@article {pmid41870696,
year = {2026},
author = {De Lucia, N and Thayanandan, T and Palomba, S and Komici, K and Maldonato, NM and Rengo, G and Femminella, GD},
title = {Neuropsychiatric and neural correlates of subjective cognitive complaint.},
journal = {Aging clinical and experimental research},
volume = {38},
number = {1},
pages = {},
pmid = {41870696},
issn = {1720-8319},
abstract = {BACKGROUND: Subjective cognitive complaint (SCC) has been reported in normal elderly (NE) and Mild Cognitive Impairment (MCI).

AIMS: We investigated the neuropsychiatric predictors of SCC in NE and MCI, and the biomarkers abnormalities, and neural correlates of SCC in MCI.

METHODS: Clinical, cognitive and imaging data of 233 MCI and 419 NE were obtained from the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI-3) database. SCC was assessed by the Cognitive Change Index (CCI) and Everyday Cognition (ECog). Neuropsychiatric symptoms were evaluated through the Neuropsychiatric Inventory (NPI). Brain amyloid and tau status were obtained from [18 F]Florbetapir-PET and [18 F]Flortaucipir-PET SUVR in predefined target regions, and brain and grey matter volumes from structural MRI.

RESULTS: SCC was significantly correlated with depression, anxiety, apathy, irritability, and sleep disorders, in MCI. Linear regression showed that depression and anxiety were significantly associated to SCC index, in MCI. SCC was neither significantly different in amyloid positive vs. negative, nor in tau positive vs. negative MCI. MCI with SCC showed significantly lower Braak 3–4 region volume and reduced amygdala volume, compared to MCI without SCC. MCI with SCC and NPI showed lower posterior cingulate cortex volume compared to MCI without SCC or NPI, whereas MCI with SCC but without NPI had lower anterior cingulate cortex volume, compared to MCI without SCC or NPI.

CONCLUSIONS: These findings recommend the crucial role of psychological therapies focused on anxiety and depression, to prevent the worsening of the subjective cognitive complaint that represent a strong factor of conversion to objective cognitive disorders.},
}

@article {pmid42151483,
year = {2026},
author = {Sanchez-Molina, P and Rosmus, DD and Brownell, D and Meral, M and Gohlich, C and Pratapa, A and Peymanfar, Y and Whitley, A and Hou, Y and Nikulina, N and Bogachuk, A and Bouchard, EL and Chiot, A and Kuhrt, H and Wieghofer, P and Woltjer, R and Svara, F and Braubach, O and Ajami, B},
title = {Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-dependent microglial cell states.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42151483},
issn = {1546-1726},
abstract = {Disease-associated microglial states are thought to contribute to Alzheimer's disease (AD) progression, but characterizing them and their relationships to pathology remains challenging. Here we introduce CODEX-CNS-a multiplexed protein imaging technology with a custom data analysis pipeline for use in human brain samples. We profiled 704,706 cells in samples from the frontal cortex of 8 people with AD and 8 healthy controls and mapped features including blood-brain barrier, meningeal components and cell-cell interactions within the same tissue sections. Amongst the myeloid cell populations we identified, we found a border-associated macrophage-like microglial subset associated with aging. Further classifying myeloid cell subsets based on their spatial neighborhood, we identified a border-associated macrophage-like microglial subpopulation that was associated significantly with dense amyloid-β plaques, which we termed human plaque-associated microglia. This work offers insights into myeloid cell heterogeneity in AD and provides a new spatial approach to characterizing brain cells at the single-cell protein level.},
}

@article {pmid42151567,
year = {2026},
author = {Tandalekar, YB and Kulshreshtha, S and Goyal, A and Jachak, SM},
title = {Physalis minima L.: A comprehensive review on phytochemistry, pharmacology, and food applications.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42151567},
issn = {1432-1912},
abstract = {Physalis minima Linn. (Solanaceae) is a widely recognized plant renowned for its diverse medicinal properties and edible applications. Traditionally, this plant has been used to prevent cancer, inflammation, diabetes, Alzheimer's, microbial growth, and leishmaniasis. It is also utilized as a diuretic and laxative. The species has been identified as having various phytoconstituents, including withanolides, flavonoids, fatty acids, and other compounds. Among these, withanolides are the most prevalent and function as the primary bioactive compounds. A total of 221 withanolides (1980-2025) were documented in this review, among which 81 were newly identified from P. minima. Previous research has identified withanolides as key bioactive constituents with notable potential in the management of inflammatory, neuroinflammatory, and cancer-related conditions, largely due to their distinctive steroidal framework and significant biological activities. Despite these promising pharmacological attributes, only a limited number of withanolides have been studied in depth. Most compounds, especially those discovered more recently, remain insufficiently explored with respect to their therapeutic potential. This knowledge gap highlights the need to further investigate compounds isolated from P. minima to better understand their pharmacological effects. We have tried to extensively appraise the data on phytoconstituents identified from this plant and their associated pharmacological activities. Collectively, the findings presented in this review provide a starting point for future research on P. minima, highlighting its promise as a valuable source of bioactive compounds for drug discovery.},
}

@article {pmid42151616,
year = {2026},
author = {Filippi, M and Ghirelli, A and Cecchetti, G and Samanes Gajate, AM and Rugarli, G and Spinelli, EG and Pisano, S and Panzacchi, A and Pepe, G and Chiti, A and Agosta, F},
title = {Serial amyloid PET as a decision tool for switching anti-amyloid therapy in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42151616},
issn = {1619-7089},
}

@article {pmid42151661,
year = {2026},
author = {König, A and Tröger, J and Mallick, E and Linz, N and Ritchie, C and Gregory, S and Hunter, M and Johnson, K and Benavides, GS and Grau-Rivera, O and Radoi, A and Porta-Mas, C and Köhler, S and Teipel, S and Hansson, O and Tideman, P and Wuestefeld, A and Palmqvist, S},
title = {Speech-based digital cognitive assessment for clinical trials: Detecting cognitive impairment stages and AD biomarker relations across European cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71462},
doi = {10.1002/alz.71462},
pmid = {42151661},
issn = {1552-5279},
support = {//Alzheimer's Drug Discovery Foundation Diagnostic Accelerator/ ; 201906//Alzheimer's Drug Discovery Foundation (ADDF)/ ; 2018897//Alzheimer's Drug Discovery Foundation (ADDF)/ ; 201809//Alzheimer's Drug Discovery Foundation (ADDF)/ ; 2016862//Alzheimer's Drug Discovery Foundation (ADDF)/ ; //Health Department of the Catalan Government/ ; CP23/00039//Instituto de Salud Carlos III (ISCIII)/ ; //Kamprad Foundation/ ; ERAPERMED2021//ERA PerMed/ ; 184//ERA PerMed/ ; 2022//Knut and Alice Wallenberg foundation/ ; 0231//Knut and Alice Wallenberg foundation/ ; //Strategic Research Area MultiPark/ ; AF-980907//Swedish Alzheimer Foundation/ ; AF-1011949//Swedish Alzheimer Foundation/ ; AF-994075//Swedish Alzheimer Foundation/ ; AF-940046//Swedish Alzheimer Foundation/ ; AF-981132//Swedish Alzheimer Foundation/ ; 1412/22//Parkinson foundation of Sweden/ ; //Cure Alzheimer's fund/ ; FRS-0004//Rönström Family Foundation/ ; FRS-0011//Rönström Family Foundation/ ; 2020//Skåne University Hospital Foundation/ ; O000028//Skåne University Hospital Foundation/ ; 2022//Regionalt Forskningsstöd/ ; 1259//Regionalt Forskningsstöd/ ; 2022//Swedish federal government/ ; Projekt0080//Swedish federal government/ ; 2022//Swedish federal government/ ; 1346//Swedish federal government/ ; },
mesh = {Humans ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Europe ; Cohort Studies ; *Speech ; Neuropsychological Tests ; tau Proteins/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) is critical for timely intervention as disease-modifying treatments emerge. Speech-based digital biomarkers offer scalable options for remotely capturing speech-derived functional changes associated with early cognitive decline, but validation across real-world populations remains limited.

METHODS: We evaluated the speech biomarker for cognition (SB-C), an automated speech-derived measure associated with cognitive status, in 736 participants across five European cohorts (Barcelonaβeta Brain Research Center's Alzheimer's at-risk cohort, European Prevention of Alzheimer's Dementia Scotland, Dementia Study of Cognitive and Biomarker Dynamics, Longitudinal Cognitive Impairment and Dementia Study, and Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER-Primary Care]). Participants completed verbal learning and semantic fluency tasks via automated phone or app-based platforms. SB-C performance was compared to Mini-Mental State Examination, Clinical Dementia Rating, Preclinical Alzheimer Cognitive Composite 5, and cerebrospinal fluid amyloid beta and phosphorylated tau181 biomarker status.

RESULTS: SB-C significantly differentiated cognitively unimpaired and impaired groups (P < 0.001), correlated with standard cognitive measures, and showed moderate-to-high area under the curve (0.56-0.82) for classifying biomarker positivity, with strongest results in BioFINDER-Primary Care.

DISCUSSION: SB-C is a scalable, remote speech-derived marker associated with cognitive status and AD biomarker group differences.},
}

Humans
Male
Female
Biomarkers/cerebrospinal fluid
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid
*Alzheimer Disease/diagnosis/cerebrospinal fluid
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Europe
Cohort Studies
*Speech
Neuropsychological Tests
tau Proteins/cerebrospinal fluid
Aged, 80 and over
Middle Aged

@article {pmid42151696,
year = {2026},
author = {Zhang, J and Zhang, J and Ding, J and Zhang, X and Wang, Y and Wei, W and Chai, Y and Zhang, S and Chen, X},
title = {Reconstructing cerebral lymphatic clearance: an emerging target in the Alzheimer's disease therapeutic pipeline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71451},
doi = {10.1002/alz.71451},
pmid = {42151696},
issn = {1552-5279},
support = {82471397//National Natural Science Foundation of China/ ; 82271399//National Natural Science Foundation of China/ ; No.25JCLZJC00280//Joint Funds of the Natural Science Foundation of Tianjin/ ; //Tianjin Health Care Elite Prominent Young Doctor Development Program/ ; //Young and Middle-aged Backbone Innovative Talent Program/ ; //Clinical Talent Training '123' Climbing Plan of Tianjin Medical University/ ; TJYXZDXK-002A//Tianjin Key Medical Discipline (Neurosurgery) Construction Project/ ; },
mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Brain/metabolism ; *Lymphatic Vessels ; Glymphatic System ; Animals ; },
abstract = {Neurotoxic protein accumulation is widely recognized as a key feature of Alzheimer's disease (AD), and increasing evidence indicates that impaired brain clearance associated with dysfunction of the meningeal lymphatic and glymphatic may contribute to this process. Disruption of these pathways may weaken homeostatic mechanisms and facilitate amyloid‑β and tau buildup. This review considers lymphatic reconstruction as a potential therapeutic direction aimed at modestly improving clearance efficiency. We summarize current findings from pharmacological approaches targeting aquaporin-4 or vascular endothelial growth factor C signaling, non-invasive methods such as photobiomodulation and focused ultrasound, and emerging surgical or lifestyle interventions designed to enhance drainage. Early clinical attempts, including deep cervical lymphovenous anastomosis (dCLVA), provide preliminary proof of concept but require careful validation. Progress in this field also depends on developing sensitive, non-invasive imaging markers and defining appropriate intervention windows. By situating lymphatic modulation within the broader AD drug-development landscape, we highlight its possible role within multimodal therapeutic strategies.},
}

*Alzheimer Disease/therapy/metabolism
Humans
*Brain/metabolism
*Lymphatic Vessels
Glymphatic System
Animals

@article {pmid42151697,
year = {2026},
author = {Visentini, AE and Reichert, KP and Schetinger, MRC and Bottari, NB and Miron, VV and Castro, MFV and da Silveira, MV and Assmann, CE and Schirmann, AA and Morsch, VMM},
title = {Resveratrol as a potential natural compound to ameliorate cognitive impairment in aluminum-exposed mice: impacts on behavior, purinergic system, and brain inflammation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42151697},
issn = {1573-7365},
}

@article {pmid42151713,
year = {2026},
author = {Stijven, F and Mallinckrodt, C and Molenberghs, G and Alonso, A and Dickson, SP and Hendrix, SB},
title = {Time-Scale Target Parameters and Two-Step Estimation in Longitudinal Trials for Progressive Diseases.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70591},
doi = {10.1002/sim.70591},
pmid = {42151713},
issn = {1097-0258},
support = {//Agentschap Innoveren en Ondernemen/ ; HBC.2022.0145//Johnson & Johnson Innovative Medicine/ ; },
mesh = {Humans ; *Disease Progression ; Longitudinal Studies ; Alzheimer Disease/drug therapy/therapy ; *Randomized Controlled Trials as Topic/statistics & numerical data/methods ; Computer Simulation ; Models, Statistical ; Time Factors ; Treatment Outcome ; Data Interpretation, Statistical ; },
abstract = {In progressive diseases such as Alzheimer's, treatments that slow progression should start early to preserve higher levels of functioning for a longer period. In corresponding clinical trials, treatment effects are usually expressed as mean differences on a clinical scale at fixed time points. Early in the disease course, however, these mean differences may appear small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. We introduce a class of target parameters that quantify treatment effects on the time scale in longitudinal studies; for instance, in terms of time saved or percentage slowing of progression. We focus on data from randomized trials where the target parameters are identified under regularity assumptions. These target parameters remain well defined if treatment was not randomized, but additional untestable assumptions are required for identification. We propose general two-step estimators. In the first step, the data can be analyzed with standard methods for longitudinal data and standard software can thus be used. In the second step, summary statistics from the first step are used for inferences about the target parameters. The second step has been implemented in the TCT R package. We study the asymptotic properties and efficiency of these two-step estimators, and evaluate them in an extensive simulation study. These estimators are used in a phase 2/3 clinical trial for Alzheimer's disease, leading to important additional insights into the treatment effect.},
}

Humans
*Disease Progression
Longitudinal Studies
Alzheimer Disease/drug therapy/therapy
*Randomized Controlled Trials as Topic/statistics & numerical data/methods
Computer Simulation
Models, Statistical
Time Factors
Treatment Outcome
Data Interpretation, Statistical

@article {pmid42151724,
year = {2026},
author = {Chong Chie, JAK and Persohn, SA and Simcox, OR and Collins, A and Salama, P and Territo, PR and , },
title = {Neurovascular-metabolic dysregulation, metabolic connectomics, and metabolic functional changes in Alzheimer's disease: A preclinical and clinical comparison.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71496},
doi = {10.1002/alz.71496},
pmid = {42151724},
issn = {1552-5279},
support = {T32AG071444//Stark Neuroscience Research Institute/ ; U54AG054345//Stark Neuroscience Research Institute/ ; },
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Animals ; Humans ; Mice ; *Brain/metabolism/diagnostic imaging/blood supply ; Disease Models, Animal ; Male ; Female ; *Connectome ; Aged ; Cerebrovascular Circulation/physiology ; Positron-Emission Tomography ; },
abstract = {Historically, imaging diagnostics in Alzheimer's disease (AD) have focused primarily on amyloid and tau accumulation; however, recent work suggests that neurometabolic and vascular dysregulation (MVD) may precede protein deposition and persist throughout the disease spectrum, preclinically and clinically. Translating these findings between human patients and preclinical mouse models remains challenging due to cross-species differences. To address this, regional MVD phenotypes were identified using cerebral metabolism and blood flow, and region-set enrichment analysis (RSEA) was conducted to assess brain functional category (BFC) changes based on metabolic variations, facilitating systematic cross-species comparisons. Clinically, MVD showed progressive alterations across the AD spectrum, while mouse models demonstrated similar genotype- and age-dependent changes. Although direct one-to-one regional correspondence is limited, RSEA revealed changes in comparable BFCs. Our findings suggest that imaging-based MVD mapping and RSEAs can bridge species differences, offering a translational framework to support early diagnostics of AD, enhance disease stratification, and enable therapeutic testing.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Animals
Humans
Mice
*Brain/metabolism/diagnostic imaging/blood supply
Disease Models, Animal
Male
Female
*Connectome
Aged
Cerebrovascular Circulation/physiology
Positron-Emission Tomography

@article {pmid42151730,
year = {2026},
author = {Sutherland, GT and Chen, A and Nguyen-Hao, HT and Mundell, H and Aladyeva, E and Hofer, MJ and Harari, O and Twigg, SM},
title = {How does type 2 diabetes modify the risk of Alzheimer's disease?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71471},
doi = {10.1002/alz.71471},
pmid = {42151730},
issn = {1552-5279},
support = {//Lucas Papaw Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/epidemiology ; *Diabetes Mellitus, Type 2/metabolism/complications ; Brain/metabolism/pathology ; Microglia/metabolism ; Risk Factors ; Blood-Brain Barrier/metabolism ; Inflammation ; Insulin Resistance ; Apolipoproteins E/metabolism ; },
abstract = {Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both increasing exponentially worldwide. T2D has also been identified as one of 14 modifiable risk factors for dementia, but the mechanism is unknown. T2D could promote dementia via vascular or AD neuropathological changes, and mechanistic hypotheses include central insulin resistance and T2D's peripheral inflammation promoting central inflammation. Here we examine these different hypotheses by reviewing the recent literature in combination with re-analysis of post mortem brain tissue molecular data. Collectively, recent studies and single-cell transcriptomic data suggest that peripheral lipid anomalies and inflammation seen in T2D act together to reduce brain-blood barrier integrity, facilitating aberrant immune signaling between the periphery and the brain. The subsequent promotion of AD-specific microglial subtypes is the most likely mechanism linking T2D and AD. These AD-specific microglial subtypes may be reduced by therapeutic targeting of triggering receptor expressed on myeloid cells 2-apolipoprotein E signaling pathway.},
}

Humans
*Alzheimer Disease/metabolism/pathology/epidemiology
*Diabetes Mellitus, Type 2/metabolism/complications
Brain/metabolism/pathology
Microglia/metabolism
Risk Factors
Blood-Brain Barrier/metabolism
Inflammation
Insulin Resistance
Apolipoproteins E/metabolism

@article {pmid42151732,
year = {2026},
author = {Hammers, DB and Foster, E and Eloyan, A and Thangarajah, M and Taurone, A and Touroutoglou, A and La Joie, R and Beckett, L and Gao, S and Vemuri, P and Nudelman, KN and Kirby, K and Dage, JL and Aisen, P and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Parand, L and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Dickerson, BC and Rabinovici, GD and Carrillo, MC and Apostolova, LG and , },
title = {Cognitive dispersion profiles and prediction of cognitive change in early-onset dementias: Results from LEADS.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71492},
doi = {10.1002/alz.71492},
pmid = {42151732},
issn = {1552-5279},
support = {AARG-22-926940/ALZ/Alzheimer's Association/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; K23 AG080071/ALZ/Alzheimer's Association/United States ; R56 AG057195/ALZ/Alzheimer's Association/United States ; U01AG6057195/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; U01 AG016976/ALZ/Alzheimer's Association/United States ; P30 AG010133/ALZ/Alzheimer's Association/United States ; P50 AG008702/ALZ/Alzheimer's Association/United States ; P50 AG025688/ALZ/Alzheimer's Association/United States ; P50 AG005146/ALZ/Alzheimer's Association/United States ; P30 AG062421/ALZ/Alzheimer's Association/United States ; P30 AG062422/ALZ/Alzheimer's Association/United States ; P50 AG023501/ALZ/Alzheimer's Association/United States ; P30 AG010124/ALZ/Alzheimer's Association/United States ; P30AG066506/ALZ/Alzheimer's Association/United States ; P30 AG013854/ALZ/Alzheimer's Association/United States ; P50 AG005681/ALZ/Alzheimer's Association/United States ; P50AG047366/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; R56AG057195/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; Neuropsychological Tests/statistics & numerical data ; *Dementia/psychology ; *Cognition/physiology ; Biomarkers ; Middle Aged ; *Alzheimer Disease/psychology ; Age of Onset ; },
abstract = {INTRODUCTION: Research into cognitive dispersion - a cognitive process score measuring the intra-individual variability (IIV) across a single testing session - suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early-onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition.

METHODS: A total of 309 participants (188 amyloid-positive EOAD, 43 amyloid-negative early-onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion-related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain-specific cognitive trajectories, and its convergence with imaging biomarkers.

RESULTS: EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD-specific biomarkers. Additionally, cognitive dispersion was associated with 12-month reliable change across several cognitive domains.

DISCUSSION: These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.},
}

Humans
Female
Male
Neuropsychological Tests/statistics & numerical data
*Dementia/psychology
*Cognition/physiology
Biomarkers
Middle Aged
*Alzheimer Disease/psychology
Age of Onset

@article {pmid42151735,
year = {2026},
author = {Landau, SM and Liu, P and Harrison, TM and Taggett, J and Ward, TJ and Murphy, A and Lockhart, SN and Lovato, LC and Koeppe, R and Farias, ST and Papp, KV and Snyder, HM and Harvey, DJ and Espeland, M and Maillard, P and DeCarli, C and Vemuri, P and Weiner, M and Baker, LD and Jagust, WJ and , },
title = {Elevated AD biomarkers do not explain cognitive performance in a community-recruited clinical trial cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71472},
doi = {10.1002/alz.71472},
pmid = {42151735},
issn = {1552-5279},
support = {U.S. POINTER-19-611541/ALZ/Alzheimer's Association/United States ; //Alzheimer's Disease Neuroimaging Initiative/ ; R01AG062689/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //Intramural Research Program of the National Institute on Aging/ ; //Center for Alzheimer's and Related Dementias/ ; //Intramural Research Program/ ; AG000546/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; *Biomarkers/cerebrospinal fluid/metabolism ; *Alzheimer Disease/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism/cerebrospinal fluid ; Aged ; Cohort Studies ; *Cognition/physiology ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: To examine the generalizability of Alzheimer's disease (AD) biomarker models in real-world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics.

METHODS: We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community-recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics.

RESULTS: Elevated β-amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk.

DISCUSSION: The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.},
}

Humans
Female
Male
*Biomarkers/cerebrospinal fluid/metabolism
*Alzheimer Disease/metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism/cerebrospinal fluid
Aged
Cohort Studies
*Cognition/physiology
Neuropsychological Tests
Aged, 80 and over

@article {pmid42151912,
year = {2026},
author = {Stuardo, N and Cáceres-Quezada, Á and Guzmán, D and Lamaizon, CM and Leal R, N and Koleske, AJ and Álvarez R, A},
title = {Abl kinase activation promotes axon initial segment disassembly and protein sorting defects in Alzheimer's disease.},
journal = {BMC biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12915-026-02624-5},
pmid = {42151912},
issn = {1741-7007},
abstract = {BACKGROUND: Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse.

RESULTS: We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function.

CONCLUSIONS: Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.},
}

@article {pmid42151941,
year = {2026},
author = {Luo, M and Zhao, FK and Wang, YM and Bian, J and Luo, Y},
title = {Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997-2025): trends and future directions.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04529-5},
pmid = {42151941},
issn = {1477-3155},
support = {Zunyi Science and Technology Talent Team Project [2024] No. 6//Zunyi Science and Technology Bureau/ ; No. 39 (2023)//Zunshi Science and Technology Cooperation Letter/ ; (QZYY-2024-094)//Science and technology research topic of traditional Chinese medicine and ethnic medicine of Guizhou Provincial Administration of Traditional Chinese Medicine/ ; No: 24QNMP019//Health Commission of Sichuan Province Medical Science and Technology Program/ ; 25MSZX259//Scientific Research Projects of the Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2026NSFSC1634//Sichuan Province Natural Science Foundation/ ; },
abstract = {Nanomaterials have demonstrated substantial promise in the diagnosis and treatment of neurological and psychiatric disorders, offering novel strategies to overcome the limitations of traditional therapies. This review utilizes bibliometric analysis to evaluate global trends in nanomaterial research for neurological and psychiatric diseases, based on a corpus of 3,987 publications retrieved from the Web of Science Core Collection spanning from 1997 to August 2025. The analysis reveals a consistent upward trajectory in annual publications, reflecting substantial and growing international interest across diverse regions. Following an overview of global research dynamics, this review explores the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia. The mechanisms underlying these conditions, including neuroinflammation, oxidative stress, protein aggregation, and neurotransmitter imbalances, are systematically discussed. Subsequently, the review focuses on how nanomaterials, including nanoparticles, nanocomposites, and nanocarriers, target these pathogenic mechanisms. The therapeutic applications of nanomaterials are evaluated with respect to their ability to modulate neuroinflammation, reduce oxidative stress, improve drug delivery to the brain, and facilitate the repair of neuronal damage. Despite the promising potential of nanomaterials, several challenges remain, including biocompatibility, targeted delivery, and scalability of treatment options. The review concludes by highlighting future directions for research, emphasizing the need for continued innovation in nanomaterial design and application to address these challenges and advance clinical treatments for neurological and psychiatric disorders.},
}

@article {pmid42152074,
year = {2026},
author = {Erisir, A and Maher, EE and Anderson, Z and Chawla, S and Hanley, L and Zhao, A and Birisik, K and Toklucu, ES and Keskinoz, EN},
title = {Dysregulated oligodendrocyte and myelin dynamics as an early pathological feature of neuropil degeneration in Alzheimer's disease: an ultrastructural study.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02320-z},
pmid = {42152074},
issn = {2051-5960},
support = {ARDRAF-16-2//Alzheimer's and Related Diseases Research Award Fund/ ; 3501- 219S307//Scientific and Technological Research Council of Turkey (TÜBİTAK), Career Development Program/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by the accumulation of amyloid‑β plaques and neurofibrillary tangles. Increasing evidence suggests that white‑matter degeneration and myelin disruption occur early in disease progression and may contribute to neuropathological vulnerability. Here, we performed ultrastructural analyses in the 3xTg and 5xFAD mouse models of AD across developmental stages (3-12 months of age), including ages preceding overt amyloid plaque formation or neuronal loss. We identify a spectrum of oligodendrocyte‑ and myelin‑associated abnormalities, including single‑membrane herniations, myelin outfolds, and ectopic myelination of neuronal processes, which are evident as early as 3 months of age and are frequently associated with altered neuropil architecture and incipient dystrophic neurite morphology. These malformations were confirmed to be oligodendrocyte‑derived through O4 immunolabeling. Collectively, our findings reveal early, widespread myelin‑associated ultrastructural alterations that form a consistent structural component of neuritic pathology in AD models. We propose that dysregulated oligodendrocyte membrane remodeling represents an early pathological feature of AD, providing a framework for future studies examining how glial pathology intersects with neuronal degeneration and plaque‑associated neuritic remodeling.},
}

@article {pmid42152119,
year = {2026},
author = {Skácelíková, E and Vyhnálek, M and Děchtěrenko, F and Nikolai, T and Veverová, K},
title = {Willingness and barriers to blood-based biomarker testing of Alzheimer's disease in the general population in the Czech Republic.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02070-z},
pmid = {42152119},
issn = {1758-9193},
support = {PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; CZ.02.01.01/00/22_008/0004595//European Regional Development Fund, under the project "Beyond Security: Role of Conflict in Resilience-Building"/ ; },
abstract = {BACKGROUND: Blood-based biomarkers (BBBM) for Alzheimer's disease (AD) are entering clinical practice with new clinical practice guidelines and the first FDA-approved blood test. Their implementation will depend not only on assay performance but also on public willingness, trust, and understanding of probabilistic results. We examined attitudes towards BBBM in the general population and psychosocial factors that may facilitate or hinder uptake.

METHODS: We conducted an online cross-sectional survey among adults aged ≥ 35 years (M = 51.08, SD = 9.79) in the Czech Republic (N = 666). The survey assessed willingness to undergo BBBM testing, sociodemographic characteristics, experience with AD, depressive symptoms (Patient Health Questionnaire, PHQ-9), concerns about developing AD, and medical distrust (Medical Distrust Index, MDI). Logistic regression models (unweighted and weighted for gender and region) were estimated to examine the association with willingness. Open-ended responses were analyzed thematically to identify motivators and barriers.

RESULTS: Overall, 92.8% of participants reported that they would undergo BBBM testing. Greater concern about developing AD was the strongest facilitator (OR = 1.59-2.34). Having AD in a close family member was associated with lower willingness (OR = 0.31-0.43), as was higher medical distrust (MDI OR = 0.79 in the fully weighted model). Education, age, gender, depressive symptoms, and AD knowledge were not significantly associated with willingness. Qualitative analyses showed that participants viewed BBBM as a way to "take action in time", "know one's health status" and "prepare for the future", whereas fear of AD, preference "not to know", perceived lack of treatment, test uncertainty/"only probability", and privacy concerns were common barriers.

CONCLUSIONS: Public willingness to undergo BBBM testing is high, but psychosocial barriers, particularly familial experience of AD and medical distrust, may limit real-world uptake. Addressing these barriers through targeted education, probabilistic risk communication, and trusted primary-care pathways will be essential for the responsible implementation of BBBM in clinical practice.},
}

@article {pmid42152268,
year = {2026},
author = {Huang, QQ and Zhang, XL and He, SJ and Zhou, YH and Wang, T and Zhang, CX},
title = {Exploring the Mechanism of Saponins from Panax japonicus in Improving Alzheimer's Disease Based on Network Pharmacology and Molecular Docking.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471394260327075445},
pmid = {42152268},
issn = {1875-5828},
abstract = {INTRODUCTION: To study the mechanism of saponins from Panax japonicus (SPJ) in improving Alzheimer's disease based on network pharmacology and molecular docking technology.

METHODS: The active components in the SPJ were obtained from the databases of CNKI, PubMed, and PubChem. The active component targets were retrieved from the databases of Swiss Target Prediction and Super-PRED. The disease targets were retrieved from the databases GeneCards, OMIM, and PharmGKB. Drug-disease intersection targets were obtained via Venny 2.1.0. The String database was utilized to establish the protein network. The drug- active ingredient- target network was constructed by Cytoscape 3.10.1 software. The Metascape database was employed to conduct the gene ontology function enrichment analysis and KEGG pathway enrichment analysis. AutoDock Tools 1.5.7 was used to perform the molecular docking analysis.

RESULTS: A total of 57 active components were obtained from the SPJ, and 438 drug targets and 2294 disease targets were identified, including 169 identical targets. The key targets were SRC, STAT3, PIK3R1, AKT1, ESR1, EGFR, and JUN. Pseudoginsenoside F11, Vina-ginsenoside R2, and Chikusetsusaponin III might be the key active components of SPJ in improving Alzheimer's disease. The key active components showed good binding energy and better binding affinity within the active targets.

DISCUSSION: Network pharmacology has screened out 57 potential active components of SPJ, including pseudo ginsenoside F11, ginsenoside R2, and III, which may exert therapeutic effects by acting on key targets such as SRC, STAT3, PIK3R1, AKT1, ESR1, EGFR, and JUN. These targets are closely related to core pathological processes of AD, such as Aβ production, Tau protein phosphorylation, neuroinflammation, neuronal survival, and synaptic plasticity. Functional analysis indicates that SPJ may act on multiple cellular sites, such as receptor complexes and synaptic membranes, by influencing biological processes such as cell migration, inflammatory response, and membrane potential regulation. Pathway enrichment suggests that its mechanism of action may be related to Alzheimer's disease pathways, the NF-κB signaling pathway, and the calcium signaling pathway. The continuous activation of NF-κB can exacerbate neuroinflammation and oxidative damage, while the disorder of the calcium signaling pathway will lead to intracellular calcium overload, mitochondrial dysfunction, and synaptic damage, all of which play key roles in the progression of AD.

CONCLUSION: SPJ exerts a therapeutic effect and provides the basis for Alzheimer's disease through multiple components, targets, and pathways.},
}

@article {pmid42152315,
year = {2026},
author = {Gao, X and Wang, L},
title = {Associations of gut bacterial classes Clostridia and Deltaproteobacteria with type 2 diabetes and Alzheimer's disease: A two-sample Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {20},
pages = {e48685},
doi = {10.1097/MD.0000000000048685},
pmid = {42152315},
issn = {1536-5964},
support = {2021C018//Development and Reform Commission of Jilin Province/ ; JJKH20210062KJ//Jilin Provincial Department of Education/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/microbiology/genetics/epidemiology ; *Alzheimer Disease/microbiology/genetics/epidemiology ; Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; },
abstract = {Using a 2-sample Mendelian randomization (MR) approach, we evaluated MR evidence for genetically proxied effects of 10 pre-specified gut bacterial classes on type 2 diabetes mellitus (T2DM) and Alzheimer disease (AD), and assessed MR evidence for a direct genetically proxied effect of T2DM on AD. Mediation by T2DM was explored where feasible. We performed 2-sample MR using MiBioGen gut microbiota GWAS summary statistics as exposure, and DIAMANTE (T2DM) and European AD GWAS data as outcomes. Inverse-variance weighted (IVW) MR was the primary analysis, with MR-Egger, weighted median, and weighted mode as sensitivity analyses. Heterogeneity and directional pleiotropy were assessed, and IVW results were false discovery rate (FDR) corrected using Benjamini-Hochberg. MR analysis using 184 independent SNPs provided no robust evidence for a direct genetically proxied effect of T2DM on AD risk (IVW odds ratio [OR] = 0.98, 95% confidence interval [CI]: 0.94-1.02, P = .28). After FDR correction, higher genetically predicted Clostridia abundance was associated with lower AD risk (IVW OR = 0.86, 95% CI: 0.77-0.96, FDR < 0.05), and higher genetically predicted Deltaproteobacteria abundance was associated with higher T2DM risk (IVW OR = 1.11, 95% CI: 1.04-1.20, FDR < 0.05). Other classes were not significant after FDR correction. Reverse MR and multivariable MR were not testable due to insufficient SNP overlap after harmonization (effective SNPs < 3). These findings provide MR evidence consistent with genetically proxied effects of Clostridia on AD and Deltaproteobacteria on T2DM and do not support robust MR evidence for a direct genetically proxied effect of T2DM on AD. Results are hypothesis-generating and require replication in diverse ancestries and follow-up mechanistic/experimental studies, given that included GWAS sources are predominantly of European ancestry.},
}

Humans
*Diabetes Mellitus, Type 2/microbiology/genetics/epidemiology
*Alzheimer Disease/microbiology/genetics/epidemiology
Mendelian Randomization Analysis
*Gastrointestinal Microbiome/genetics
Polymorphism, Single Nucleotide
Genome-Wide Association Study

@article {pmid42152579,
year = {2026},
author = {Shi, W and Zhu, Z and Wu, M and Cheng, W and Xu, H},
title = {Hip Bone Marrow Adiposity as a Risk Factor for Alzheimer's Disease: Insights From Mendelian Randomization Analysis.},
journal = {Annals of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/ahg.70041},
pmid = {42152579},
issn = {1469-1809},
support = {//Key Clinical Research Project of the Morning Light Program under the Exploration Program of Wuhan Natural Science Foundation/ ; //Youth Project of the Natural Science Foundation of Hubei Province/ ; },
abstract = {BACKGROUND: The bone-brain axis has emerged as a critical framework linking skeletal metabolism to neurodegeneration. Within this axis, bone marrow adipose tissue (BMAT) represents a unique fat depot with distinct endocrine and hematopoietic functions, yet its contribution to Alzheimer's disease (AD) remains unclear.

METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics to assess the causal effects of six fat depots-abdominal subcutaneous, visceral, spinal, femoral head, total hip, and femoral diaphysis fat-on AD risk. Mediation analysis was further performed to evaluate whether femoral neck bone mineral density (BMD) mediates these associations.

RESULTS: Among the six depots, only total hip BMAT showed a significant causal association with AD risk (OR = 1.28, 95% CI: 1.09-1.51, p = 0.003). Total hip BMAT was inversely related to femoral neck BMD (β = -0.43, 95% CI: -0.61 to -0.24, p < 0.001), whereas no causal relationship was detected between BMD and AD (OR = 1.01, 95% CI: 0.89-1.15, p = 0.849), excluding bone loss as a mediator.

CONCLUSIONS: This study provides the first genetic evidence that excessive hip BMAT increases the risk of AD, supporting the bone-brain axis hypothesis. These findings highlight BMAT as a novel target for understanding and potentially preventing AD.},
}

@article {pmid42152586,
year = {2026},
author = {Yuan, L and Asghar, MA and Zhang, Y and Yang, Y and Zhang, X and Zhao, Q},
title = {Effective Amelioration of Alzheimer's Disease in Preclinical Models With Electrophilic Compounds via Nrf2 Pathway Activation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {6},
pages = {e70909},
doi = {10.1002/jbt.70909},
pmid = {42152586},
issn = {1099-0461},
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; *NF-E2-Related Factor 2/metabolism ; Humans ; Animals ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; *Signal Transduction/drug effects ; Disease Models, Animal ; *Phytochemicals/therapeutic use/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes, with no effective treatments currently available. Oxidative stress has been shown to be associated with AD, but the causal relationship of AD by oxidative stress remains unestablished. Activation of the Nrf2 pathway is a powerful way to counteract oxidative stress. There are lines of evidence that the pathological features, including Aβ deposition, Tau phosphorylation, neuroinflammation, and mitochondrial dysfunction, could be ameliorated by different antioxidant measures. A group of Nrf2 pathway activators, functioning as Michael acceptors, can covalently modify the Keap1 protein. Such a reaction triggers a conformational change of Keap1, facilitating the release of functional Nrf2 and its subsequent translocation into the nucleus. As a result, a cascade of antioxidant related proteins is expressed. Many plant-derived compounds with Nrf2 pathway activation properties were shown to improve the AD symptom in animal models. This review summarizes the phytochemicals and FDA-approved drugs with diverse structure, including isothiocyanates, polyphenols, phenylpropanoids, flavonoids, terpenes, and alkaloids, but all with Nrf2 pathway activation function and effects on the ameliorating effects on AD symptoms. Three of FDA-approved drugs, being Nrf2 activators, are for the disorders in nervous system. Therefore, Nrf2 could be a promising target for future drug development based on rational design or on the screening from the phytochemicals.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
*NF-E2-Related Factor 2/metabolism
Humans
Animals
*Oxidative Stress/drug effects
*Antioxidants/therapeutic use/pharmacology
*Signal Transduction/drug effects
Disease Models, Animal
*Phytochemicals/therapeutic use/pharmacology

@article {pmid42152587,
year = {2026},
author = {Atasoy, T and Sajedi, H and Khodadadi, D and Tozoğlu, B and Güler, MŞ and Aka, ST and Babaei, M},
title = {Intermittent Fasting Potentiates Aerobic Exercise to Reduce Hippocampal Amyloid Burden and Oxidative Stress via Suppression of NF-κB/NLRP3 Signaling in an Aβ-Injected Rat Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e9921337},
doi = {10.1155/omcl/9921337},
pmid = {42152587},
issn = {1942-0994},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Hippocampus/metabolism/pathology ; Male ; *Oxidative Stress ; Rats ; *Amyloid beta-Peptides/toxicity/metabolism ; *Fasting ; Rats, Wistar ; *Physical Conditioning, Animal ; *NF-kappa B/metabolism ; Signal Transduction ; Disease Models, Animal ; *Alzheimer Disease/metabolism/pathology ; Intermittent Fasting ; },
abstract = {NOD-like receptor protein 3 (NLRP3) inflammasome-driven neuroinflammation contributes to Alzheimer's disease (AD) progression, yet effective strategies to target this pathway are limited. We investigated whether aerobic exercise performed in a fasted state, rather than the fed state, would potentiate β-hydroxybutyrate (BHB)-dependent inhibition of NLRP3 inflammasome signaling. Twenty-month-old male Wistar rats were randomly assigned to five groups: AD, AD + intermittent fasting (ADIF), AD + aerobic exercise (ADAE), ADIF + aerobic exercise (ADIFAE), and sham-injected control (SC). AD-like pathology was induced by bilateral intrahippocampal injection of amyloid-β (Aβ)1-42. The IF regimen consisted of a daily 14-h fast (06:00-20:00). Exercise consisted of moderate-intensity treadmill running (5 days/week for 4 weeks), either in the fed state or after ∼12.5 h of fasting. Aβ injection impaired spatial learning and memory, elevated soluble Aβ1-42 (sAβ), malondialdehyde (MDA), NF-κB, NLRP3, caspase-1, interleukin-1β (IL-1β), and IL-18, and reduced superoxide dismutase (SOD) activity and brain-derived neurotrophic factor (BDNF) expression in the hippocampus (p < 0.05). Both IF and exercise partially reversed cognitive impairments by reducing sAβ and oxidative stress, increasing BHB, suppressing NF-κB/NLRP3 signaling, and restoring BDNF (p < 0.05), while fasted-state exercise produced significantly larger effects than either intervention alone (p < 0.05). Our findings suggest that performing exercise in a fasted state provides complementary metabolic, anti-inflammatory, and cognitive benefits that exceed those of either intervention alone. This combined regimen may represent a promising nonpharmacological strategy for targeting metabolic-immune and neurotrophic pathways relevant to AD progression.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Hippocampus/metabolism/pathology
Male
*Oxidative Stress
Rats
*Amyloid beta-Peptides/toxicity/metabolism
*Fasting
Rats, Wistar
*Physical Conditioning, Animal
*NF-kappa B/metabolism
Signal Transduction
Disease Models, Animal
*Alzheimer Disease/metabolism/pathology
Intermittent Fasting

@article {pmid42152599,
year = {2026},
author = {Casey, N and Faraco, G},
title = {Mechanisms of neurovascular regulation in health and disease: Insights from experimental animal models.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261448670},
doi = {10.1177/0271678X261448670},
pmid = {42152599},
issn = {1559-7016},
abstract = {The brain is an energetically demanding organ that relies on a continuous and precisely regulated blood supply to sustain neuronal function. This regulation is achieved through an intricate vascular network and sophisticated control mechanisms that dynamically match cerebral blood flow (CBF) to local metabolic demands. Central to this process is the neurovascular unit (NVU), a multicellular ensemble composed of endothelial cells, mural cells, astrocytes, neurons, microglia, and extracellular matrix components. Through coordinated interactions, the NVU governs vascular tone, blood-brain barrier integrity, and metabolic exchange. In this Review, we first describe the structural organization of the cerebrovascular tree and the specialized features of its cellular constituents. We then examine the principal mechanisms controlling CBF, including neurovascular coupling, cerebrovascular autoregulation, and endothelial regulation of vascular tone, highlighting the underlying molecular and cellular pathways. Emphasis is placed on mechanistic insights derived from experimental animal models, which have been fundamental for dissecting the basic biology of neurovascular regulation. Finally, we discuss how disruption of these regulatory systems contributes to cerebrovascular and neurodegenerative diseases, including hypertension and Alzheimer's disease (AD), primarily drawing on preclinical evidence.},
}

@article {pmid42152645,
year = {2026},
author = {Kishor, K and Arora, A and Yashika, and Yadav, S and Singh, A},
title = {Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Immunotherapy Links, and Clinical Translation.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128464813260512100753},
pmid = {42152645},
issn = {1873-4286},
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, neuroinflammation, and cognitive impairment. Although amyloid-β and tau continue to serve as core biomarkers and therapeutic targets, the clinical efficacy of recent biologic agents targeting amyloid has led to a new paradigm in AD treatment. Nevertheless, emerging data show that lipid metabolism is an important and well-established aspect of AD pathophysiology rather than a new theory. Lipid processing in microglia, astrocytes, and neurons is disrupted, leading to chronic inflammation, impaired amyloid clearance, mitochondrial dysfunction, and synaptic dysfunction. This review critically analyzes how lipid accumulation and lipid droplet biology contribute to Alzheimer's disease using cellular, animal, and human studies. Special focus is placed on enzymatic regulators such as DGAT2, cholesterol transport, and neuron-glia metabolic linkages. This review synthesizes existing mechanistic and translational data to emphasize lipid dysregulation as a complementary therapeutic target and potential biomarker axis that may improve current amyloid- and taudirected therapeutic strategies.},
}

@article {pmid42152660,
year = {2026},
author = {Younas, S and Badshah, I and Akbar, K and Al-Otaibi, JS and Khan, H},
title = {3-(2,4-Dimethylbenzylidene)-6-chloroindolin-2-one Alleviates Memory Impairment in D-Galactose-induced Alzheimer Like Pathology in a Mouse Model.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X434400260421062719},
pmid = {42152660},
issn = {1875-6190},
abstract = {INTRODUCTION: Oxidative stress and neuroinflammation are the main contributors to Alzheimer's disease (AD). The current study evaluated the neuroprotective efficacy of 3-(2,4- dimethylbenzylidene)-6-chloroindolin-2-one (DMO) against D-Galactose (GAL)-induced neuroinflammation, oxidative stress, and memory impairment in mice.

METHODS: Swiss Male albino mice weighing (25-30 g) were assigned to five experimental groups (n=6) (i) Normal group (received normal saline 0.9%) (ii) Control group (received GAL 100 mg/kg i.p) (iii) Standard group (received Donepezil 5 mg/kg + GAL 100 mg/kg i.p) (iv) Treatment group 1 (received DMO 5 mg/kg + GAL 100 mg/kg i.p) and Treatment group 2 (received DMO 10 mg/kg + GAL 100 mg/kg i.p) once daily for 8 weeks. After treatment, the mice were subjected to behavioral analysis, followed by sacrifice for further analysis.

RESULTS: DMO alleviated GAL-induced cognitive impairment as shown by the Morris water maze test (MWM), Y-maze, elevated plus maze (EPM), and open field (OF) test. Brain tissue histology showed reversal of distorted neuronal structures and decreased pyknosis upon DMO treatment. DMO also decreased the levels of Glutathione-S-Transferase (GST), reduced Glutathione (GSH), and catalase (CAT), concomitant with increased lipid peroxidase (LPO). Furthermore, levels of TNF-α and NF- ҡB, were significantly reduced in the DMO treatment groups as quantified by ELISA. In addition, Reverse transcription polymerase chain reaction (RT-PCR) showed a substantial decrease in the expression of β-amyloid and Tau protein.

DISCUSSION: The results showed that DMO inhibits D-gal induced oxidative stress, neuroinflammation and consequently alleviates memory impairment.

CONCLUSION: Our novel findings suggest that DMO could be a promising therapeutic modality for the treatment of brain aging-associated disorders.},
}

@article {pmid42152663,
year = {2026},
author = {Xu, G and Li, R and Hong, Z and Gan, D and Wu, Y and Yang, X and Wang, C},
title = {CREB-Mediated Regulation of Microglial Polarization in Central Nervous System Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X446686260228190032},
pmid = {42152663},
issn = {1875-6190},
abstract = {The cAMP response element-binding protein (CREB) is a crucial transcription factor that regulates cell survival, synaptic plasticity, and immune responses in the central nervous system (CNS). Recent studies have highlighted its key role in modulating microglial polarization, a pivotal process in neuroinflammation. CREB activation promotes the anti-inflammatory M2 phenotype by upregulating IL-10 and Arg-1, while repressing M1-associated pro-inflammatory genes such as TNF-α and COX-2. Beyond these direct transcriptional effects, CREB functions as a signalintegration hub that interfaces with cAMP/PKA, NF-κB, PI3K/Akt and MAPK cascades, and cooperates with metabolic regulators, including PGC-1α, Nrf2 and PPARγ, to coordinate mitochondrial function and redox balance. CREB also influences neurotrophic factor expression (e.g., BDNF and NGF), inflammasome activity, and phagocytic responses, thereby coupling microglial states to neuronal survival. This review summarizes current advances in the molecular mechanisms of CREBregulated microglial polarization and discusses how these pathways contribute to CNS disorders such as Alzheimer's and Parkinson's disease, cerebral ischemia, multiple sclerosis, affective disorders, and pain-related disorders. Finally, we outline emerging CREB-targeted pharmacological and biological strategies, and highlight key knowledge gaps and safety considerations that must be addressed before CREB-based modulation of microglia can be translated into effective neuroimmune therapies.},
}

@article {pmid42152670,
year = {2026},
author = {Bjørklund, G and Izmailovich, M and Glushkova, N and Semenova, Y},
title = {Vitamin E in Alzheimer's Disease: A Perspective on Antioxidant Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673386940251024110821},
pmid = {42152670},
issn = {1875-533X},
abstract = {This study explores the relationship between vitamin E and Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline, memory loss, and language impairment. Vitamin E is a fat-soluble antioxidant crucial in protecting cells from oxidative damage. The biochemistry and bioavailability of vitamin E are discussed, including its absorption, transport, and storage in the body. The section on interactions between vitamin E and other nutrients and herbals highlights how combining vitamin E supplements with other supplements or medications can affect its absorption, metabolism, and effectiveness. This study also discusses the potential therapeutic effects of vitamin E on AD, including its ability to reduce oxidative stress and inflammation, which are thought to play a role in the pathophysiology of AD. It explores the synergistic effects of vitamin E with pharmaceuticals and potential side effects, and covers the use of vitamin E in combination with other drugs for AD treatment, such as cholinesterase inhibitors and memantine, as well as the possible adverse effects of vitamin E supplementation. Overall, this study highlights the importance of vitamin E in preventing and managing AD and underscores the need for further research in this area.},
}

@article {pmid42152699,
year = {2026},
author = {Oba, GMJ and Sahu, R and Shah, K and Singh, AP},
title = {Interesting Potential Derivatives Based on the Coumarin Scaffold for the Treatment of Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575449515260428094401},
pmid = {42152699},
issn = {1875-5607},
abstract = {As the most common and deadly age-related neurodegenerative disease, Alzheimer's Disease (AD) affects the vast majority of elderly individuals. As such, new drugs are being produced, and their safety is still being assessed. Coumarin-based medications are among the most important pharmacophores in both natural and synthetic medicinal compounds. Targeting several essential receptors or enzymes, this six-membered aromatic heterocycle, linked by two oxygen atoms, has numerous therapeutic applications in research and offers many opportunities for future improvements in anti-Alzheimer's drugs. Several coumarin compounds have been shown to inhibit not just enzymes and receptors but also a wide range of additional targets involved in the battle against AD. The expansion of new derivatives based on coumarins in conjunction with other moieties for the treatment of AD is the current focus of research. In order to help scientists design effective drugs with the right pharmacological activity, this study sheds light on the current therapeutic expansion of coumarin-based derivatives as well as their synthesis methods.},
}

@article {pmid42152706,
year = {2026},
author = {Karayat, M and Kaushik, N and Paliwal, D},
title = {Scopoletin as a Potential Therapeutic Agent for Neurodegenerative Disorders: Mechanisms and Perspectives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266399675251201111538},
pmid = {42152706},
issn = {1873-4294},
abstract = {Neurodegenerative diseases, such as Alzheimer's and Parkinson's, continue to pose significant challenges due to their complex aetiology and limited treatment options. Scopoletin, a naturally occurring coumarin found in a variety of medicinal plants, is being explored as a potential therapeutic agent because of its broad pharmacological profile. This review investigates scopoletin's neuroprotective potential, with particular emphasis on its antioxidant, anti-apoptotic, and cholinergic-regulating properties. It also highlights its ability to reduce oxidative stress, modulate neurotransmitter balance, and prevent protein aggregation, which are key pathological features of neurodegeneration. Despite promising preclinical findings, further research is required to establish its efficacy, optimise its bioavailability, and evaluate its safety in clinical settings. Overall, scopoletin demonstrates considerable potential as a neuroprotective compound, offering new avenues for the development of innovative therapeutics for neurodegenerative disorders. This comprehensive review aims to provide a foundation for future research and the advancement of scopoletin as a promising agent against neurodegeneration.},
}

@article {pmid42152708,
year = {2026},
author = {Singh, K and Sethi, P and Jain, D and Gupta, JK and Waqar, Z and Singh, B and Syed, R and Tabish, M and Sharma, MC},
title = {Molecular Mechanisms of Neurodegeneration: A Focus on Cholinergic Dysfunction and the Therapeutic Potential of Rivastigmine Derivatives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266380856251204044937},
pmid = {42152708},
issn = {1873-4294},
abstract = {Neurodegenerative diseases progressively impair neuronal structure and function, leading to cognitive decline, motor dysfunction, and paralysis. Among the underlying mechanisms, cholinergic dysfunction-characterized by degeneration of cholinergic neurons and reduced acetylcholine (ACh) levels-plays a central role in disease progression, particularly in Alzheimer's disease (AD) and Parkinson's disease (PD). According to the cholinergic hypothesis, memory loss and cognitive impairment are directly linked to disrupted ACh-mediated neurotransmission. Rivastigmine, a dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor, enhances synaptic ACh levels but is limited by a short half-life, modest efficacy, and gastrointestinal side effects. This review highlights the molecular mechanisms underlying cholinergic dysfunction, including oxidative stress, mitochondrial impairment, protein aggregation, neuroinflammation, and synaptic dysregulation, while emphasizing rivastigmine and its derivatives as emerging therapeutic candidates. Structural modifications of rivastigmine have yielded multifunctional derivatives with improved selectivity, blood-brain barrier penetration, and neuroprotective properties, including antioxidant, anti-amyloid, and anti-inflammatory activities. These advances suggest that rivastigmine derivatives could serve as promising multi-targeted agents for neurodegenerative disorders. Future directions include integrating these compounds with nanotechnology-based delivery systems and precision medicine approaches to overcome pharmacokinetic limitations and optimize patient outcomes.},
}

@article {pmid42152767,
year = {2026},
author = {Han, S and Naderi, E and Wang, K and Ma, Y and Biessels, GJ and Ahmadizar, F},
title = {Prediabetes as a critical stage for risk of dementia and stroke: evidence from the UK Biobank and Mendelian Randomization.},
journal = {European journal of preventive cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurjpc/zwag278},
pmid = {42152767},
issn = {2047-4881},
abstract = {BACKGROUND AND AIMS: Type 2 diabetes (T2D) is a recognized risk factor for dementia and stroke, but whether risks begin during prediabetes remains unclear. We aimed to determine the risks of these neurological conditions among individuals with prediabetes and the glycemic thresholds at which risks emerge.

METHODS: We studied 432,887 adults (mean age, 57 years; 55% women) from the UK Biobank who were free of dementia or stroke at baseline, categorized by glycemic status (normoglycemia, prediabetes, and T2D). Incident dementia, stroke, and Magnetic Resonance Imaging (MRI)-derived brain markers, including brain volumes and white matter hyperintensity volumes, were assessed for these conditions. HbA1c was modeled continuously using natural cubic splines to assess linear and non-linear effects. Outcomes were estimated using Cox proportional hazards and linear regression models, adjusted for demographic, lifestyle, and clinical factors. Two-sample Mendelian randomization (MR) was used to test causality.

RESULTS: During a median 13.7 years of follow-up, prediabetes (n=52,693) was associated with higher risks of vascular dementia (hazard ratio (HR):1.36; 95% confidence interval (CI): 1.14-1.61), stroke (HR:1.09; 95% CI: 1.01-1.16), ischemic stroke (HR:1.10; 95% CI: 1.02-1.19), and intracerebral hemorrhage (HR:1.19; 95% CI: 1.01-1.39) compared with normoglycemia, after adjustment for major confounding factors and across extensive sensitivity analyses. In the brain MRI cohort (N=39,996), gray matter volumes (β = -0.04, 95% CI -0.07 to -0.01) and hippocampal volumes (β = -0.03, 95% CI -0.06 to 0.00) were smaller, and log-transformed white matter hyperintensity volume (β = 0.04, 95% CI 0.01 to 0.07) was larger in prediabetes. Spline models indicated that adverse outcomes were associated with higher HbA1c levels, even before the diagnostic threshold for T2D was reached. Risks were further elevated in T2D. MR analyses supported causal effects of glycemia on dementia, stroke and hippocampal atrophy.

CONCLUSION: Prediabetes is not a benign state: even modest HbA1c elevations are linked to vascular dementia, stroke, and brain structural decline. These risks emerge below current diagnostic glycemic thresholds, underscoring prediabetes as a critical stage for early intervention to preserve brain health.},
}

@article {pmid42153007,
year = {2026},
author = {Keyvanfard, F and Nasiraei-Moghaddam, A},
title = {Blind Identification of Altered Functional Subnetworks in Alzheimer's Disease Using Resting-State fMRI.},
journal = {Biomedical engineering and computational biology},
volume = {17},
number = {},
pages = {11795972251404254},
pmid = {42153007},
issn = {1179-5972},
abstract = {INTRODUCTION: Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to examine functional connectivity (FC) alterations in neurological disorders such as Alzheimer's disease (AD). Traditional studies either employ whole-brain analyses or focus on specific regions, yet the vast number of FCs and their interrelations complicate interpretation. This study adopts a data-driven, hypothesis-free approach to detect altered functional subnetworks in AD.

METHODS: Independent component analysis (ICA) was applied to FC matrices from 34 AD patients and 49 healthy controls (HCs) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). After pruning, significant subnetworks distinguishing AD from HC were identified. Graph theoretical parameters were computed for each subnetwork, and their associations with Mini-Mental State Examination (MMSE) scores were assessed.

RESULTS: Three subnetworks effectively differentiated AD patients from HCs. One subnetwork showed significant group differences in network strength, clustering coefficient, and local efficiency, despite no whole-brain differences. Abnormal functional lateralization also emerged within subnetworks. Moreover, FC weights in the identified subnetworks positively correlated with MMSE scores, linking cognitive performance to subnetwork connectivity.

CONCLUSION: These results demonstrate the utility of a data-driven approach in detecting AD-specific altered subnetworks. By providing a modular perspective, this method facilitates targeted examination of connectivity changes, improves interpretability, and deepens understanding of functional disruptions in AD.},
}

@article {pmid42153198,
year = {2026},
author = {Khosh Ravesh, R and Khodashenas, V and Goudarzi, M and Mohammadi, L and Baluchnejadmojarad, T and Roghani, M},
title = {Promising Therapeutic Potential of miR-220-3p Mimic Against Murine Trimethyltin Hippocampal Injury.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {25},
number = {1},
pages = {e165755},
pmid = {42153198},
issn = {1726-6890},
abstract = {BACKGROUND: Trimethyltin (TMT) is an organotin compound known to induce neurotoxicity within the limbic system of the brain, particularly in the hippocampal region, with neurodegenerative changes resembling those of Alzheimer's disease (AD).

OBJECTIVES: This investigation examined the impact of miRNA-220-3p (miR-220-3p) on TMT-induced neurotoxicity and associated behavioral abnormalities, such as spatial learning and memory impairments, and identified the potential molecular mechanisms.

METHODS: To induce neurotoxicity, TMT was injected (8 mg/kg, i.p. once), and after 1 hour, miR-220-3p was microinjected intraventricularly (ICV route, once) for the possible mitigation of TMT-induced neurotoxicity. Different behavioral assessments were employed to determine spatial learning and memory function. Moreover, hippocampal measurements of brain-derived neurotrophic factor (BDNF) and Sirtuin-1, oxidative stress-, apoptosis-, and neuroinflammation-related factors, and histochemical changes were performed.

RESULTS: The TMT injection led to behavioral abnormalities in the novel object discrimination and Barnes maze tests, heightened oxidative stress [elevating reactive oxygen species (ROS) levels, nitrite, and lipid peroxidation and decreasing the activities of antioxidant enzymes, including catalase (CAT) and superoxide dismutase (SOD)], reduced BDNF and Sirtuin-1 levels, increased neuroinflammation [escalating the secretion of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)], raised activities of acetylcholinesterase (AChE), myeloperoxidase (MPO), beta-secretase 1 (BACE-1), caspase-1, and caspase-3, accompanied by a reduced number of CA1 pyramidal neurons and higher glial fibrillary acidic protein (GFAP) immunoreactivity. In contrast, microinjection of miR-220-3p reversed most of these alterations.

CONCLUSIONS: The findings of this investigation imply that miR-220-3p may mitigate TMT-induced neurotoxicity, which is attributed to the suppression of hippocampal oxidative stress, neuroinflammation, and caspase-dependent apoptosis and pyroptosis, and part of its beneficial effect is associated with the upregulation of BDNF and Sirtuin-1.},
}

@article {pmid42153219,
year = {2026},
author = {Urso, D and Volpe, G and Valguarnera, A and Vilella, D and Vitulli, A and Gnoni, V and Giugno, A and Rollo, E and Griffiths, MD and Logroscino, G},
title = {Problematic Internet Use in Frontotemporal Dementia: A Case Series.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70417},
pmid = {42153219},
issn = {2328-9503},
support = {D.G.R. n. 2117 of 21.11.2018 (CUPB84I18000540002)//Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione./ ; },
abstract = {The present study investigated problematic internet use (PIU) among 61 patients with frontotemporal dementia (FTD) compared to a cohort of 354 patients with mild cognitive impairment (MCI) and Alzheimer's dementia. PIU was identified in 22.9% of FTD patients compared to only 0.8% of AD patients (p < 0.001). Behaviors included compulsive social media use, gaming, and online shopping. These findings suggest that PIU may represent an emerging behavioral feature associated with FTD, significantly more prevalent than in MCI and Alzheimer's dementia. Recognizing these digital behaviors could provide valuable clinical insights for diagnosis and management in the digital age.},
}

@article {pmid42153492,
year = {2026},
author = {Palmqvist, S and Tengzelius, R and Schöll, M and Nägga, K and Mattsson-Carlgren, N and Zetterberg, H},
title = {[New blood-based biomarkers for Alzheimer's disease].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42153492},
issn = {1652-7518},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; *tau Proteins/blood ; Amyloid beta-Peptides/blood ; },
abstract = {Blood-based biomarkers, particularly plasma p-tau217, have rapidly improved the detection of Alzheimer's disease pathology and can in some settings replace cerebrospinal fluid analysis or amyloid PET in clinical diagnostics. Clinically available assays now achieve high accuracy, especially when using a two-cutoff approach that classifies results as negative, intermediate, or positive, thereby supporting their use for confirming or ruling out disease. Implementation is likely to be straightforward in specialized clinics but more challenging in settings without prior biomarker experience or access to confirmatory testing for intermediate results, such as primary care.},
}

Humans
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid
*Biomarkers/blood/cerebrospinal fluid
*tau Proteins/blood
Amyloid beta-Peptides/blood

@article {pmid42153497,
year = {2026},
author = {Borgh Skillbäck, T and Palmqvist, S and Eriksdotter, M and Skoog, I and Kern, S},
title = {[Alzheimer's disease and other neurocognitive disorders - epidemiology and new diagnostic criteria].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42153497},
issn = {1652-7518},
mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; Sweden/epidemiology ; Biomarkers/blood ; *Neurocognitive Disorders/diagnosis/epidemiology ; },
abstract = {Neurocognitive disorders are progressive conditions leading to brain atrophy and functional decline, representing the third leading cause of death in Sweden after cardiovascular disease and cancer. Approximately 150 000 individuals live with a dementia diagnosis, with Alzheimer's disease (AD) comprising two-thirds of cases, followed by vascular cognitive impairment. Diagnosis is usually initiated in primary care through patient history, cognitive testing, laboratory analyses, and brain imaging, while more advanced assessments in specialist clinics may include cerebrospinal fluid or blood biomarkers. Traditionally, diagnoses in Sweden have relied on ICD-10, emphasizing cognitive decline affecting daily life. Recently, biomarker-based frameworks such as NIA-AA and IWG have redefined AD either as a purely biological entity (NIA-AA) or as a clinico-biological construct (IWG). While these are primarily used in research, they highlight the importance of integrating biological markers with clinical evaluation. Preventive strategies remain crucial, as pathological processes can precede symptoms by decades.},
}

Humans
*Alzheimer Disease/diagnosis/epidemiology
Sweden/epidemiology
Biomarkers/blood
*Neurocognitive Disorders/diagnosis/epidemiology

@article {pmid42154093,
year = {2026},
author = {Mohan, AA and Talwar, P},
title = {Gene Expression Analysis of Mitochondria-Associated Membrane (MAM)-Related Genes in ER Stress and Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01726-6},
pmid = {42154093},
issn = {1573-6830},
abstract = {Alzheimer's Disease (AD) is a devastating neurodegenerative disease, strongly linked to cellular stress originating from the accumulation of the Amyloid-beta (Aβ) peptide and phosphorylated tau protein. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) are reported as early events in the AD pathology. Mitochondria-Associated Membrane (MAM) is a proteinaceous tethering between the ER and mitochondria that plays a role in regulating ER stress and related responses. A high level of ER-mitochondria tethering, thereby mitochondrial Calcium (Ca[2+]) overload and cell death, has been reported in AD brain cells. Despite the independent recognition of these pathways, a precise mechanism that integrates MAM activity, ER stress response, and AD pathogenesis remains elusive. We used three transcriptomic datasets collected from the NCBI-Gene Expression Omnibus (GEO) database, which deal with AD, ER stress, and MAM, and processed them with a multi-layered bioinformatics approach combining differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), protein interaction network construction, and identification of hub genes using different cytoHubba topological algorithms. Four hub genes, namely Calreticulin (CALR), Calnexin (CANX), Heat Shock Protein 90 Beta Family Member 1 (HSP90B1), and Valosin-Containing Protein (VCP), were identified. CALR, CANX, and HSP90B1 are known chaperones that regulate proteostasis. VCP is an ER ATPase that induces autophagy. These genes are not only associated with MAM regulation and ER stress but also with AD pathology. The results suggest hub genes as a new set of biomarkers and the likely existence of a 'three-component system' among MAM, ER stress, and Neurodegeneration. The study highlights the potential of MAM-related genes as therapeutic targets of AD.},
}

@article {pmid42154301,
year = {2026},
author = {Zhong, G and Shi, J and Jiang, Y and Li, S and Wang, X and Zhang, T and Chen, Z and Wang, Q and Liu, S},
title = {Mechanistic study on the alleviating effects of cinnamaldehyde on aluminum chloride-induced cognitive impairment in zebrafish through modulating the TLR4/NF-κB signaling pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42154301},
issn = {1573-7365},
support = {82274616//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Acrolein/analogs & derivatives/pharmacology/therapeutic use ; Zebrafish ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; Aluminum Chloride/toxicity ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Molecular Docking Simulation ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative condition distinguished by intricate pathological mechanisms. Cinnamaldehyde, a natural active chemical sourced from the bark of Cinnamomum species, exhibits remarkable neuroprotective properties that have been validated in various neurological disorders. In this study, network pharmacology alongside zebrafish experiments was employed to investigate the molecular mechanisms and signaling pathways through which cinnamaldehyde ameliorates AD. Potential targets of cinnamaldehyde were found using the SuperPred, TargetNet, SwissTargetPrediction, and SEA databases, whilst AD-related targets were obtained from TTD, OMIM, GeneCards, and DrugBank databases. Subsequently, protein-protein interaction analysis was performed using the STRING database, followed by GO and KEGG enrichment studies via the DAVID platform. Finally, molecular docking validation was conducted using CB-Dock2. The network pharmacology results indicated that cinnamaldehyde might impact its beneficial effects on AD via regulating the toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-κB) signaling pathway. To further validate this mechanism, an AD model was established in zebrafish induced by aluminum chloride (AlCl3). Behavioral assays demonstrated that cinnamaldehyde significantly improved AlCl3-induced cognitive impairment. Hematoxylin-eosin and Nissl staining revealed that cinnamaldehyde attenuated neuropathological damage. Biochemical analyses indicated that cinnamaldehyde alleviated oxidative stress and restored cholinergic dysfunction. Furthermore, RT-qPCR findings indicated that cinnamaldehyde reduced inflammatory mediator expression and diminished TLR4 and NF-κB p65 mRNA levels, while western blotting confirmed reduced TLR4 and phosphorylated NF-κB p65 protein expression. In summary, cinnamaldehyde may mitigate neuroinflammation through suppressing the TLR4/NF-κB signaling pathway, thereby ameliorating AlCl3-induced cognitive impairment, neuropathological injury, oxidative stress imbalance, and cholinergic system dysfunction in zebrafish.},
}

Animals
*Acrolein/analogs & derivatives/pharmacology/therapeutic use
Zebrafish
*Toll-Like Receptor 4/metabolism
*NF-kappa B/metabolism
*Signal Transduction/drug effects
Aluminum Chloride/toxicity
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Molecular Docking Simulation

@article {pmid42154338,
year = {2026},
author = {Attia, MSM and Ahmad, SF and Nadeem, A and Ansari, MA and Al-Hamamah, MA and Harisa, GI and Bakheet, SA and Emran, TB and Singh, T and Attia, SM},
title = {Tirzepatide attenuates neurotoxicity by suppressing inflammation, apoptosis and restoring neurotrophin expression in an Alzheimer's disease-like rat model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42154338},
issn = {1573-7365},
support = {ORF-2026-748//King Saud University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology ; *Apoptosis/drug effects ; Rats ; Male ; Disease Models, Animal ; *Inflammation/metabolism/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nerve Growth Factors/metabolism/biosynthesis ; Rats, Sprague-Dawley ; Galactose/toxicity ; Amyloid beta-Peptides/metabolism ; Tirzepatide ; },
abstract = {BACKGROUND: Despite numerous milestones in Alzheimer's disease (AD) research, the disease remains incurable, with a high prevalence and significant financial burdens. As a result, researchers are keen to look for new medications that can help manage or prevent the disease.

MATERIALS AND METHODS: The effects of long-term exposures to tirzepatide, a novel dual GIP/GLP-1 receptor agonist, on neurotoxicity and behavioral changes in the D-galactose/aluminium chloride (D-gal/AlCl3)-induced rats' AD-like pathological model were evaluated. Additionally, we investigated the underlying mechanism for tirzepatide's protective effects against neurotoxicity caused by D-gal/AlCl3.

RESULTS AND CONCLUSION: The present findings show that long-term administration of tirzepatide effectively reduced D-gal/AlCl3-induced AD-like neuronal and behavioral deficits and improved rats' learning, spatial memory, and locomotor activity. Tirzepatide restored the aberrant levels of acetylcholine, Aβ1-42, and pTau proteins, major AD hallmarks. Tirzepatide can alleviate behavioral impairments in D-gal/AlCl3-exposed rats by lowering acetylcholinesterase activation and inflammatory markers COX-2, IL-6, and TNF-α levels. This suggests that tirzepatide may alleviate inflammation, leading to restoring the level of acetylcholine and increasing the expression of the neurotrophin BDNF to reduce Aβ-induced neurodegeneration and apoptosis in rats exposed to D-gal/AlCl3. The neuroprotective effect of tirzepatide was also confirmed by lowering the histopathological alterations generated by D-gal/AlCl3 administration, highlighting the possibility of using tirzepatide as a therapeutic candidate to treat AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology
*Apoptosis/drug effects
Rats
Male
Disease Models, Animal
*Inflammation/metabolism/drug therapy
*Neuroprotective Agents/pharmacology/therapeutic use
*Nerve Growth Factors/metabolism/biosynthesis
Rats, Sprague-Dawley
Galactose/toxicity
Amyloid beta-Peptides/metabolism
Tirzepatide

@article {pmid42154340,
year = {2026},
author = {Bagwe Parab, S and Tripathi, P and Barve, K and Kaur, G},
title = {Neuroprotective effects of trans-anethole on AlCl3-induced memory impairment: targeting AChE, oxidative stress, and NLRP3 inflammasome: a promising approach for neurodegeneration prevention.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42154340},
issn = {1573-7365},
mesh = {Animals ; *Oxidative Stress/drug effects ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Memory Disorders/chemically induced/metabolism/prevention & control/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Aluminum Chloride/toxicity ; Male ; *Acetylcholinesterase/metabolism ; *Inflammasomes/metabolism/drug effects ; *Allylbenzene Derivatives/pharmacology/therapeutic use ; *Anisoles/pharmacology/therapeutic use ; Rats, Wistar ; *Neurodegenerative Diseases/prevention & control/chemically induced/metabolism ; Maze Learning/drug effects ; },
abstract = {Aluminum, a widely occurring environmental metal, has been implicated as a neurotoxic agent and is associated with the development of several neurodegenerative conditions, including Alzheimer's disease (AD). Its neurotoxicity is largerly attributed to the induction of oxidative stress , which exacerbates neuroinflammation, leading to cognitive deficits and progressive neuronal dysfunction. Trans-anethole (TA) possesses diverse pharmacological activities, including anti-inflammatory, antioxidant, antifungal, and anticancer effects. However, its neuroprotective potential against AlCl3-induced neurodegeneration, particularly in the context of memory impairment mediated by inflammation and oxidative stress, remains unknown. Therefore, this study was conducted to evaluate the potential role of TA in mitigating neurodegeneration. To establish an aluminum-induced neuroinflammation-associated neurodegenerative model, rats received oral administration of 150 mg/kg AlCl3 for 90 days. TA was administered at three different dosages between days 31 and 90: 40, 80, and 160 mg/kg between days 31 and 90. Cognitive performance was assessed using the Morris water maze (MWM) and passive avoidance test (PAT). Neuroprotective effects were evaluated by analyzing acetylcholinesterase (AChE) activity, oxidative stress markers (catalase, glutathione, and malondialdehyde levels), and neuroinflammatory mediators (NLRP3 inflammasome, Interleukin-1β, and TNF-α) in AlCl3-exposed rats. TA significantly mitigated aluminum-induced neuronal damage by restoring antioxidant defence, inhibiting AChE activity, and downregulating inflammatory proteins, including NLRP3, TNF-α, and IL-1β. Histopathological analysis further confirmed its neuroprotective role. The findings of this study suggests that TA holds therapeutic potential for neurodegenerative disorders by mitigating memory deficits, neuroinflammation, and oxidative stress.},
}

Animals
*Oxidative Stress/drug effects
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Memory Disorders/chemically induced/metabolism/prevention & control/drug therapy
*Neuroprotective Agents/pharmacology/therapeutic use
Rats
Aluminum Chloride/toxicity
Male
*Acetylcholinesterase/metabolism
*Inflammasomes/metabolism/drug effects
*Allylbenzene Derivatives/pharmacology/therapeutic use
*Anisoles/pharmacology/therapeutic use
Rats, Wistar
*Neurodegenerative Diseases/prevention & control/chemically induced/metabolism
Maze Learning/drug effects

@article {pmid42155171,
year = {2026},
author = {Czuba, M and Szafrańska, K and Kolaczkowski, M and Marcinkowska, M},
title = {Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118951},
doi = {10.1016/j.ejmech.2026.118951},
pmid = {42155171},
issn = {1768-3254},
abstract = {TRPML1, a lysosomal Ca[2+] channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.},
}

@article {pmid42155345,
year = {2026},
author = {Peng, G and Yang, Y and Wang, Y and Chandekar, SA and Yu, J},
title = {Biomarkers in preclinical and early Alzheimer's disease in China: a scoping review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100599},
doi = {10.1016/j.tjpad.2026.100599},
pmid = {42155345},
issn = {2426-0266},
abstract = {This scoping review synthesizes evidence on fluid and neuroimaging biomarkers for preclinical and early Alzheimer's disease (AD)-including mild cognitive impairment (MCI) and mild AD dementia-in Chinese populations, where a comprehensive overview has been lacking despite AD's increasing biomarker-based definition. We systematically searched four English databases (PubMed, EMBASE, Cochrane, and Web of Science) and three Chinese databases (CNKI, Wanfang, and CQVIP) for studies (2013-2023) reporting diagnostic accuracy of these biomarkers in Chinese preclinical and early AD (eAD) cohorts for clinical use. Due to rapid advancements in biomarker research in China, a supplementary search was conducted in the four English databases for studies published between 2024 and April 30, 2025. Of the 366 included studies investigating fluid or neuroimaging biomarkers in AD, 48 specifically evaluated biomarker performance in biomarker‑confirmed AD populations. Plasma p-tau217 showed strong performance for diagnosing MCI due to AD, and plasma p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 effectively classified amyloid-β (Aβ) pathology. Multimodal combinations and MRI-based biomarkers also performed well, though evidence is limited. In China, biomarker diagnosis of MCI due to AD is advancing rapidly, while approaches for preclinical AD, machine learning, and multi-protein panels remain in early development.},
}

@article {pmid42155557,
year = {2026},
author = {Gonzalez, AI and Martinez, JE and Giudicessi, A and Rowe, M and Ku, V and Tristão-Pereira, C and He, B and Malotaux, V and Quiroz, YT},
title = {Clinical and biological relevance of objectively-defined subtle cognitive decline in Alzheimer's disease: a narrative review of neuroimaging, biomarker, and clinical progression studies.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100604},
doi = {10.1016/j.tjpad.2026.100604},
pmid = {42155557},
issn = {2426-0266},
abstract = {Preclinical Alzheimer's Disease stages represent possible targets for disease-modifying intervention as well as opportunity for early identification of risk for future decline. Recent research has explored the use of objectively-defined subtle cognitive decline (Obj-SCD), an emerging classification that may identify individuals at risk for neurodegeneration before the onset of mild cognitive impairment (MCI). The Edmonds/Thomas actuarial Obj-SCD criteria (> 1 SD below expectations, single cognitive test impaired per domain) aims to capture those who exhibit minimal cognitive difficulties that do not meet a MCI or dementia diagnosis. Given the novelty of the Obj-SCD classification, this narrative review provides an overview of neuroimaging, biomarker, and clinical progression studies to evaluate its biological and clinical significance. Using fluid-based biomarkers, neuroimaging, and longitudinal designs, studies have indicated that the Obj-SCD classification has the potential to capture AD-related pathological changes detectable before the clinical onset of MCI. In particular, recent studies indicate a unique pathological profile of Obj-SCD, differentiating it from the cognitively unimpaired and MCI stages. Studies comparing Obj-SCD and subjective cognitive complaints show that the Obj-SCD criteria may be more closely associated to early AD pathology. While the existing literature is limited, findings uphold Obj-SCD as a sensitive classification able to identify individuals at risk for future cognitive impairment. Studies on Obj-SCD indicate utility in research settings, although it faces challenges regarding its clinical implementation and effectiveness.},
}

@article {pmid42155784,
year = {2026},
author = {Brechtel, J and Lietz, C and Adscheid, SA and Friedland, K},
title = {Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108227},
doi = {10.1016/j.phrs.2026.108227},
pmid = {42155784},
issn = {1096-1186},
abstract = {Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.},
}

@article {pmid42155790,
year = {2026},
author = {Liu, X and Du, T and Gu, Q and Zhang, Z and Hui, L and Tao, L and Shan, H and Chen, X and Zhang, M},
title = {Hydrogen selenide and selenium donors: From Gasotransmitter biology to precision Neurotherapeutics.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112609},
doi = {10.1016/j.cellsig.2026.112609},
pmid = {42155790},
issn = {1873-3913},
abstract = {Hydrogen selenide (H2Se), selenium's central metabolic intermediate, is emerging as the candidate fourth gasotransmitter. This membrane permeable gas mediates rapid redox signaling and serves as the obligate precursor for selenoprotein biosynthesis, essential for neuronal redox homeostasis and survival. Engineered selenium donors, designed for controlled H2Se release or targeted selenoprotein support, exert neuroprotection by attenuating oxidative stress, reducing neuroinflammation, inhibiting ferroptosis, and preserving synaptic integrity across Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury, and stroke. Advances in stimuli-responsive donor chemistry and nanocarrier platforms enable spatiotemporally precise delivery, mitigating selenium's narrow therapeutic window. However, H2Se is cytoprotective at physiological concentrations but toxic at supraphysiological levels and its clinical translation demands rigorous pharmacokinetic optimization, context-aware targeting, and dynamic biomarkers. This review bridges gasotransmitter biology with translational pharmacology, delineating H2Se metabolism, donor design principles, and disease-specific applications. By integrating mechanistic insights with precision delivery strategies, we provide a roadmap for harnessing H2Se and selenium donors as next-generation, clinically viable neurotherapeutics.},
}

@article {pmid42155951,
year = {2026},
author = {Zhang, X and Han, W and Li, Y and Yang, P and Jia, Y and Sun, L and Wang, R and Shi, M and Zheng, X and Zhang, Y and Zhu, Z},
title = {Association of sarcopenia, sarcopenic obesity with incident dementia, cognitive functions, and brain structure: findings from the UK Biobank Study.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {7},
pages = {100879},
doi = {10.1016/j.jnha.2026.100879},
pmid = {42155951},
issn = {1760-4788},
abstract = {BACKGROUND: Several small-sample studies have suggested that sarcopenia and sarcopenic obesity are implicated in cognitive decline. We aimed to prospectively investigate the associations of possible sarcopenia, sarcopenia and sarcopenic obesity with incident dementia, cognitive functions, and brain structure based on the UK Biobank.

METHODS: A total of 420,916 participants without dementia and cardiovascular diseases at baseline were analyzed. Sarcopenia status was defined according to the European Working Group on Sarcopenia in Older People 2. Obesity was defined according to body mass index. Cox models were applied to evaluate the longitudinal associations.

RESULTS: During a median follow-up of 13.69 years, 4,019 incident all-cause dementia events (including 2,650 Alzheimer's disease and 527 vascular dementia) were recorded. Comparted with individuals without sarcopenia, the multivariable-adjusted hazard ratios (95% confidence interval) of all-cause dementia were 1.44 (1.32-1.58), 1.37 (1.03-1.82) and 3.06 (1.89-4.93) for those with possible sarcopenia, sarcopenia and severe sarcopenia, respectively. Individuals with sarcopenic obesity (hazard ratios = 1.69, 1.41-2.03) had the highest risk of all-cause dementia than those with obesity only, sarcopenia only or neither. The significant associations remained in all dementia types (Alzheimer's disease or vascular dementia). In addition, those with sarcopenic obesity was associated with unfavorable cognitive functions, and worse brain structure.

CONCLUSIONS: Our findings suggested that possible sarcopenia, sarcopenia and sarcopenic obesity were associated with a higher risk of all-cause dementia and its subtypes.},
}

@article {pmid42142451,
year = {2026},
author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ},
title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {29-40},
doi = {10.1016/j.neurobiolaging.2026.04.006},
pmid = {42142451},
issn = {1558-1497},
abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.},
}

@article {pmid42142504,
year = {2026},
author = {Abd-Eldayem, AM and Mohammed, RA},
title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.},
journal = {Current opinion in pharmacology},
volume = {88},
number = {},
pages = {102632},
doi = {10.1016/j.coph.2026.102632},
pmid = {42142504},
issn = {1471-4973},
abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.},
}

@article {pmid42142537,
year = {2026},
author = {Saido, TC},
title = {Animal models of Alzheimer's disease and related disorders.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105069},
doi = {10.1016/j.neures.2026.105069},
pmid = {42142537},
issn = {1872-8111},
}

@article {pmid42142562,
year = {2026},
author = {Keramat, SA and Dao-Tran, TH and Nguyen, KH and Welch, A and Comans, T},
title = {Assessing the agreement between self- and proxy-reported responses for measuring health-related quality of life in people with dementia using the Alzheimer's Disease Five Dimensions instrument.},
journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jval.2026.04.011},
pmid = {42142562},
issn = {1524-4733},
abstract = {BACKGROUND: The level of agreement between utility values derived from self- and proxy-reports, assessed using the preference-based health-related quality of life (HRQoL) instrument, the Alzheimer's Disease Five Dimensions (AD-5D), remains unclear. We aimed to investigate the agreement between self- and proxy-reported HRQoL, measured using the AD-5D, a dementia-specific, preference-based HRQoL instrument.

METHODS: The data comprise 77 Australian dyads of people with dementia and their caregivers. The agreement between AD-5D utility values derived from self- and proxy-reports was analysed using a Bland-Altman plot. The ordinary least squares regression technique was employed to identify factors associated with the AD-5D utility value sets and to assess agreement between the resulting AD-5D utility values derived from self- and proxy-reports.

RESULTS: The mean AD-5D utility value derived from self-reports (0.667) was higher than the value derived from proxy-reports (0.523). The Bland-Altman plot shows that 7.79% of the differences in AD-5D utility values fell outside the limits of agreement. The regression results indicated that the AD-5D utility value derived from self-reports for people with dementia aged 80 years or older was, on average, 0.20 points lower (β = 0.20, SE = 0.10) than that for people with dementia aged less than 70 years.

CONCLUSION: Utility values derived from self-reports were higher than those derived from caregiver proxy-reports. While proxy reporting is a necessary alternative when self-reporting is not feasible, these perspectives are not interchangeable. Future economic evaluations should incorporate sensitivity analyses to account for this systematic 'proxy-gap'.},
}

@article {pmid42142620,
year = {2026},
author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH},
title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.},
journal = {Life sciences},
volume = {398},
number = {},
pages = {124468},
doi = {10.1016/j.lfs.2026.124468},
pmid = {42142620},
issn = {1879-0631},
abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.},
}

@article {pmid42142765,
year = {2026},
author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118074},
doi = {10.1016/j.bcp.2026.118074},
pmid = {42142765},
issn = {1873-2968},
abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.},
}

@article {pmid42143322,
year = {2026},
author = {Gröbner, LS and Pietrzik, CU},
title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00812-7},
pmid = {42143322},
issn = {2045-8118},
abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.},
}

@article {pmid42143738,
year = {2026},
author = {Budrovic, K and Gunstad, J and Hamrick, P},
title = {Formulaic and novel language dissociate in Alzheimer's clinical syndrome: evidence for the Dual-Process Model.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13803395.2026.2674224},
pmid = {42143738},
issn = {1744-411X},
abstract = {INTRODUCTION: Spontaneous speech is commonly disrupted in persons with Alzheimer's disease (AD) and/or Alzheimer's clinical syndrome (ACS). Importantly, different aspects of speech (e.g. formulaic versus more novel or flexible speech) place different demands on distinct cognitive systems. Formulaic language may rely on automatized procedural processes, while more novel or diverse speech requires more flexible lexical-semantic processes associated with the subsystems of declarative memory. Given that AD/ACS are associated with impaired declarative processes and relatively spared procedural processes, we predicted that individuals with ACS may show increased reliance on formulaic language along with reduced diversity in speech.

METHOD: We analyzed the spontaneous speech of 81 individuals with ACS (aged 56-88) and 61 healthy controls (aged 47-80) who completed a picture description task using computational tools for the analysis of formulaic language (operationalized as proportion of frequent trigrams produced and mutual information score of trigrams) and novel language (operationalized as root type-token ratio, measure of textual lexical diversity, and semantic diversity).

RESULTS: Across all measures, individuals with ACS produced significantly more formulaic language than control participants and significantly less novel language than control participants, with small-to-medium overall model effect sizes. Machine learning classifiers trained on these patterns of formulaic and novel language distinguished between controls and individuals with ACS with reasonable accuracy, sensitivity, and specificity.

CONCLUSION: The spontaneous speech of individuals with ACS contains more formulaic language and less novel language than that of healthy controls, consistent with the Dual-Process Model. These differences may have clinical relevance and warrant further investigation. Keywords: Alzheimer's Disease, Alzheimer's clinical syndrome, formulaic language, lexical diversity, spontaneous speech.},
}

@article {pmid42144109,
year = {2026},
author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M},
title = {Krill oil increase plasma omega-3 fatty acids more than fish oil in healthy adults: a double blind randomized controlled trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.ajcnut.2026.101346},
pmid = {42144109},
issn = {1938-3207},
abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E4 allele (APOE4), and the chemical form of the supplement. Krill-oil delivers ω-3 FAs primarily as phospholipids (PL), whereas fish oil provides them as triglycerides (TG).

OBJECTIVE: To compare EPA and DHA concentrations after a supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modifies responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and body mass index (BMI). Participants received 1.1 g/day ω-3 FAs through either krill oil (n=36) or fish oil (n=36) for 12 weeks. Plasma fatty acids were measured at baseline and at weeks 1, 2, 4, and 12 by gas chromatography-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex and APOE4 status, were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (p = 0.0001) and DHA (p = 0.005), with krill oil resulting in ∼ 1.5-fold higher ΔEPA and ΔDHA compared to fish oil. The time-by-sex interaction was significant only for EPA (p = 0.026), with females having 1.5-fold greater increase than males at 12 weeks. Following supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA respectively, compared to baseline; however, these increases were not significantly different from those found in non-carriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared to fish oil supplementation.

REGISTRATION NUMBER: NCT04279743. In https://clinicaltrials.gov.},
}

@article {pmid42144116,
year = {2026},
author = {Qiang, Q and Skudder-Hill, L and Toyota, T and Huang, Z and Wei, W and Adachi, H},
title = {Combination of CSF α-synuclein seed amplification assay and amyloid-β42 predicts cognitive decline in Parkinson's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107452},
doi = {10.1016/j.nbd.2026.107452},
pmid = {42144116},
issn = {1095-953X},
abstract = {Cognitive impairment is a disabling non-motor feature of Parkinson's disease (PD). Cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) reflects Lewy body pathology, while reduced CSF amyloid-β42 (Aβ42) indicates Alzheimer's type co-pathology in PD. This study examined whether combined CSF α-synuclein SAA and Aβ42 status improves prediction of cognitive decline and dementia risk in PD. A total of 692 participants (145 controls and 547 individuals with PD) from the Parkinson's Progression Markers Initiative with available CSF α-synuclein SAA and Aβ42 measurements were included. Participants were classified into four biomarker-defined groups based on α-synuclein/amyloid (S/A) status: S - A- (n = 140), S - A+ (n = 67), S + A- (n = 307), and S + A+ (n = 178). At baseline, α-synuclein SAA positivity was highly prevalent in PD (87.2%). APOE ε4 carrier frequency differed significantly across groups (p < 0.001), with the highest prevalence in S - A+ (50.8%) and S + A+ (33.7%). The S + A+ group exhibited the lowest baseline cognitive scores, with intermediate deficits in S + A-. Longitudinally, S + A+ participants showed the steepest cognitive decline (p < 0.001), whereas the S + A- and S - A+ groups demonstrated more modest but significant declines. In multivariable Cox regression, each one-category increase in S/A status was associated with a higher hazard of dementia (HR = 2.72, 95% CI 1.80-4.08, p < 0.001). Combined CSF α-synuclein and Aβ42 stratification identifies subgroups at high risk for accelerated cognitive decline and dementia, offering a potential strategy to improve prognostic precision and clinical trial design in PD.},
}

@article {pmid42144205,
year = {2026},
author = {Ma, J and Yang, B and Jiang, X and Wang, L and Wei, W and Cao, Y and Li, H},
title = {Microglial senescence and epigenetic reprogramming in alzheimer's disease: An immunometabolic perspective.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113177},
doi = {10.1016/j.exger.2026.113177},
pmid = {42144205},
issn = {1873-6815},
abstract = {Microglial senescence has emerged as a potentially important aging-related mechanism in Alzheimer's disease (AD), shaped in part by epigenetic reprogramming and closely coupled to immunometabolic dysfunction. While microglia initially mount adaptive responses to amyloid-beta (Aβ), tau, and tissue stress, persistent exposure to chronic neurodegenerative cues may drive subsets of microglia toward senescence-like states characterized by altered chromatin regulation, transcriptional remodeling, stable cell-cycle arrest, and a sustained senescence-associated secretory phenotype (SASP). These changes are accompanied by impaired phagocytosis, lysosomal and autophagic dysfunction, mitochondrial stress, and disrupted lipid handling, collectively weakening homeostatic surveillance and promoting a neurotoxic microenvironment. In turn, senescence-associated microglial dysfunction may contribute to amyloid and tau pathology, synaptic injury, neurovascular unit impairment, and chronic neuroinflammation across the AD continuum. In this review, we synthesize current evidence on the phenotypic and molecular features of senescent microglia, with particular emphasis on epigenetic and transcriptional reprogramming as an organizing framework linking aging, immune dysregulation, and metabolic vulnerability. We further discuss how senescent microglia relate to other disease-associated microglial states, and we highlight unresolved questions regarding causality, biomarker specificity, and the distinction between chronic activation and true senescence in human AD. Finally, we evaluate emerging therapeutic approaches-including senolytic strategies, microglial depletion-repopulation paradigms, and metabolic or epigenetic interventions-and discuss their opportunities, limitations, and translational challenges. Together, this perspective positions microglial senescence not as an isolated driver, but as a biologically relevant and potentially targetable component of the aging neuroimmune landscape in AD.},
}

@article {pmid42144627,
year = {2026},
author = {Bufi, AA and Papait, A and Ponsaerts, P and Silini, AR and Parolini, O},
title = {Mesenchymal stromal cells and neuroinflammation: a multimodal approach to neuroprotection and future therapeutic horizons.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42144627},
issn = {2047-9158},
support = {(Linea D1 OP)//Università Cattolica del Sacro Cuore/ ; 5x1000//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Mesenchymal Stem Cells ; *Mesenchymal Stem Cell Transplantation/methods/trends ; Animals ; *Neuroinflammatory Diseases/therapy/immunology ; *Neuroprotection/physiology ; *Neurodegenerative Diseases/therapy ; },
abstract = {As the global population ages, neurodegenerative and neuroinflammatory diseases are becoming a rapidly growing public health challenge, with available interventions remaining largely symptomatic and often only modestly affecting long-term disease progression. Therapies involving mesenchymal stromal cells (MSCs) have attracted substantial attention as a potential clinical therapeutic strategy across chronic central nervous system (CNS) disorders, due to their multifaceted ability to modulate immune response and confer neuroprotection. While initially explored for their multilineage differentiation potential, MSCs are now predominantly recognized for their paracrine functions, including secretion of soluble factors and extracellular vesicles. These acellular mediators induce diverse neuroprotective effects by attenuating neuroinflammation, stabilizing the blood-brain barrier, reprogramming glial and lymphocyte activity, and delivering regulatory microRNAs that modulate neuronal apoptosis and inflammatory gene networks. In this review, we summarize molecular evidence from in vitro and in vivo preclinical models, and early clinical investigations that demonstrate how tissue source and immunobiological plasticity shape the efficacy of MSCs. We further highlight emerging trends toward acellular MSC-derived therapies, offering a mechanistically versatile platform for therapeutic interventions for common neurodegenerative and neuroinflammatory disorders of the CNS, particularly Alzheimer's disease, Parkinson's disease and multiple sclerosis, a primary autoimmune demyelinating disorder.},
}

Humans
*Mesenchymal Stem Cells
*Mesenchymal Stem Cell Transplantation/methods/trends
Animals
*Neuroinflammatory Diseases/therapy/immunology
*Neuroprotection/physiology
*Neurodegenerative Diseases/therapy

@article {pmid42144687,
year = {2026},
author = {Zhao, Q and Yu, Y and Wang, F and Wang, Y and Shao, P and Zhao, L},
title = {TARDBP Mediates the MAP3K11/SLC3A2/GPX4 Axis in Alzheimer's Disease Rats by Enhancing KRAS mRNA Stability.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {10},
pages = {e71181},
doi = {10.1111/jcmm.71181},
pmid = {42144687},
issn = {1582-4934},
support = {HAB202113//Huai'an Natural Science Research Program/ ; },
mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism/genetics/pathology ; PC12 Cells ; *RNA Stability/genetics ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; *Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Male ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Ferroptosis/genetics ; Amyloid beta-Peptides ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; },
abstract = {Ferroptosis is an emerging pathological mechanism in Alzheimer's disease (AD). The aim of the present study was to investigate the potential mechanisms by which TARDBP is involved in AD by promoting ferroptosis. An AD rat model was established by injecting homocysteine (Hcy). Memory function was assessed using the Morris water maze test and contextual fear conditioning test. Hippocampal neurons' morphology was observed by HE staining, and intracellular iron deposition in the hippocampus was evaluated by Perls' blue staining. PC12 cells were treated with 20 μM Aβ1-42 to establish an AD cell model in vitro. Cell viability was measured by MTT assay; LDH release, intracellular ROS levels and Fe[2+] concentrations were determined. The mRNA stability of KRAS was assessed by actinomycin D assay. Activation of the MAP3K11/SLC3A2/GPX4 pathway was assessed by Western blot. Treatment with Fer-1 or down-regulation of TARDBP improved memory function and reduced intracellular iron deposition in the hippocampus of AD rats. Furthermore, these interventions inhibited Aβ1-42-induced PC12 cell damage, ROS production and iron accumulation. Mechanistically, down-regulating TARDBP reduced the mRNA stability of KRAS, inhibited MAP3K11 expression and subsequently promoted the expression of SLC3A2 and GPX4. Conversely, up-regulation of KRAS reversed the protective effects induced by TARDBP knockdown in both AD rats and Aβ1-42-induced PC12 cells. TARDBP promotes the development of AD by enhancing the mRNA stability of KRAS, thereby mediating the MAP3K11/SLC3A2/GPX4 axis to induce ferroptosis.},
}

Animals
Rats
*Alzheimer Disease/metabolism/genetics/pathology
PC12 Cells
*RNA Stability/genetics
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics
*Proto-Oncogene Proteins p21(ras)/genetics/metabolism
Male
Hippocampus/metabolism/pathology
Disease Models, Animal
Ferroptosis/genetics
Amyloid beta-Peptides
Reactive Oxygen Species/metabolism
Iron/metabolism
RNA, Messenger/genetics/metabolism
Rats, Sprague-Dawley
Signal Transduction

@article {pmid42145047,
year = {2026},
author = {Jung, J and Kim, Y and Cirunduzi, AC and Yoon, S and Bang, S and Yang, SH},
title = {Multi-Target-Directed Ligands (MTDLs) as Potential Therapeutic Candidates Targeting Multiple Pathogenic Factor of Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70919},
doi = {10.1002/cns.70919},
pmid = {42145047},
issn = {1755-5949},
support = {RS-2026-25481528//The National Research Foundation of Korea/ ; RS-2024-00350442//The National Research Foundation of Korea/ ; RS-2024-00411952//The National Research Foundation of Korea/ ; //Korea Environment Industry & Technology Institute (KEITI) through Technology Development Project for Safety Management of Household Chemical Products/ ; RS-2025-02223058//Korea Ministry of Environment (MOE)/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; Ligands ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Molecular Targeted Therapy/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and a chronic neurodegenerative disorder in older adults. AD is not driven by a single factor but by the interaction of multiple pathological processes, including amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and chronic neuroinflammation. Aβ aggregates into plaques that disrupt neuronal signaling, while hyperphosphorylated tau forms neurofibrillary tangles, leading to neuronal loss. These processes act synergistically to amplify toxicity. Persistent activation of microglia and astrocytes further promotes neuroinflammation, worsening Aβ and tau pathology.

CURRENT LIMITATIONS: Single-target therapies directed at Aβ or tau have shown limited clinical success and failed to alter disease progression, underscoring the complexity of AD.

OBJECTIVES: In response, multi-target-directed ligands (MTDLs) have emerged as a promising strategy. By simultaneously modulating several disease pathways, MTDLs can inhibit Aβ aggregation, reduce tau phosphorylation, and exert antioxidant and anti-inflammatory effects. This review summarizes recent progress on MTDLs, highlighting their mechanisms of action, representative drug candidates, and outcomes from preclinical and clinical studies.

CONCLUSIONS: Multi-target strategies have the potential to achieve more effective and disease-modifying outcomes than conventional approaches. A critical evaluation of their opportunities and challenges may guide future therapeutic development and the advancement of precision medicine for Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Animals
Ligands
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Molecular Targeted Therapy/methods

@article {pmid42145109,
year = {2026},
author = {Saxena, P and Kothiyal, P and Ratan, P},
title = {Evaluation of neuroprotective effects of Pyracantha crenulata (D. Don) M. Roem against aluminium chloride induced memory impairment of rats.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2026.2673060},
pmid = {42145109},
issn = {1743-1328},
abstract = {Pyracantha crenulata, traditionally used in Himalayan folk medicine, valued for enhancing vitality, mental clarity, and combating age-related cognitive decline due to its antioxidant constituents.

AIM: This study evaluated the neuroprotective effect of hydroalcoholic extract of P. crenulata against aluminium chloride (AlCl3)-induced Alzheimer's disease in rats.

MATERIALS AND METHODS: Alzheimer's pathology was induced using AlCl3, and rats were treated with P. crenulata extract (250 and 500 mg/kg) for 21 days. Cognitive and behavioural performance were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM). Biochemical parameters, including oxidative stress markers (SOD), cholinesterase activity (AChE), and myeloperoxidase levels (MPO), were measured. Histopathological examination of the hippocampus and cerebral cortex was conducted.

RESULTS: Aluminium intoxication led to marked deficits in learning and memory, as evidenced by performance in the Morris Water Maze and Elevated Plus Maze tests. Treatment with P. crenulata extract significantly enhanced spatial and long-term memory in a dose-dependent manner, with the higher dose producing the most pronounced improvement.

CONCLUSION: The findings of this study highlight the notable neuroprotective effects of P. crenulata, demonstrated through modulation of biochemical parameters and suppression of amyloid precursor protein and Tau, key pathological hallmarks of Alzheimer's disease, further validated by histopathological evidence.},
}

@article {pmid42145110,
year = {2026},
author = {Wimo, A and Jönsson, L},
title = {[Health economic aspects of dementia].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42145110},
issn = {1652-7518},
mesh = {Humans ; *Dementia/economics/diagnosis/epidemiology ; Sweden/epidemiology ; Cost-Benefit Analysis ; Health Care Costs ; Cost of Illness ; Quality of Life ; Alzheimer Disease/economics ; Life Expectancy ; },
abstract = {The societal costs of dementia in Sweden are very high: about SEK 90-100 billion per year. A purely demographic projection to 2050 gives a cost increase of about 80%. In addition to the costs, dementia also entails a loss of life expectancy for those with dementia and of quality of life for those affected and their relatives. At present, it is not possible to assess whether the antibody treatment against Alzheimer's disease is cost-effective in Sweden because no price is yet available. Blood-based biomarkers for Alzheimer's disease and other diagnostic methods, if included in the pricing basis for new drugs, can be a valuable addition to cost-effectiveness analyses.},
}

Humans
*Dementia/economics/diagnosis/epidemiology
Sweden/epidemiology
Cost-Benefit Analysis
Health Care Costs
Cost of Illness
Quality of Life
Alzheimer Disease/economics
Life Expectancy

@article {pmid42145180,
year = {2026},
author = {Zhang, Q and Li, W and Kundu, S and Long, Q},
title = {Knowledge-guided Bayesian biclustering model for omics data with noisy graphs.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag070},
pmid = {42145180},
issn = {1541-0420},
support = {RF1AG063481/NH/NIH HHS/United States ; R01AG071174/NH/NIH HHS/United States ; },
mesh = {Bayes Theorem ; Humans ; *Models, Statistical ; Cluster Analysis ; Algorithms ; Computer Simulation ; Alzheimer Disease/genetics ; Data Interpretation, Statistical ; Gene Regulatory Networks ; Gene Expression Profiling ; Genomics/statistics & numerical data ; },
abstract = {Extracting biologically meaningful information from high-dimensional, heterogeneous omics data is one of the key challenges in many biomedical studies. Among various biomedical applications, disease subtyping is of particular interest due to its critical role in improving diagnosis and designing personalized treatments. To address this, biclustering has become a widely used statistical method for subtyping. Additionally, it has been demonstrated across various statistical learning methods that incorporating biological graph knowledge such as gene regulatory network can significantly enhance variable selection, prediction accuracy, and model interpretability. However, existing graph-guided methods, while often yielding promising results, tend to overlook potential misspecifications, such as false positive (FP) and false negative (FN) edges in the graphs. Ignoring this noise can lead to suboptimal identification of biclusters. Therefore, it is essential to develop biclustering methods that can effectively handle noisy graphs as well as provide biological insight. We propose a Bayesian denoising knowledge-guided biclustering method that enables to integrate multiple graphs simultaneously. The incorporated graphs, viewed as noisy variations of the underlying true graph, are de-noised through modeling of FP and FN errors. A Markov chain Monte Carlo algorithm is developed to estimate the biclusters. Extensive simulation studies and real data analyses, including gene expression and proteomics datasets of Alzheimer's disease, have been conducted to validate the superior performance of the proposed method.},
}

Bayes Theorem
Humans
*Models, Statistical
Cluster Analysis
Algorithms
Computer Simulation
Alzheimer Disease/genetics
Data Interpretation, Statistical
Gene Regulatory Networks
Gene Expression Profiling
Genomics/statistics & numerical data

@article {pmid42145345,
year = {2026},
author = {Prasad, S and Gupta, S and Omega Oraon, AP and Molina Recalde, AP and Cañarte Moreira, JJ and Moyano Salazar, GN and Torres Cañarte, PD and Racines Navas, CI},
title = {Blood - brain barrier breakdown and neurovascular unit failure in the progression of Alzheimer's disease.},
journal = {Bioinformation},
volume = {22},
number = {3},
pages = {1673-1678},
pmid = {42145345},
issn = {0973-2063},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β deposition and tau pathology. Recent research highlights the role of blood-brain barrier (BBB) breakdown and neurovascular unit (NVU) dysfunction in disease initiation and progression. These factors contribute to neuroinflammation, cerebral hypoperfusion and impaired waste clearance. Despite this, the relationship between BBB integrity, NVU function and cognitive decline in AD remains inadequately understood. Data shows that blood-brain barrier disruption and neurovascular unit dysfunction are critical predictors of cognitive decline in Alzheimer's disease.},
}

@article {pmid42145602,
year = {2026},
author = {Clos-Garcia, M and Wretlind, A and Muk, T and Hooshmand, K and Simonsen, AH and Winchester, LM and Proitsi, P and Marioni, RE and Ahluwalia, TS and Kümler, T and Hasselbalch, SG and Legido-Quigley, C and , and , },
title = {Polyol pathway dysregulation in CSF links glucose metabolism to tau pathology independently of amyloid and genetic predisposition.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.26352559},
pmid = {42145602},
abstract = {Dementia affects approximately 60 million people worldwide, yet molecular mechanisms linking early neuropathological changes to clinical progression remain poorly understood. We performed targeted and untargeted metabolomics in plasma and cerebrospinal fluid (CSF) from 166 memory clinic patients spanning no cognitive impairment, mild cognitive impairment due to Alzheimer's disease (AD), AD dementia, and mixed AD-cerebrovascular dementia. Using a data-driven approach, we identified a CSF polyol signature characterized by elevated sorbitol, meso-erythritol, and d-glucose/erythritol ratio consistently associated with phosphorylated tau (pTau) and total tau (tTau), but not amyloid-β. This association was validated in an independent CSF metabolomics (n=687) and proteomics (n=737) cohorts. Structural equation modelling confirmed that polyol metabolites predict tau burden, with less than 3% attenuation following genetic adjustment, establishing a non-genetic, metabolically driven mechanism. These findings define a tau-dominant, amyloid-independent metabolic axis in neurodegeneration, implicating the polyol pathway as a potentially modifiable therapeutic target.},
}

@article {pmid42145614,
year = {2026},
author = {Morrison, C and Dadar, M and Zeighami, Y},
title = {Sex differentiated and domain specific patterns of longitudinal cognitive decline across subjective cognitive decline and amyloid positivity groups.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.26352563},
pmid = {42145614},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is associated with increased cognitive impairment and dementia. However, limited research has explored how amyloid (A) pathology contributes to these cognitive changes over time and whether these changes differ by sex.

METHODS: 1185 cognitively normal older adults (955 A-, 230 A+; 959 SCD-, 226 SCD+) from the National Alzheimer's Coordinating Center dataset were included. Linear mixed effects examined the interactions between SCD, sex, and amyloid positivity in predicting cognitive decline.

RESULTS: SCD+ and A+ individuals exhibited increased global cognition declines (p <.05), and A+SCD+ individuals showed the steepest decline in global cognition and function status (p <.05). A+ males exhibited increased functional deficits (p <.05), while A+SCD+ females exhibited increased language deficits (p <.05).

DISCUSSION: Our findings suggest that SCD and amyloid-positivity differentially impact global cognition, functional status, and language in males versus females, with important implications for clinical trials and therapeutic interventions.

HIGHLIGHTS: Few studies have explored the independent and joint effects of amyloid and sex in SCDSCD is associated with increased rates of global cognitive declineAmyloid positive females with SCD exhibit increased language declinesAmyloid positive males exhibit increased functional status declines.

RESEARCH IN CONTEXT: Systematic review: We reviewed the literature using traditional sources (e.g., PsycInfo, PubMed) and found that there are limited findings exploring longitudinal cognitive trajectories in people who are amyloid positive with SCD and whether these trajectories differ by sex.Interpretation: Our findings suggest that SCD and amyloid positivity jointly interact to influence global cognitive and functional declines. Females experience language deficits when they have both SCD and amyloid positivity whereas males with amyloid positivity exhibit increased functional deficits. Together these findings suggest that SCD status and amyloid positivity differentially impact females and males.Future directions: More research is needed using grouping amyloid, tau, neurodegeneration, and vascular pathologies together to explore the joint impact on cognitive change and conversion in people with SCD.},
}

@article {pmid42145619,
year = {2026},
author = {Sherva, R and Bayly, H and Zhang, R and Harrington, K and Mez, J and Miller, MW and Tsuang, D and Wolf, E and Zeng, Q and Le Guen, Y and Tejeda, M and , and , and , and Gaziano, JM and Panizzon, MS and Hauger, RL and Merritt, VC and Farrer, LA and Logue, MW},
title = {A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.26352216},
pmid = {42145619},
abstract = {INTRODUCTION: Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer's disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.

METHODS: Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.

RESULTS: Apart from the APOE region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene PAX7 in ADRD cases and controls.

DISCUSSION: MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.},
}

@article {pmid42145631,
year = {2026},
author = {Ghanbarian, E and Zheng, L and Qian, T and Glover, CM and Sajjadi, SA and Corrada, MM and Grill, JD and , and Ezzati, A},
title = {CSF p-tau Predicts Asymmetric Hippocampal Atrophy in Cognitively Unimpaired Older Adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.26352391},
pmid = {42145631},
abstract = {BACKGROUND: Hippocampal atrophy is a core marker of neurodegeneration in dementia, particularly in Alzheimer's disease (AD). However, most studies focus on total hippocampal volume loss and overlook hemispheric asymmetry, which may reflect distinct biological processes. While tau pathology is closely linked to medial temporal lobe degeneration, it remains unclear whether tau is associated with asymmetric patterns of hippocampal atrophy.

METHODS: We analyzed 483 cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline cerebrospinal fluid (CSF) phosphorylated tau (p-tau181) and amyloid-β (Aβ42) measurements and longitudinal structural MRI data over 10 years of follow-up. Total hippocampal volume and hemispheric asymmetry, defined as the absolute difference between left and right hippocampal volumes (|L-R|), were quantified at each visit. Linear mixed-effects models assessed associations between baseline CSF biomarkers and longitudinal changes in hippocampal asymmetry, adjusting for demographic factors, APOE ε4 status, and baseline hippocampal volume.

RESULTS: Higher baseline CSF p-tau181 was associated with greater increases in hippocampal asymmetry over time (β = 1.20, SE = 0.43, p = 0.006). This association remained significant after additional adjustment for total hippocampal volume and baseline CSF Aβ42. CSF total tau was highly correlated with p-tau181 (Spearman's ρ =0.98, p < 0.001) and showed comparable associations with hippocampal measures. In contrast, baseline Aβ42 was not associated with subsequent changes in hippocampal asymmetry. Both p-tau181 and Aβ42 were associated with faster decline in total hippocampal volume. In amyloid-stratified analyses, p-tau181 was associated with increasing hippocampal asymmetry only among amyloid-negative individuals, whereas its association with total hippocampal atrophy was observed primarily in amyloid-positive individuals.

CONCLUSIONS: CSF p-tau181 is associated not only with overall hippocampal atrophy but also with progressive hemispheric asymmetry, suggesting that tau-related neurodegeneration may manifest as both magnitude and imbalance of tissue loss. These findings support hippocampal asymmetry as a complementary neuroimaging marker that may capture non-amyloid-related medial temporal lobe degeneration in cognitively unimpaired older adults.},
}

@article {pmid42145632,
year = {2026},
author = {O'Shea, DM and Galvin, JE},
title = {Comparative analyses of Alzheimer's disease blood biomarkers and cognitive domains.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352316},
pmid = {42145632},
abstract = {INTRODUCTION: Whether Alzheimer's disease (AD) blood biomarker-cognition associations differ across cognitive domains, analytic context, and biomarker modeling strategy in population-based cohorts is unclear.

METHODS: In 1,170 older adults from the Health and Retirement Study Harmonized Cognitive Assessment Protocol, we examined cross-sectional (2016) and prospective (2016-2022) associations of blood p-tau181, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and amyloid-β42/40 with memory, executive function, language, visuospatial ability, and global cognition using individual biomarker, principal components analysis-derived composite, and multibiomarker panel models.

RESULTS: Cross-sectionally, NfL and GFAP showed the broadest associations. Prospectively, p-tau181 was independently associated with memory and global cognition, whereas GFAP was associated with executive function, memory, and global cognition. P-tau181 also showed relative memory-versus-executive selectivity. The comparatively best-fitting modeling approach differed by cognitive domain and analytic context.

DISCUSSION: AD blood biomarker-cognition associations in community-dwelling older adults are domain-differentiated and context-dependent, supporting domain-specific outcomes and flexible biomarker modeling strategies.},
}

@article {pmid42145634,
year = {2026},
author = {Aguilar-Dominguez, P and Colceriu, CM and Holland, TM and Lockhart, SN and Masdeu, JC and Vasconcellos Neumann, LT and Snyder, HM and Baker, LD and Bejanin, A and Landau, SM and Arenaza-Urquijo, E},
title = {Association of neighborhood deprivation with Alzheimer's Disease pathology, brain structure, and cognition by race and ethnicity, sex, and APOE ε4 status.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.05.26352370},
pmid = {42145634},
abstract = {BACKGROUND: We investigated associations of neighborhood disadvantage with Alzheimer's Disease (AD)-related outcomes by biological and social factors in at-risk older adults.

METHODS: 1,880 U.S. POINTER participants with Area Deprivation Index (ADI) and cognition (PACC) were included. 868 had amyloid, tau PET, white matter hyperintensities (WMH), and/or gray matter volumes. We conducted exploratory, linear models testing ADI interactions with sex, race and ethnicity, and APOE ε4, adjusting for age and education.

RESULTS: "White/European American", "Hispanic/Latinx/Spanish" and "Others" showed lower cognitive scores with higher ADI, while "White/European American" showed the highest cognitive scores across ADI levels. APOE ε4 carriers from high-ADI areas showed higher WMH and tau, and "Hispanic/Latinx/Spanish" from more deprived areas showed higher WMH. Females from moderate-ADI areas showed higher tau. Amyloid burden was higher in APOE ε4 carriers from low-ADI areas.

CONCLUSION: Differential associations of ADI with AD-related outcomes across biological and social factors may reflect systemic health disparities and study design.},
}

@article {pmid42145636,
year = {2026},
author = {Lorenzi, M and Custo, A and Frisoni, GB and Garibotto, V},
title = {A data-driven Alzheimer's disease progression simulator for retrospective validation and prospective Phase III power design.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352317},
pmid = {42145636},
abstract = {Anti-amyloid immunotherapies have recently demonstrated the first significant slowing of cognitive decline in Alzheimer's disease (AD), yet clinical benefit varies markedly across drugs and scales with the completeness of amyloid clearance. Pharmacokinetic/pharmacodynamic (PK/PD) models are currently the standard tool for trial simulation, but they typically operate on single biomarkers and rely on drug-concentration assumptions, leaving the multi-scale cascade from amyloid clearance through tau, neurodegeneration, and cognition largely unmodelled. No existing framework has been jointly validated against the quantitative outcomes of multiple real-world phase III trials, spanning clearance kinetics, multi-modal biomarker trajectories, and statistical power. We present a trial simulation platform based on SimulAD, a disease progression model trained exclusively on longitudinal observational data from ADNI, with no access to trial-arm labels or drug-specific outcomes. SimulAD encodes intervention as piecewise amyloid clearance terms within a latent ordinary differential equation system that jointly governs amyloid, tau, structural MRI, and cognitive trajectories under the amyloid cascade hypothesis. We retrospectively simulated six landmark phase III anti-amyloid trials (TRAILBLAZER-ALZ2, CLARITY AD, EMERGE and ENGAGE, GRADUATE I and GRADUATE II) using a single trained model with trial-specific calibration limited to amyloid clearance kinetics. SimulAD reproduced published mean centiloid reductions within 5% error across all six trials and generated CDR-SB distributions broadly consistent with reported placebo and treated-arm outcomes. In a retrospective power analysis, calibrated simulations separated the three positive from the three null trials, with EMERGE near the decision boundary and ENGAGE and both GRADUATE trials below it. Across trials, higher amyloid-clearance rates were associated with larger calibrated clinical effects and lower estimated sample sizes. These results establish SimulAD as a valid disease-progression-centric trial simulator providing quantitative guidance on sample size planning and treatment kinetics optimisation that is grounded in the full multi-modal biomarker cascade of AD.},
}

@article {pmid42145643,
year = {2026},
author = {Cook, N and Zeng, Y and Yang, C and Jiang, Z and Wang, TC and Le Guen, Y and Cody, K and Johnson, M and Zhang, R and Merritt, VC and Hauger, RL and , and , and Koran, ME and Mormino, EC and Gordon, B and DeCasien, A and Andrews, S and Dumitrescu, L and Archer, D and Hohman, TJ and Pottier, C and Cruchaga, C and Sherva, R and Logue, M and Napolioni, V and Greicius, MD and Belloy, ME},
title = {An APOE *4-Informed Genomic Atlas of the X Chromosome in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.05.26352461},
pmid = {42145643},
abstract = {The genetic contributions of the X chromosome to Alzheimer's disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.},
}

@article {pmid42145644,
year = {2026},
author = {Karlsson, L and Strandberg, O and Smith, R and Tang, W and Arvidsson, I and Åström, K and Oliveira Hauer, K and Janelidze, S and Stomrud, E and Palmqvist, S and Verghese, PB and Braunstein, JB and , and , and Klein, G and Shcherbinin, S and Jagust, WJ and Villeneuve, S and La Joie, R and Rabinovici, GD and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Generating synthetic tau-PET scans in Alzheimer's disease from MRI, blood biomarkers and demographics with deep learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.26352540},
pmid = {42145644},
abstract = {Tau protein aggregation in the brain is a hallmark of Alzheimer's disease (AD). Positron emission tomography (PET) is the only in vivo method to visualize tau pathology and estimate both its burden and regional distribution, but the use of tau-PET is constrained by high cost and limited accessibility. Here, we develop a deep learning model to synthesize tau-PET scans from more accessible data: structural magnetic resonance imaging (MRI), demographics, and when available, blood biomarkers. We included 5,191 participants across the AD continuum or with another neurological disorder from 13 cohorts (mean age 70 years, 51% female) and optimized a 3D U-Net neural network with residual and attention units for this task. In held-out test data, synthetic tau-PET reliably modeled tau burden, with correlations of R=0.77-0.86 with true tau-PET across individuals in common AD regions of interest. Spatial similarity between synthetic and true tau-PET was likewise high, with mean regional correlation of R=0.75. Synthetic scans also captured clinically meaningful prognostic information comparable to true tau-PET, including distinction between early (HR=12, p<0.001) and late (HR=45, p<0.001) stages of tau accumulation. These findings demonstrate that clinically informative synthetic tau-PET scans can be generated from widely available modalities using deep learning, potentially offering a scalable and cost-effective approach for estimating tau AD pathology in the brain.},
}

@article {pmid42145703,
year = {2026},
author = {Chen, F and Xue, M and Wang, H and He, H},
title = {Chronic two-photon microscopy reveals neuronal activity patterns in the cerebral cortex of an Alzheimer's disease mouse model.},
journal = {Biomedical optics express},
volume = {17},
number = {5},
pages = {2228-2241},
pmid = {42145703},
issn = {2156-7085},
abstract = {Chronic two-photon microscopy is used to investigate neuronal activity patterns in the primary visual cortex of Alzheimer's disease mice (5×FAD). We find that under resting conditions, individual AD neurons exhibit hyperactivity while the neuronal networks show rigid, hypersynchronous connectivity. Following precise optical stimulation of an individual neuron, the network hyperconnectivity is partially reduced. Morphological analysis of dendritic calcium signals reveals that AD neurons exhibit non-specific, widespread calcium propagation upon excitation and significantly increased dendritic length and branching density compared to WT mice, providing a potential link between single-neuron hyperactivity and network-level rigidity. These results demonstrate a hyperactive but rigid network phenotype in AD, providing a circuit-level explanation for early cognitive dysfunction.},
}

@article {pmid42145784,
year = {2026},
author = {Tamima, U and Gebril, HM and Hasan, MR and Quintero, MA and Aryasomayajula, A and Chengappa, D and Attarwala, I and Truong, BL and Moghe, PV and Uhrich, KE},
title = {Theranostic Nanoparticles for Fluorosensitive Visualization and Inhibition of Amyloid Beta-Induced Neuroinflammation.},
journal = {Particle & particle systems characterization : measurement and description of particle properties and behavior in powders and other disperse systems},
volume = {43},
number = {2},
pages = {e00220},
pmid = {42145784},
issn = {0934-0866},
abstract = {The emerging field of microglial therapies has significant potential to alleviate fibrillar amyloid beta (fAβ)-associated neuroinflammation, which exacerbates neurodegeneration in Alzheimer's disease (AD). New therapeutic strategies integrate with diagnostic capabilities to robustly elucidate the mechanisms and consequences of intervention. Amphiphilic macromolecules (AMs), comprising a hydrophilic sugar backbone, hydrophobic aliphatic side chains, and poly(ethylene glycol) (PEG) segments for enhanced stability, exhibit significant potential for biomedical applications due to their biocompatibility and self-assembled nanoscale structures. This study presents rhodamine B-tagged (Rh) AMs (Rh-AMs) that create stable nanoparticles (Rh-AM-NPs) with potential neurotherapeutic and diagnostic applications. Rh-AMs were successfully synthesized and validated using NMR, FTIR, UV-vis, and fluorescent spectroscopy. The ratio of labeled to unlabeled AMs necessary for Rh-AM-NPs formation was optimized via flash nanoprecipitation to confirm the minimum quantity required for direct visualization within cells. Using an in vitro BV2 microglial model, we demonstrated that Rh-AM-NPs exhibit multifunctional properties, suppressing the microglial inflammatory response and reducing microglial uptake of fAβ within a low-toxicity range, while simultaneously enabling in situ tracking of cellular interactions. This work validates a novel nanoplatform for combined AD therapy and diagnostics.},
}

@article {pmid42145981,
year = {2026},
author = {Hu, X and Li, G and Dai, K and Tang, S and Jin, X and Yang, W and Lu, T},
title = {Burden of dementia attributable to smoking among adults aged ≥40 years: A secondary dataset analysis of Global Burden of Disease 1990-2021 with projections to 2035.},
journal = {Tobacco induced diseases},
volume = {24},
number = {},
pages = {},
pmid = {42145981},
issn = {1617-9625},
abstract = {INTRODUCTION: Dementia persists as a critical global health challenge. Smoking is a modifiable behavioral factor associated with dementia, although improvements in healthcare have reduced dementia prevalence and mortality. Evaluating long-term changes in the smoking-attributable dementia burden provides a useful reference for informing and contextualizing dementia prevention efforts.

METHODS: This study is a secondary analysis of Global Burden of Disease (GBD) 2021 estimates. We examined smoking-attributable deaths and disability-adjusted life years (DALYs) for dementia among adults aged ≥40 years, across 204 countries and territories from 1990 to 2021. We assessed temporal trends using age-standardized rates and estimated annual percentage changes (EAPC), evaluated inequality across sociodemographic development levels, and projected the burden to 2035 using a Bayesian age-period-cohort (BAPC) model.

RESULTS: In 2021, the global burden of dementia attributable to smoking reached 1533214 DALYs (95% UI: 635494-3540712), representing an approximate twofold increase compared with 1990. However, the age-standardized DALY rate (ASDR) declined significantly over the same period, with an EAPC of -0.88 (95% CI: -0.92 - -0.83). Population growth and population ageing were the dominant contributors to the increase in DALYs, accounting for 112.17% and 26.02%, respectively, whereas epidemiological improvements partially offset the burden (-38.19%). In terms of regional variation, East Asia bore the heaviest absolute burden. BAPC projections indicated that despite continued declines in ASDR, smoking-attributable dementia DALYs are expected to keep increasing through 2035.

CONCLUSIONS: Despite declining age-standardized rates, the absolute burden of smoking-attributable dementia continues to rise, partly because reductions in smoking exposure are insufficient to counter demographic pressures from population ageing and growth. Persistent disparities across sociodemographic index groups further indicate that gains in tobacco control do not consistently translate into proportional reductions in dementia burden. Aligning tobacco control with ageing-responsive health system strategies will be essential to moderating future burden growth.},
}

@article {pmid42146216,
year = {2026},
author = {de Oliveira, TM and Pereira Bento, LD and Santos de Melo Wiermann, I and de Souza Fonseca, B and Tsui, GS and Pereira de Jesus, CJ and Sales, RO and Pereira Prado, MA and de Castro, MS and Reis Moura, JP and Gomes, EN and Bastos, LB and Lima Orsine, IC and de Souza Esteves, L and Silva Soares, MC and Falkoski, DL and da Silva, MP and de Oliveira, TA and da Silva, AM and Bechelane Maia, EH and Andrade Leite, FH and Valle, MS and de Carvalho, PB and Costa Vanessa Pereira Mendes, L and Taranto, AG and Moreira Damázio, LC},
title = {Integrative In Silico and In Vivo Evidence of Quercetin as a Multitarget Neuroprotective Agent in Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {18},
pages = {27115-27127},
pmid = {42146216},
issn = {2470-1343},
abstract = {Alzheimer's disease requires therapeutic strategies targeting multiple pathological mechanisms. This study investigates the neuroprotective potential of quercetin using an integrated approach combining in silico modeling and in vivo validation. Computational analyses examined the binding behavior of quercetin toward three key enzymes implicated in disease pathophysiology: acetylcholinesterase, butyrylcholinesterase, and beta-secretase 1. Molecular dynamics simulations reveal consistent interaction patterns and stable binding profiles across independent trajectories. For experimental validation, Wistar rats with surgically induced Alzheimer's disease were orally treated with quercetin (30 mg/kg) for 5 weeks. Histological and immunohistochemical analyses of the hippocampus and subventricular zone evaluated neuronal density and astrocytic activation using glial fibrillary acidic protein and vimentin markers. Computational results supported the multitarget potential of quercetin through stable enzyme interactions. Consistently, in vivo assays demonstrated increased neuronal density and reduced astrocytic marker expression, suggesting a protective modulation of neuroinflammatory processes. These findings highlight quercetin as a promising scaffold for multitarget therapeutic strategies aimed at mitigating the progression of Alzheimer's disease.},
}

@article {pmid42146238,
year = {2026},
author = {Mishra, A and Satapathy, BS and Sahu, PK and Ghose, A and Paidesetty, SK},
title = {Epigenetic Modulation Is a Key Mechanism in Cognitive Deficit: Unveiling Garcinol as a Potent HAT Inhibitor in Improving Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {18},
pages = {26129-26150},
pmid = {42146238},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a global concern. Conventional FDA-approved drugs mostly provide symptomatic relief but largely fail to address the underlying pathophysiology of AD. Further, chronic use of prescribed anti-AD drugs causes unpredictable, countless side effects, which thus evokes exploration for novel, safer, nontoxic, affordable, yet potent alternative modalities. Among various predicted pathophysiological hall marks in the progression of AD, aberrant histone acetylation has been identified as one of the major culprits, which leads to dysregulated gene expression and gradual neuronal degeneration. Thus, histone acetyl transferase (HAT) inhibitors are considered lucrative anti-AD agents. Active phyto constituents in recent times have occupied the center stage in addressing challenging neurodegenerative disorders in place of routine drug therapy. Garcinol (GL), a phytoactive constituent from Garcinia indica, possesses potent HAT inhibitory effect. Reports show that GL exhibits profound antioxidant, anti-inflammatory, anticancer, and neuroprotection effects. Neuroprotection of GL could be attributed to its ability to reduce oxidative stress and modulate important signaling pathways involved in neuronal degeneration. Present review unveils potentiality of HAT inhibitors in improving memory functions and neuroprotection; with a special focus on GL. Mechanical insights into activity of GL in ameliorating neurodegeneration have been discussed with rationalized evidence of various preclinical reports. Side by side, a portion has been devoted to update the trending drug delivery approaches investigated in recent times for GL toward improved pharmacological performance.},
}

@article {pmid42146335,
year = {2026},
author = {Lauderdale, K and Yan, Z and Mendiola, AS and Zhang, Y and Mallen, D and Nambiar, P and Brady, E and Miller, SR and Acevedo, RM and Cabriga, B and Jiang, F and Kaliss, N and Shen, K and Shin, J and Herbert, J and Ma, K and Ryu, JK and Agrawal, A and Schuck, R and Alzamora, MDPS and Sanz-Ros, J and Cobos, I and Stavenhagen, J and Kantor, AB and Ellisman, MH and Akassoglou, K and Palop, JJ},
title = {Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer's disease-related hyperexcitability and brain network dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.722324},
pmid = {42146335},
issn = {2692-8205},
abstract = {UNLABELLED: Brain network dysfunction-including hyperexcitability, altered oscillations, and sleep disruption-is prominent in Alzheimer's disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg [γ390-396A] mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg [γ390-396A] mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis-currently under clinical evaluation with the humanized antibody THN391- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026). [110].

HIGHLIGHTS: Fibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD miceFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD miceGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunctionAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit.},
}

@article {pmid42146347,
year = {2026},
author = {Capener, JL and Badillo-Martinez, A and Awada, B and Davis-Gilbert, ZW and Kramer, TW and Blair, CS and Bashore, FM and Al-Ali, H and Axtman, AD},
title = {Development of NanoBRET cellular target engagement assays in primary neurons for activating mutants of p21-activated kinase 1.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.722513},
pmid = {42146347},
issn = {2692-8205},
abstract = {The p21-activated kinases (PAKs) are a group of serine-threonine kinases central to multiple signaling pathways that govern cell survival and proliferation. Aberrant activity of PAK1, the most well characterized member of the PAK family, drives progression of several malignancies and brain disorders, including Alzheimer's disease and neurodevelopmental disorders. Despite growing interest in PAK1 as a drug target for these diseases, there is no assay to evaluate the intracellular target engagement of PAK1 inhibitors. To address this need, we developed first-in-class NanoBRET assays for wild-type PAK1 and a neurodevelopmental disorder-causing gain-of-function PAK1 mutant. Furthermore, we executed our novel PAK1 NanoBRET assay to evaluate target engagement of PAK1 inhibitors in primary hippocampal neurons. To the best of our knowledge, this is the first demonstration of a NanoBRET cellular target engagement assay in primary neurons, thereby increasing the relevance of our work by confirming PAK1 inhibitor binding to the aberrant form of the protein in primary neurons.},
}

@article {pmid42146356,
year = {2026},
author = {Riaz Rajoka, MS and Valladares, KN and Prairie, C and Li, W and King, P and Katz, J and Michalek, SM and Zhang, P},
title = {Porphyromonas gingivalis promotes lipid droplet-mediated microglial dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.722306},
pmid = {42146356},
issn = {2692-8205},
abstract = {Growing evidence supports a strong association between periodontitis and Alzheimer's disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased lipid droplet (LD) accumulation, heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that Pg infection induces robust LD accumulation in BV2 microglial cells and in microglia from Pg -infected App KI mice. This Pg -driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacological inhibition of LD with a triglyceride synthesis inhibitor effectively reversed Pg -induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.},
}

@article {pmid42146366,
year = {2026},
author = {Lutz, MW and Man, Z and Zheng, Y and Venkatesan, S and Chiba-Falek, O},
title = {A diagnostic plasma omics-biomarker for Alzheimer's disease informed by microglial single-cell transcriptomics: A pilot study.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721959},
pmid = {42146366},
issn = {2692-8205},
abstract = {BACKGROUND: The current biomarker framework for the diagnosis and staging of Alzheimer's disease (AD) relies mainly on neuropathological features; thus, its performance for diagnosis is limited prior to the initiation of neurodegeneration. Here, we leveraged transcriptomic data to develop a new framework for omic-informed blood-based diagnostic biomarkers for AD from early-stage.

METHODS: Microglial gene expression from single-nucleus (sn)RNA-seq data was analyzed via 6 statistical methods to identify candidate panels of genes predictive of AD. A total of 78 gene panels, 30-2000 genes in size, were selected and evaluated for their ability to distinguish AD patients from controls. Three top-ranked panels of 300, 50 and 30 genes were transferred to blood (monocyte) transcriptomic data obtained from living subjects via a graph-based mapping approach based on optimal transport statistics.

RESULTS: The 300-panel method resulted in an AUC of 0.7 and moderate accuracy (75%) in classifying AD; however, the accuracy in predicting cognitively normal patients was lower (53%). While the 300 genes provided high accuracy, inspection of the distribution of p values for the gene set revealed that the panel could be greatly reduced in size to capture the most significant differences between AD patients and cognitively normal individuals. The accuracy and specificity of the 50 and 30 panels demonstrated similar AUC values but improved the balance between the prediction of AD patients and normal controls. Specifically, the 50-gene panel resulted in an AUC of 0.7, with 65% AD accuracy and 71% normal accuracy.

CONCLUSIONS: Integrating multiomics datasets into the AD biomarker discovery pipeline offers a powerful modality to increase precision and comprehensiveness in AD research and clinical applications.},
}

@article {pmid42146419,
year = {2026},
author = {Cho, G and Kam, K and Chen, A and Mao, Y and Benveniste, H and Mecca, A and Valencia, DI and Martillo, KR and Chu, SS and Kumar, A and Bubu, OM and Osorio, RS and Ayappa, I and Liu, X and Miner, B and Varga, AW},
title = {Hypoxic burden predicts weaker coordination between brain pulsations and CSF flow independent of non-hypoxic arousals: Implications for glymphatic activity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.25.720853},
pmid = {42146419},
issn = {2692-8205},
abstract = {OBJECTIVE: To examine whether hypoxic burden is distinctly associated with key drivers of glymphatic activity, independent of sleep fragmentation.

BACKGROUND: OSA is a robust risk factor for multiple neurodegenerative conditions, including Alzheimer's disease, with glymphatic impairment representing a potential mechanistic pathway. However, it remains unknown whether distinct pathological features of OSA, including hypoxic burden and sleep fragmentation, are differentially associated with the two key physiological drivers of glymphatic activity: (1) coordination between brain pulsations and CSF flow and (2) brain pulsation strength.

METHOD: Twenty-eight individuals with newly identified OSA and eight healthy individuals without OSA completed either in-lab polysomnography or WatchPAT, providing estimates of hypoxic burden, quantified as time spent below 90% oxygen saturation (T90), and sleep fragmentation, quantified as non-hypoxic respiratory effort-related arousals (RERAs). Participants also completed 7T resting-state fMRI to quantify the coordination between brain pulsations and CSF flow using gBOLD-CSF coupling (i.e., cross-correlation between g ray matter b lood o xygen level d ependent signal pulsations and CSF inflow) and brain pulsation strength using gBOLD amplitude. Hierarchical regression and Pearson correlations were used to examine associations between sleep measures and fMRI-derived metrics.

RESULTS: Greater T90 was associated with weaker gBOLD-CSF coupling, independent of age, sex, race, and RERAs (Table 2; β=0.07, p =0.008). T90 also significantly improved model-explained variance in gBOLD-CSF coupling (Table 2; ΔR [2] =0.20, p =0.008). Contrary to expectations, greater T90 was associated with higher gBOLD amplitude across the temporal lobe and multiple frontal and parietal regions. Within regions showing T90-linked elevations in gBOLD amplitude, higher gBOLD amplitude was not associated with stronger region-specific gBOLD-CSF coupling. This contrasted with regions not associated with T90, where higher gBOLD amplitude was associated with stronger gBOLD-CSF coupling (difference in β=0.0006, p<0.001). RERAs were not associated with gBOLD-CSF coupling and gBOLD amplitude throughout the cerebral cortex.

CONCLUSIONS: In OSA, hypoxic burden, rather than respiratory effort-related sleep fragmentation, may be the primary pathological feature associated with impaired brain pulsation and CSF dynamics, both of which are key drivers of glymphatic activity. These alterations may be most prominent in the temporal lobe, potentially reflecting its elevated metabolic demand and vulnerability to hypoxemia.},
}

@article {pmid42146439,
year = {2026},
author = {Xu, Z and Chen, W and Ren, W and Xu, T and Amaechina, S and Khan, R and Chen, Y and Province, M and Payne, P and Li, F},
title = {Interpreting Omics Data Analysis with Large Language Models for Disease Target and Drug Discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721768},
pmid = {42146439},
issn = {2692-8205},
abstract = {In biomedical scientific discovery, synthesizing prior knowledge from the literature is an essential component of interpreting numerical omics data analyses for disease target identification and drug discovery. Large language models (LLMs) alone can rapidly retrieve disease mechanisms from biomedical text, but text-only outputs are general and unreliable for target and drug prioritization without cohort-specific quantitative evidence. Herein, we propose a provenance-aware Text-to-Target framework that couples schema-constrained multi-model LLM retrieval with numeric omics data analysis. The key design is a modality-aware fusion step: candidates are partitioned into overlap-supported anchors, retrieval-only hidden hubs, and network-emergent novelty nodes, then propagated into staged hypothesis and strategy generation under topology constraints. We evaluate the model in Alzheimer's disease (AD) and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the workflow produced a balanced 75-gene candidate universe and a 23-strategy portfolio, with significant DepMap support at both target level and strategy level. In AD, stricter candidate controls yielded a compact 34-gene universe and 14 strategies; under an expanded CRISPRbrain registry, both target-level axes were significant, with strong strategy-level enrichment. Across both diseases, final strategies preserved full provenance closure to the candidate pool, enabling end-to-end auditability from retrieval artifacts to validation outputs. These results support a transferable discovery architecture in which omics evidence constrains biological activity, LLM retrieval expands mechanistic search space, and network-aware fusion preserves interpretability. The framework provides a reproducible basis for dual-disease target prioritization and motivates continuous literature-mechanism concordance with agentic evidence-refresh loops.},
}

@article {pmid42146485,
year = {2026},
author = {Siebrand, CJ and Mayeri, Z and Brown, I and Andersen, JK and Walton, CC},
title = {In vitro comparison of Aβ-targeting SNIPR, synNotch, and TRUCK for cell-based drug delivery in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721717},
pmid = {42146485},
issn = {2692-8205},
abstract = {Pioneering research is adapting chimeric antigen receptors (CARs) from oncology to Alzheimer's disease (AD) by targeting amyloid beta (Aβ). Newer synthetic receptor systems can go beyond, transforming cells into targeted biological drug factories that can couple Aβ detection to synthesis and secretion of genetically encoded therapeutics. Among candidate systems, T cells Redirected for Universal Cytokine Killing (TRUCK), synthetic Notch (synNotch), and Synthetic Intramembrane Proteolysis Receptors (SNIPR) have shown promise in oncology. Here, we adapt these platforms to AD using a shared Aβ-targeting binding domain derived from Aducanumab (Aduhelm), coupled to inducible expression cassettes driving identical transgenes: secreted Metridia luciferase (MetLuc) and a Lecanemab (Leqembi)-based chimeric human-mouse antibody (chLecanemab). To validate these systems in vitro , Jurkat clones expressing each receptor were treated with oligomer-enriched Aβ (AβO) to model AD, and receptor output was quantified by media MetLuc levels and chLecanemab colocalization with Aβ aggregates. For TRUCK systems, we show the Aβ-targeting CAR successfully activated Jurkat cells by flow cytometry. We also show that six Nuclear Factor of Activated T-cells (NFAT) tandem repeat response elements (6xNFAT) paired with either minimal interleukin-2, synthetic TATA box, or minimal cytomegalovirus promoters resulted in functional regulatory regions. Despite this, all TRUCK variants failed to significantly upregulate MetLuc in response to AβO. In contrast, both synNotch and SNIPR responded robustly to AβO, with SNIPR outperforming synNotch in both MetLuc and chLecanemab production. These findings establish SNIPR and synNotch as promising platforms for future research on cell-based targeted therapeutic delivery in AD.},
}

@article {pmid42146492,
year = {2026},
author = {Cordi, CV and Falkenberg, NG and Clark, GT and Allen, NG and Chuah, JR and Ulbrich, R and Herzog, AA and Lanka, M and Collins, EJ and Bentley, M and Dordick, JS and Jankowski, MS and Hurley, JM},
title = {Circadian disruption induces sex-specific Alzheimer's pathophysiology and immune cell reprogramming.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721994},
pmid = {42146492},
issn = {2692-8205},
abstract = {UNLABELLED: Circadian disruption (CD) is increasingly recognized as a sex-specific risk factor for Alzheimer's disease (AD). However, the mechanisms linking CD to AD, and the role of biological sex in this interaction, are unclear. Immunometabolic regulation is extensively circadianly timed, has sex-specific phenotypes, and plays a role in AD. Therefore, we hypothesized that CD affects the timing of immunometabolism, contributing to the sex-specific effects of CD on AD. To demonstrate this, we subjected male and female APP/PS1 mice to chronic disruptive lighting to model circadian disruption, finding CD induced a female-specific reduction in amyloid plaque burden but an increase in the infiltration of peripheral macrophages into the brain. Concomitantly, we found macrophages exhibited CD-associated immune reprogramming, which in females led to altered immunometabolic timing, an increase of macrophages in the activated state, and elevated levels of reactive oxygen species (ROS), supporting a role for immunometabolism in the sex-specific effects of CD in AD.

HIGHLIGHTS: Circadian disruption reduces Aβ plaque load specifically in female micePeripheral immune infiltration correlates with reduced Aβ plaques in femalesCircadian disruption coordinates phasing of circadian immunometabolic proteinsIn females, circadian phase advancement correlates with increased ROS.},
}

@article {pmid42146512,
year = {2026},
author = {Bhattrai, A and Raikes, AC and Brinton, RD},
title = {Addition of humanized APP to humanized APOE mouse model reduces brain size and increases the ratio of cortical representation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722764},
pmid = {42146512},
issn = {2692-8205},
abstract = {INTRODUCTION: Age, Apolipoprotein E4 (APOE 4) genotype, and biological sex are major risk factors for late-onset Alzheimer's disease (LOAD). Neuroimaging is central to its characterization, and preclinical mouse models enable controlled investigation of these factors. To date, humanized APOE 4 has not recapitulated LOAD-relevant brain phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (hAPP) alongside humanized APOE (h APOE) may therefore improve translational modeling of structural brain changes.

METHODS: Aged mice (mean age = 23.25 months) carrying murine (m) or humanized (h) APP and either murine Apoe or h APOE 3/3, h APOE 3/4, or h APOE 4/4 underwent in-skull ex vivo volumetric MRI. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, APOE genotype, and sex, with FDR correction applied within contrasts.

RESULTS: Brain volumes were primarily determined by APP background, with hAPP globally reducing total and regional volumes relative to mAPP mice. Across hAPP models, h APOE 4/4 exhibited the greatest brain-wide reductions, which was mitigated by a single h APOE 3 allele. In contrast, mouse APP exerted modest effect in h APOE , with hAPOE4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, hAPP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independent of APP or APOE genotype.

DISCUSSION: These findings demonstrate that APP background is a primary driver of mouse brain volume, with hAPP producing global reductions amplified by the h APOE 4/4 genotype. In contrast, h APOE 4 effects in the mAPP background were modest and nonspecific, consistent with normative aging. Together, these results suggest that hAPP and h APOE 4 act synergistically, and that h APOE 4 alone is insufficient to recapitulate AD-relevant brain changes in mice. The hAPP/h APOE 4/4 model yields a brain-wide phenotype consistent with LOAD-associated volumetric patterns, whereas mAPP/h APOE models may better reflect non-pathological aging.},
}

@article {pmid42146521,
year = {2026},
author = {Shahani, N and Banerjee, R and MacMullen, C and Sharma, N and Habibi, M and Wasserman, HD and Noyes, NC and Zhao, P and Elgendy, B and Cameron, MD and Bannister, TD and Hegazy, L and Finck, BN and Davis, RL},
title = {Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.722019},
pmid = {42146521},
issn = {2692-8205},
abstract = {UNLABELLED: Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.

TEASER: Dipyridamole, an FDA-approved drug, restores mitochondrial function and protects neurons in ALS and Alzheimer's disease.},
}

@article {pmid42146576,
year = {2026},
author = {Bhaskar, U and Kos, MZ and Carless, MA},
title = {A Cell-Type-Resolved Meta-Analysis Reveals Glial DNA Methylation Changes Associated with Aging and Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722662},
pmid = {42146576},
issn = {2692-8205},
abstract = {Epigenome-wide association studies implicate DNA methylation in the development and progression of Alzheimer's disease (AD). Although recent studies show that the epigenetics of non-neuronal cell types contribute to disease risk, the role of the methylome in individual glial cell types (i.e., astrocytes, oligodendrocytes) in biological aging and AD pathogenesis is unclear. In this study, we examined archived DNA methylation data across 13 cohorts and performed cell type deconvolution in silico to identify novel epigenetic signatures associated with aging and AD in glial cells. We observed pronounced age-associated methylation in astrocytes within the prefrontal cortex, whereas oligodendrocytes of the entorhinal cortex show the most differential methylation with AD status. Astrocytes, along with neurons, within the prefrontal cortex, emerge as key players in Braak stage-associated methylation, exhibiting strong concordance with previously reported associations at the brain tissue level. Age-associated changes in oligodendrocytes exhibit strong directional correlation with, and amplification of age-related effects with AD that affect neurodevelopmental processes, while AD-related methylation changes at age-associated sites in astrocytes diverge from those representative of normative aging processes. Our study expands on previous findings and reveals glial-specific methylation patterns associated with epigenetic aging and AD.},
}

@article {pmid42146583,
year = {2026},
author = {Shahin, S and Vit, JP and Rentsendorj, A and Fuchs, DT and Swerdlow, N and Gaire, BP and Robinson, E and Kissel, A and Hagerman, L and Williams, A and Ljubimov, AV and Hawes, D and Schneider, LS and Mirzaei, M and Black, KL and Koronyo, Y and Koronyo-Hamaoui, M},
title = {Sex-specific retina-brain signatures link ERα/ERβ imbalance with gliosis in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.722000},
pmid = {42146583},
issn = {2692-8205},
abstract = {Women face a twofold higher lifetime risk of Alzheimer's disease (AD) than men, yet the mechanisms underlying female-biased vulnerability and sex-specific disease signatures across the retina-brain axis remain unknown. By integrating clinicopathological and proteomic datasets from paired retinal and brain tissues from 182 donors, we identified sex-divergent molecular and pathological features across the AD continuum. Despite comparable retinal and cerebral amyloid and tau burdens between sexes, females exhibited a more severe neuroinflammatory-neurodegenerative phenotype with intensified gliosis and tissue atrophy, whereas males displayed a dominant vasculopathy, marked by increased retinal vascular Aβ 40 deposition, tight-junction disruption, and cerebral amyloid angiopathy. In females, this profile coincided with inflammation-associated estrogen receptor (ER)-α remodeling and reduced global and astrocytic-nuclear ER-β, which associated more strongly with cognitive decline than in males. These results indicate that comparable AD proteinopathy is associated with divergent downstream consequences across the retina-brain axis and identify astrocytic ERα/ERβ imbalance as a sex-linked glial mechanism associated with female vulnerability in AD.},
}

@article {pmid42146604,
year = {2026},
author = {Allen, NG and Cordi, CV and Llabre, JE and Chuah, J and Clark, GT and Kubik, AJ and Falkenberg, NG and Jankowski, MS and Cahill, RA and Herzog, AA and Chander, MS and Vashishth, D and Hurley, JM and Blaber, EA},
title = {Alzheimer's Disease and circadian disruption sex-specifically contribute to a loss of bone maintenance in APP/PS1 model mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.722089},
pmid = {42146604},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's Disease and Related Dementias (ADRDs) are linked to reduced bone integrity and increased fracture risk, but the mechanisms that underlie this risk remain poorly defined. Current research suggests that environmental factors, such as diet, sleep, and light exposure can modulate the brain-bone axis, increasing susceptibility to bone loss and fractures. Circadian disruption (CD) associated with ADRDs may exacerbate the effects of disease and aging in the bone. In particular, regulation of bone marrow progenitors may be acutely susceptible to disruption along this axis. Here, we explore the interplay among genetic and environmental factors that influence bone structure, marrow progenitor cell activity, and monocyte-derived macrophages. The APP/PS1 transgenic mouse model (AP) is used as an in vivo model of amyloid-beta deposition. High-resolution micro-computed tomography (μCT) identified sex- and genotype-specific responses in trabecular morphometry. Follow-up analysis with Raman spectroscopy (RS) found accumulation of non-enzymatic modifications of the organic matrix and notched three-point bending identified concomitant loss of bone toughness due to both CD and AP. Single-cell RNA sequencing (scRNA-seq) confirmed the presence of oxidative stress signals in the cellular populations of the bone marrow. We further mapped significantly differentially expressed genes (DEGs) from monocytes in the bone marrow to circadian-regulated proteins in monocyte-derived macrophages, revealing dysregulation of circadian timing in macrophages in vitro . These findings offer new insights into how environmental disruptions can exacerbate the progression of neurodegenerative disease and bone degradation.

LAY SUMMARY: Patients with Alzheimer's disease have an increased bone fracture risk, but the biological link between brain and bone disease is not well understood. Everyday factors such as altered light exposure (shift work, screens late at night, etc.) can worsen outcomes in the brain and skeleton. Using a mouse model of Alzheimer's disease, we found that both genetic risk and circadian disruption contribute to weaker bone and altered bone quality. We also identified inflammation and stress responses in bone marrow cells, suggesting that bone marrow may play a key role in linking brain disease to bone fragility.},
}

@article {pmid42146610,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722733},
pmid = {42146610},
issn = {2692-8205},
abstract = {INTRODUCTION: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

@article {pmid42146614,
year = {2026},
author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y},
title = {Discovery of a CI-994 derivative as a dual modulator of class I HDACs and Wnt/β-catenin signaling for Alzheimer's disease therapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721954},
pmid = {42146614},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.},
}

@article {pmid42146648,
year = {2026},
author = {Yan, Z and Mendiola, AS and Lauderdale, K and Kim, KY and Yong, Y and Leng, K and Bushong, EA and Schuck, R and Meyer-Franke, A and Agrawal, A and Traglia, M and Gill, N and Thomas, R and Keller, JN and Karvelas, N and Vasquez, MF and Ballard, DC and Madany, M and Simms, J and Guo, B and Tognatta, R and Alzamora, MDPS and Meza-Acevedo, R and Cabriga, B and Pierson, KN and Kourita, L and Han, K and Ryu, JK and Miller, BL and Elahi, FM and Ellisman, MH and Palop, JJ and Akassoglou, K},
title = {Resilience to neuronal hyperactivity and restoration of the neuroimmune interactome and decision-making by blocking fibrin in a model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.722077},
pmid = {42146648},
issn = {2692-8205},
abstract = {UNLABELLED: Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimer's disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand-receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimer's disease and related conditions.

HIGHLIGHTS: Vascular-microglia axis drives neuronal hyperactivityFibrin inflammatory activity disrupts the microglia-neuron interactomeMicroglia activation by fibrin impairs decision-making in AD miceSynaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients.},
}

@article {pmid42146666,
year = {2026},
author = {Liu, Z and Ma, X and Ribas, RA and Medina, T and Quinones, S and Son, J and Wu, L and Ryan, AM and Shedlock, C and Ziani, B and Barco-Caiaffa, V and Rao, N and Wong, K and Titus, A and Larson, R and Vander Kooi, CW and Chandel, NS and Gentry, MS and Chen, L and Sun, RC},
title = {Metabolic Coherence of the Mouse Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.07.723592},
pmid = {42146666},
issn = {2692-8205},
abstract = {The brain's metabolic demands are well established, but how metabolism is coordinated across anatomically distinct regions remains poorly understood. Here, using matrix-assisted laser desorption/ionization (MALDI) imaging integrated with the Allen Brain Atlas and optimal transport-based computational analysis, we map the spatial metabolome across twelve major mouse brain divisions. We define an optimal-transport-derived inter-regional metabolite similarity metric and refer to it as metabolic coherence. This structure is largely preserved in an amyloid mouse model of Alzheimer's disease despite widespread changes in individual metabolite and lipid levels. Individual metabolites and lipids shift in a coordinated manner across regions, sustaining inter-regional relationships even as absolute levels change in patterns indicative of mitochondrial dysfunction. To test whether the coherence metric is responsive to local intervention, we targeted the left hippocampus of mice from this model via lentiviral shHIF1α knockdown or neuronal AAV-mediated AOX expression. Both interventions were associated with metabolite normalization at the injection site. More importantly, normalization extended across distal regions sharing high metabolic similarity with the hippocampus and was accompanied by improved social memory in a single behavioral assay. Gene modulation and amyloid plaque reduction localized to the injection site.},
}

@article {pmid42146670,
year = {2026},
author = {Yang, Y and Gao, N and Sharma, N and Dai, S and Su, G and Dinga, R and Selvaggi, P and Krüger, J and Cai, Y and Liang, L and Liu, Z and Rutherford, S and Guo, T and Wolfers, T and , },
title = {Lamellar Normative Modelling of the Hippocampus Across the Human Lifespan.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.02.722431},
pmid = {42146670},
issn = {2692-8205},
abstract = {The hippocampus is a central hub of human memory and cognition and is closely associated with brain disorders. Studies have shown that it exhibits complex structural variation across the lifespan, yet the details of hippocampal morphology changes remain poorly understood. Here, we establish norms over the hippocampal geometry that resolve lamellar morphology and map lifespan trajectories across more than 27,000 individuals from 158 scanning sites. Hippocampal geometry shows spatially non-uniform developmental and ageing patterns across the lifespan, with lamellar thickness, width and length following dissociable trajectories. Across multiple brain disorders, this representation reveals localized and heterogeneous alterations beyond conventional subfield-level summaries, and uncovers a dichotomy in disease-associated patterns, with neurodegenerative conditions and schizophrenia showing predominant atrophy, whereas some other disorders exhibit focal or regionally selective hypertrophy. Transfer to a longitudinal Alzheimer's Disease Neuroimaging Initiative cohort further supports out-of-sample generalization of our approach and enables individual-level tracking and conversion risk stratification. Overall, this work establishes a population-scale geometric reference for the hippocampus, extends normative brain mapping from coarse regional phenotypes to anatomically organized subcortical structure, and enables anatomically grounded characterization of disease-related alterations and individual-level deviation mapping, providing a principled basis for understanding and stratifying brain disorders across the lifespan in health and disease.},
}

@article {pmid42146687,
year = {2026},
author = {Xu, FH and Duong-Tran, D and Huang, H and Saykin, AJ and Thompson, PM and Davatzikos, C and Zhao, Y and Shen, L and , },
title = {Gene-Modulated Network Diffusion for Improved Modeling of Amyloid- β Spread in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722725},
pmid = {42146687},
issn = {2692-8205},
abstract = {Understanding the pathogenesis of amyloid- β pathology in Alzheimer's Disease (AD) proves to be a challenge. In this work, we expand upon the application of network diffusion models (NDM) to study pathophysiological spread of amyloid- β throughout white matter structural brain networks. We found that the NDM successfully recaptures subpopulation-level spatial patterns (Pearson's R=0.45-0.48, P FDR < 0.01) of amyloid- β deposition in the Alzheimer's Disease Neuroimaging Cohort at a regional level, but with drawbacks in mechanism interpretability. We then moved to an extended NDM framework (eNDM), including a protein synthesis term to better reflect the role of amyloid- β metabolism, as well as including regional vulnerability using spatial transcriptomics from the Allen Human Brain Atlas to modulate the region-level rate parameters of the synthesis term. The novel gene eNDMs exhibited significant performance increases in Pearson's correlation (Steiger's Z, P FDR < 0.10) over baseline NDM performance in mild cognitive impairment and AD groups using APOE, SORL1, and FGL2 for gene modulation. The results were robust and replicable when testing on an external cohort of the Alzheimer's Disease Sequencing Project. The study thus demonstrates the importance of regional genetic vulnerability, in conjunction with network diffusion mechanisms, in improving the modelling and prediction of amyloid- β pathophysiological spread.},
}

@article {pmid42146696,
year = {2026},
author = {Li, Y and Margoliash, J and Goren, A and Gymrek, M},
title = {The contribution of short tandem repeats to splicing variation in the human cortex.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.721407},
pmid = {42146696},
issn = {2692-8205},
abstract = {Splicing disruption has been implicated in a range of heritable phenotypes, including numerous psychiatric and neurological disorders. Recent studies have identified thousands of common genetic variants impacting splicing in brain and other tissues, but have focused largely on single nucleotide polymorphisms or short indels. Despite growing evidence that genetic variation at short tandem repeats (STRs) influences splicing, large-scale studies of STR-mediated splicing in brain have been limited by low sample sizes of available RNA-seq data or exclusion of certain classes of STRs, such as homopolymers which account for around half of all STRs. In this study, we leveraged deep RNA-seq and SNP array data from 336 human dorsolateral prefrontal cortex (DLPFC) samples collected by the Human Brain Collection Core (HBCC). We imputed 445,720 STRs into available genotype data and identified 51,343 unique STRs for which copy number is significantly associated with one or multiple alternative splicing events of nearby genes (spliceSTRs). We prioritized and characterized candidate causal spliceSTRs using three orthogonal fine-mapping strategies which identified 1,313 high-confidence fine-mapped spliceSTRs. Our analyses revealed strong associations between copy number of certain repeat units and binding of specific RNA-binding proteins (RBPs), including a previously known relationship between HNRNPL and AC repeat length, suggesting that the functional impact of some spliceSTRs may be mediated through their binding affinity for RBPs. Finally, co-localization analyses using summary statistics from genome-wide association studies (GWAS) for 6 brain-related disorders identified multiple signals that may be driven by spliceSTRs, including a previously identified GT n repeat that is a spliceSTR for PLEKHA1 associated with Alzheimer's disease as well as a newly identified AGG n spliceSTR in SEPTIN3 co-localized with schizophrenia. Together, our findings highlight the role of STRs in regulating alternative splicing in the human brain, suggest a general relationship between STR polymorphism and RBP-mediated splicing events, and support the hypothesis that splicing variation mediated by STRs plays a role in risk for brain-related disorders.},
}

@article {pmid42146852,
year = {2026},
author = {D'Amelio, C and Feroleto, C and Caligiuri, C and Li Puma, DD and De Chiara, G and Paoletti, I and Codazzi, C and D'Alelio, F and Miraglia, F and Pappalettera, C and Nucci, L and Frasca, F and Ventura, L and Manca, A and Morrone, M and Leone, L and Deriu, F and Morotti, M and Grassi, C and Vecchio, F and Podda, MV},
title = {EEG-motor correlation as early Alzheimer's disease index in herpes simplex virus type-1-infected mice.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag128},
pmid = {42146852},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.},
}

@article {pmid42146858,
year = {2026},
author = {Core, LB and Froud, SA and Wastling, S and Jiang, J and Levett, BA and Mancini, L and Dymerska, B and Hardy, CJD and Zeidman, P and Warren, JD},
title = {Functional neuroanatomy of musical object processing in Alzheimer's disease and frontotemporal dementia.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag161},
pmid = {42146858},
issn = {2632-1297},
abstract = {Music, besides its emotional and social resonance, models a complex sensory environment exemplifying auditory objects corresponding to sources (musical instruments) and information streams (melodies). These musical dimensions can be variably preserved or blighted by neurodegenerative disease. Music is, therefore, an attractive way to investigate the neural mechanisms of sensory object processing in these diseases. Here, we assessed the functional neuroanatomy underlying the perceptual, semantic, and apperceptive processing of musical objects in Alzheimer's disease and temporal variant frontotemporal dementia. We studied 35 patients (20 Alzheimer's disease, 15 temporal variant frontotemporal dementia; 14 females; mean [standard deviation] age 70.3 [8.4] years) in relation to 25 cognitively healthy volunteers (16 females; age 69.5 [6.8] years). In a functional MRI experiment with sparse image acquisition to minimise the impact of scanner noise, participants passively listened to monophonic melodies. We varied timbre (same/change), timbre familiarity (natural/artificial instruments), melody familiarity (familiar/novel), and apperception (melodies with interpolated timbre changes); these manipulations allowed us to assess the functional neuroanatomical correlates of musical feature perception, melody familiarity, constancy, novelty, and instrument familiarity. Behavioural correlates were assessed in post-scan tasks and disease-related atrophy patterns using voxel-based morphometry of participants' structural scans. All contrasts were assessed at P < 0.05, corrected for multiple voxel-wise comparisons within pre-specified anatomical regions of interest. For timbre change perception, all participant groups demonstrated comparable temporo-parietal cortical activation anchored in planum temporale. For melodies, processing of semantic familiarity in all participant groups engaged a common network including supplementary motor area and inferior frontal gyrus, with reduced supplementary motor area activation in the Alzheimer's disease group compared with other groups, while melody novelty comparably engaged postero-medial cortical circuitry across groups. Apperceptive coding of melody constancy was associated with activation of the posterior superior temporal cortex in the healthy volunteers, but greater activation of the temporal polar cortex in the temporal variant frontotemporal dementia group than in healthy volunteers. For instrument familiarity, the temporal variant frontotemporal dementia group showed reduced activation of the temporal polar cortex, but increased activation of the anterior insula compared to healthy volunteers. Brain activation profiles were not influenced by behavioural performance on post-scan tasks and did not coincide with regional atrophy. Our findings delineate complex, differentiated functional neuroanatomical profiles of musical object processing in Alzheimer's disease and frontotemporal dementia, with implications for our understanding of the neural mechanisms that decode complex sensory environments and the design and evaluation of interventions in these diseases.},
}

@article {pmid42146883,
year = {2026},
author = {García-Alberca, JM and Mendoza, S and DE LA Guía, P and López DE LA Rica, M},
title = {Effectiveness of Souvenaid® combined with acetylcholinesterase inhibitors on caregiver burden in Alzheimer´s disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70262},
pmid = {42146883},
issn = {2352-8737},
abstract = {INTRODUCTION: The burden experienced by caregivers of Alzheimer´s disease (AD) patients is a complex and stressful situation influenced by distinct variables, such as the patient´s need for monitoring, social isolation, mental or physical health problems, or financial challenges. In additon, behavioral and psychological symptoms of dementia are strongly associated with caregiver experiences of burden.

METHODS: This was a 12-month, retrospective, single-center, real-world study to evaluate the effectiveness of the combined treatment with Souvenaid and acetylcholinesterase inhibitors (AChEI) compared to treatment with either AChEI alone or Souvenaid alone on caregiver burden, anxiety and depression in patients, and AD patients attending a memory clinic. Assessments were conducted using the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory-State (STAI-S), and the Neuropsychiatric Inventory-Caregiver distress scale (NPI-D). A mixed model for repeated measures was conducted to evaluate differences from baseline to month 12 between caregivers in the three treatment groups.

RESULTS: At 12 months, caregiver burden, depression, anxiety levels, and the emotional distress in the context of behavioral and psychological symptoms of dementia (BPSD) improved in caregivers in the Souvenaid plus AChEI group (n = 70) compared to those in the AChEI group (n = 84) and those in the Souvenaid group (n = 66).The mean change for the ZBI score was found to be significantly higher in the Souvenaid plus AChEI group than in the AChEI group (p < 0.001) and the Souvenaid group (p < 0.001). In addition, there was a significant difference in the mean change for the BDI, STAI-S, and NPI-D scores between groups, favoring the Souvenaid plus AChEI group over the AChEI and Souvenaid groups.

DISCUSSION: In addition to assessing patients' cognitive, behavioral, and daily functioning, it is recommended regular monitoring of caregiver burden while providing support for patients with dementia. The combined treatment with Souvenaid and AChEI may have a significant impact on caregivers' experience of burden.},
}