardini, E and Cotta Ramusino, M and Costa, A and Gagliardi, S},
title = {pTau217 immunoassays in Alzheimer's disease continuum: A comparative study of Ella and Lumipulse.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500491},
doi = {10.1177/13872877261500491},
pmid = {42920272},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau 217 (pTau217) has emerged as one of the most accurate biomarkers for Alzheimer's disease (AD). However, direct comparisons of pTau217 levels between different automated immunoassays remain limited.ObjectiveIn this context, our work aimed to compare Lumipulse and Ella platforms for the measurement of plasma pTau217 across the AD continuum.MethodsBlood samples were collected from 32 subjective cognitive decline (SCD), 25 mild cognitive impairment (MCI), and 10 Alzheimer's disease (AD) patients. Plasma pTau217 levels were assessed using Lumipulse G600II automated system and Ella immunoassay SR-X platform. Associations with clinical variables and agreement between platforms were assessed.ResultsPlasma pTau217 levels increased from SCD to AD with both assays. Lumipulse showed a significant difference between SCD and AD (p = 0.0011), while Ella detected differences between SCD and MCI (p = 0.0198) and SCD and AD (p = 0.0001). Both assays showed a significant inverse correlation with Mini-Mental State Examination (Lumipulse: r = -0.4913; p = 0.0001. Ella: Pearson r = -0.5139; p = 0.0001). A moderate correlation between platforms was observed. Bland-Altman analysis revealed a negative bias, with Lumipulse yielding lower values than Ella and increasing variability at higher concentrations.ConclusionsLumipulse and Ella provided consistent qualitative information on plasma pTau217 across the AD continuum and show similar associations with cognitive performance, meaning that they are both comparable techniques. However, systematic bias and proportional variability limit their quantitative interchangeability, highlighting the need for cross-platform standardization.},
}

@article {pmid42920275,
year = {2026},
author = {Liu, B and Wu, J and Liu, J and Mo, Y and Lin, G and Zhang, Y and Wei, C and Tao, R},
title = {A five-gene mitochondrial-lipid metabolism signature for Alzheimer's disease diagnosis identified by machine learning and validated in independent cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500762},
doi = {10.1177/13872877261500762},
pmid = {42920275},
issn = {1875-8908},
abstract = {BackgroundMitochondrial dysfunction and lipid metabolism dysregulation represent early key events in Alzheimer's disease (AD), yet integrated transcriptomic signatures combining these two biological processes for AD diagnosis remain poorly defined.ObjectiveThis study aimed to construct and validate a mitochondrial-lipid metabolism (MLM) gene-based diagnostic classifier for AD using machine-learning approaches and explore its underlying biological mechanisms.MethodsTwo public GEO datasets GSE5281 (training) and GSE28146 (independent validation) were included. Candidate MLM genes were retrieved from MSigDB. Differentially expressed MLM genes were screened by limma, followed by two-step feature selection with LASSO regression and random forest. Four machine-learning algorithms were compared. Model performance was evaluated by AUC, calibration, decision-curve analysis and subgroup analysis across AD severity. GSVA and hypergeometric test were applied for mechanistic exploration.ResultsA five-gene signature (SDR16C5, EGR1, ASAH2B, HIP1R, CKMT1B) was finally identified. Logistic regression model achieved 5-fold cross-validated AUC of 0.953 in training cohort and AUC = 0.892 (95%CI:0.768-1.000) in validation cohort. The signature maintained high diagnostic accuracy across incipient, moderate and severe AD stages. Hypergeometric test demonstrated significant MLM-set enrichment (p = 3.85 × 10[-5]). GSVA revealed close correlations between this signature with oxidative stress, synaptic dysfunction and apoptosis pathways.ConclusionsThis validated five-gene MLM signature exhibits favorable diagnostic performance for AD and reflects disturbed mitochondrial-lipid metabolic network. It provides a promising transcriptomic biomarker for AD diagnosis.},
}

@article {pmid42920282,
year = {2026},
author = {Mowafi, S and Nassar, L and Ezzeldin, S and Salama, M and Chun, S},
title = {The uncinate fasciculus in frontotemporal dementia subtypes: A systematic review and meta-analysis of diffusion-tensor imaging studies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500138},
doi = {10.1177/13872877261500138},
pmid = {42920282},
issn = {1875-8908},
abstract = {BackgroundFrontotemporal dementia (FTD) is a leading cause of early-onset neurodegeneration with selective frontal and temporal lobe degeneration. Despite well-characterized gray and white matter atrophy patterns across FTD subtypes, the extent of degeneration of the uncinate fasciculus (UF) tract has not been systematically quantified across FTD subtypes.ObjectiveTo compare uncinate fasciculus fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity between frontotemporal dementia subtypes and healthy controls.MethodsWe systematically searched PubMed, Scopus, and Web of Science and performed a random-effects meta-analysis of diffusion tensor imaging studies published between 2011 and October 2025 according to PRISMA 2020 guidelines.ResultsWe systematically reviewed 11 studies and performed a meta-analysis of 540 participants across 10 studies. We found that all FTD subtypes demonstrated significant degeneration of the UF compared to controls. The greatest effect sizes were observed when comparing the left UF between the semantic variant primary progressive aphasia (svPPA) and controls (FA: SMD = -2.5396, 95% CI: -3.7914, -1.2878, p < 0.0001; RD: SMD = 2.2414, 95% CI:1.7972, 2.6855, p < 0.0001; AD: SMD = 1.9831, 95% CI: 1.1434, 2.8227, p < 0.0001; MD: SMD = 2.5268, 95% CI: 1.9993, 3.0542, p < 0.0001), while the behavioral variant (bvFTD) showed the largest reduction in right UF fractional anisotropy. Within-group analyses revealed significant left-right asymmetry in svPPA and non-fluent aphasia (nfvPPA), with greater left UF involvement, while bvFTD and controls showed no hemispheric differences.ConclusionsWe highlight the UF as a promising tract for understanding disease mechanisms and developing imaging biomarkers in FTD.},
}