@article {pmid41998020,
year = {2026},
author = {Bisht, M and Gomes, MC and Bordon Sosa, FH and Mano, JF and Pandey, S and Ventura, SPM and Coutinho, JAP},
title = {Superbase ionic liquid mediated solubilization of curcumin for improved bioavailability and anticancer efficacy.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41998020},
issn = {2045-2322},
support = {REDE/1517/RMN/2005//Fundação para a Ciência e a Tecnologia/ ; PDF/2019/001024//Government of India/ ; },
abstract = {UNLABELLED: Curcumin is a promising natural drug for the treatment of various diseases ranging from cancer to Alzheimer’s. However, a major hindrance in its use as a drug is its low aqueous solubility, rapid degradation, and poor cellular uptake. In recent years, the use of ionic liquids (ILs) in biomedical applications has gained significant attention due to their unique properties and tunability. In this study, we demonstrate the capacity of the superbase ionic liquid (SBIL) 5-Methyl-1,5,7-triaza-bicyclo[4.3.0]non-6-enium acetate [mTBNH][OAc] to dissolve highly hydrophobic and water-insoluble curcumin. An optimized concentration of 4 mol.kg[-1] of SBIL was used to dissolve 3.5 mg.g[-1] of curcumin, resulting in a formulation (curcumin/SBIL) that could be easily dispersed in an aqueous medium. Compared to the aqueous solubility of curcumin alone, the curcumin/SBIL formulation exhibited almost an 8,000-fold increase in solubility, also demonstrating a reduction of ~ 60% of human triple-negative breast cancer epithelial cells (MDA-MB-231) viability with only 10 µg.mL[-1] of curcumin (the active compound), without any cytotoxic effects on non-tumorogenic mouse fibroblasts (L929). Our study presents a straightforward methodology for improving the solubility and bioavailability of curcumin, which holds promise for its clinical application as an effective anti-cancer drug.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-44082-7.},
}

@article {pmid42015307,
year = {2026},
author = {Terao, CM and Erani, F and Urias, U and Lopez, F and Chang, F and Banks, SJ and Gilbert, PE and Coughlin, DG and Bangen, KJ and Thomas, KR},
title = {Global and domain-specific cognitive intraindividual variability associations with neurodegenerative diagnoses and postmortem pathologies.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42015307},
issn = {1758-9193},
support = {1RF1AG082726-01/NH/NIH HHS/United States ; 1RF1AG082726-01/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Cognitive intraindividual variability (IIV) or within-person variation in neuropsychological test performance relates to in vivo biomarkers of neurodegeneration and progression to mild cognitive impairment (MCI) and dementia. The current study aimed to explore longitudinal associations between global and domain-specific IIV with cognitive status and neuropathological findings at autopsy, and whether these associations differed by sex.

METHODS: The sample included 20,715 older adults from the National Alzheimer’s Coordinating Center (NACC) who completed cognitive testing as part of the Uniform Data Set. Participants were cognitively unimpaired at Visit 1. Baseline neuropsychological data was used to calculate coefficient of variation IIV (intraindividual standard deviation/mean performance) for global, executive, language, and memory domains. Global and domain-specific IIV associations with final visit cognitive status, etiological diagnosis, and progression to MCI/dementia were examined. Associations between each IIV score and neuropathological data were examined for participants with available autopsy data (ns = 1184–1717). Secondary models explored sex by IIV interactions.

RESULTS: Greater IIV (i.e., more variability) in global and specific domains related to worse cognitive status at final visit and final etiological diagnosis. Across all IIV domains, higher IIV related to greater risk of progressing to MCI/dementia. Higher global IIV related to greater postmortem burden of amyloid-β plaques, neurofibrillary tangles (NFT), AD neuropathologic change (ADNC) scores, hippocampal atrophy, substantia nigra neuron loss, hypopigmentation in the locus coeruleus, and cerebral amyloid angiopathy (CAA). Domain-specific effects included: higher executive IIV related to greater NFT, neuritic plaques, ADNC scores, and CAA; and higher memory IIV related to greater neuritic plaques and NFT. There were no significant interactions of sex and IIV.

CONCLUSIONS: Among cognitively unimpaired older adults, global IIV was a sensitive but non-specific marker associated with cognitive decline and neuropathology at autopsy. Domain-specific IIVs were also associated with cognitive progression but offered more specificity in neuropathologic outcomes. Associations were largely consistent across sexes, indicating IIV is robust to sex-specific effects. Findings highlight IIV as sensitive to long-term cognitive health and neuropathological burden and may improve early risk stratification for dementia.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02041-4.},
}

@article {pmid42267694,
year = {2026},
author = {Verma, M and Mohd Siddique, MU and Singh, NK},
title = {Corrigendum to: Neuroactive Phytoconstituents of Glycyrrhiza glabra for the Treatment of Alzheimer's Disease.},
journal = {Current topics in medicinal chemistry},
volume = {26},
number = {4},
pages = {422},
doi = {10.2174/156802662604260406111327},
pmid = {42267694},
issn = {1873-4294},
abstract = {It has come to our notice that in the published version of this article [1], the reference [96] was cited erroneously. The author has now corrected the reference sequence, and it is now cited as [95]. The revised section is provided below. The original article can be found online at https://www.eurekaselect.com/article/145138.},
}

@article {pmid42267709,
year = {2026},
author = {Toyli, A and Zhao, C and Su, KJ and Shen, H and Deng, HW and Chen, QH and Sha, Q and Zhou, W},
title = {Cardiovascular Disease Subtypes and Alzheimer's Disease: Phenotypic and Genetic Associations in the UK Biobank and All of Us Research Program.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e046172},
doi = {10.1161/JAHA.125.046172},
pmid = {42267709},
issn = {2047-9980},
abstract = {BACKGROUND: Cardiovascular disease (CVD) and Alzheimer's disease (AD) are major public health concerns that share overlapping risk factors and potential mechanistic pathways. Although vascular contributions to cognitive decline are well documented, the specific relationships between AD and different CVD subtypes remain poorly understood.

METHODS: In this cross-sectional study, we examined associations between AD and 11 CVD subtypes using logistic regression models in 2 large biobanks: the UK Biobank (n=502 133) and the All of Us Research Program (n=287 011). Models were adjusted for demographic, lifestyle, and clinical covariates. We also explored genetic overlap between AD and CVD traits through proximity-based analysis of significant single nucleotide variants (P<5 × 10[-8]) using genome-wide association study data.

RESULTS: Most CVD subtypes were significantly associated with AD in both cohorts. Hypotension had the strongest and most consistent association, although it has been comparatively understudied in AD research. Strong associations were also consistently observed between AD and hypertension and cerebral infarction. Notably, acute myocardial infarction was not significantly linked to AD. Genetic analyses revealed shared loci between AD- and CVD-related traits, particularly in regions near APOE, MAPT, and genes influencing myocardial structure and vascular function.

CONCLUSIONS: This study identifies subtype-specific CVD associations with AD across 2 diverse cohorts and highlights shared genetic architecture underlying heart-brain interactions. These findings underscore the importance of vascular health in AD risk and suggest that certain CVD subtypes, especially hypotension, may play underrecognized roles in cognitive decline.},
}

@article {pmid42267754,
year = {2026},
author = {Katti, VB and Kolusu, AS and Madhana, RM and Pindiprolu, SKSS and Tummala, UK and Samudrala, PK},
title = {Therapeutic Potential of Stearylamine-Conjugated Phenylboronic Acid-Modified Nanocarriers of 4-Allyl Pyrocatechol in Modulating Sialylation and Neuroinflammation in Scopolamine-Induced Cognitive Impairment in the Rat Model.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c01768},
pmid = {42267754},
issn = {1543-8392},
abstract = {Alzheimer's disease is a progressive neurodegenerative condition and is regarded as the most prevalent type of dementia among older adults. It is characterized by the accumulation of beta-amyloid, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, neuroinflammation, and neuronal loss, all of which contribute to the gradual decline in cognitive function. Recent research has highlighted the role of sialylation in the pathogenesis of Alzheimer's disease. Sialylation plays a critical role in the pathophysiology of Alzheimer's disease, influencing amyloid plaque formation, neuroinflammation, and synaptic function. CD33 plays a significant role in regulating immune responses, particularly in the central nervous system, and has been implicated in the progression of Alzheimer's disease. In this study, we explore the neuroprotective effect of stearylamine-conjugated phenyl boronic acid-modified 4-allyl pyrocatechol (PAPS) nanoparticles in modulating sialylation and neuroinflammation against scopolamine-induced Alzheimer's disease in rats. 4-Allyl pyrocatechol is known to possess antioxidant and anti-inflammatory activities. On the other hand, stearylamine-conjugated phenyl boronic acid (PBSA) not only is a potential vehicle for delivering drugs or therapeutic agents to the brain but also has a propensity to inhibit the interaction of sialic acid-conjugated ligands with CD33 receptors, which facilitates clearance of amyloid beta through microglia-mediated phagocytosis. A total of 36 animals were divided into 6 groups (n = 6) as control group, disease group, standard group, PBSA carrier group, 4-allyl pyrocatechol group, and PAPS group, which were treated with 5% carboxy methyl cellulose (p.o.), scopolamine 3 mg/kg (i.p.), donepezil 3 mg/kg (i.p.), stearylamine-conjugated phenyl boronic acid 2 mL/kg (p.o.), 4-allyl pyrocatechol 10 mg/kg (p.o.), and PAPS 10 mg/kg (p.o.) respectively. The study was designed for 16 days. From day 8, all the groups except the control group were administered scopolamine 3 mg/kg (i.p.) 45 min before they were given their respective treatments. Behavioral tests (open field test, novel object recognition test, Y-maze, and Morris' water maze) were conducted from day 8 to day 15. On day 16, animals were euthanized by cervical dislocation, brains were isolated, and the hippocampus and prefrontal cortex were separated and homogenized, followed by centrifugation at 4 °C, 10,000 rpm for 15 min. The biochemical estimations like acetylcholinesterase activity were used; oxidative and antioxidant parameters like nitric oxide, malondialdehyde, and reduced glutathione were determined; enzyme-linked immunosorbent assays for amyloid beta, inflammatory cytokines, brain-derived neurotrophic factor, and CD33 were performed. The results from behavioral and biochemical tests suggested that the PAPS formulation had a more significant impact on slowing the progression of scopolamine-induced cognitive impairment compared to the stearylamine-conjugated phenyl boronic acid carrier and 4-allyl pyrocatechol alone treatments. The histopathological studies revealed a decline in neural degeneration and showed improved neuronal morphology in the PAPS-treated group compared with the disease group. From the data obtained, the PAPS nanoparticle formulation would be an effective strategy for reducing the progression of cognitive impairment.},
}

@article {pmid42268233,
year = {2026},
author = {Shakoor, A and Elhenawy, AA and Alam, A and Ahmad, I and Rahman, MU and Khan, A and Zouidi, F and Almutairi, TM and Al-Harrasi, A and Khan, M},
title = {Benzimidazole derived hydrazone Schiff bases as potent cholinesterase inhibitors: synthesis, in vitro and in silico approaches.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17568919.2026.2684691},
pmid = {42268233},
issn = {1756-8927},
abstract = {AIMS: The current study aimed to synthesize and evaluate benzimidazole Schiff bases as dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

METHODS: Ten benzimidazole Schiff bases were synthesized and characterized by spectroscopic techniques. These compounds were assessed for in vitro AChE and BuChE inhibitory activities. Density functional theory (DFT) analysis was carried out to know the electronic properties, while molecular docking studies were performed to expose protein ligand interactions.

RESULTS: In the series, compounds (2c, 2f, 2h, 2a, and 2b) displayed potent inhibition against AChE and BuChE comparable to the standard galantamine. DFT study showed that compounds having higher electrophilicity (ω), lower hardness (η), higher softness (σ), and lower energy gap (ε) increase the inhibitory activity. In addition, electron donating groups at meta position of the benzene improved the potency, while docking studies confirmed favorable binding interactions with the active site of the enzymes.

DISCUSSION: These consequences show that both geometric and electronic properties have a vital role in determining the cholinesterase inhibition. These derivatives facilitate multiple interactions within the enzyme active site, supporting its potential as biologically relevant nucleus.

CONCLUSION: The experimental and computational findings provide valuable insights for the optimization and rational design of new therapeutic agents for Alzheimer's disease.},
}

@article {pmid42268276,
year = {2026},
author = {Zakharov, AV and Komarova, YS and Moskvitina, PM and Pavlova, ON and Romanchuk, NP and Sergeeva, MS and Shirolapov, IV},
title = {[Bidirectional links between sleep deprivation and neurodegenerative diseases].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {5. Vyp. 2},
pages = {74-80},
doi = {10.17116/jnevro202612605274},
pmid = {42268276},
issn = {1997-7298},
mesh = {Humans ; *Sleep Deprivation/complications/metabolism/physiopathology ; *Neurodegenerative Diseases/etiology/metabolism ; Risk Factors ; Alzheimer Disease ; },
abstract = {Sleep is essential for maintaining homeostatic functions, supporting optimal brain activity, and facilitating recovery processes. The clinical consequences of sleep deprivation and sleep disorders require an integrated approach to diagnosis and therapy, as these conditions affect the progression and development of various diseases and systemic pathological processes. Sleep disturbances are a significant global health concern. This article reviews the potential impact and bidirectional associations between sleep deprivation and the risk of neurodegenerative diseases.The mechanisms underlying the imbalance between the formation and clearance of abnormal proteins, which are central to the pathogenesis of proteinopathies associated with sleep disorders or deprivation, are examined. Although treating Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions remains challenging, recent research may enable prevention and targeted interventions at early stages, including extensive screening and modification of risk factors such as sleep deprivation and disturbance.},
}

Humans
*Sleep Deprivation/complications/metabolism/physiopathology
*Neurodegenerative Diseases/etiology/metabolism
Risk Factors
Alzheimer Disease

@article {pmid42268277,
year = {2026},
author = {Agaltsov, MV},
title = {[Sleep-disordered breathing in older adults: clinical features and effects on the nervous system and mental health].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {5. Vyp. 2},
pages = {81-86},
doi = {10.17116/jnevro202612605281},
pmid = {42268277},
issn = {1997-7298},
abstract = {Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder characterized by upper airway collapse, intermittent hypoxemia, intrathoracic pressure fluctuations, and sleep fragmentation. In older adults, the clinical presentation and consequences of OSA differ from those observed in middle-aged individuals, necessitating age-specific management strategies. This review discusses age-related aspects of OSA epidemiology and pathophysiology, as well as associations with neurological and psychiatric outcomes in later life. Evidence demonstrates that OSA prevalence increases with age in both sexes, with postmenopausal hormonal and metabolic changes further elevating risk in women. Aging is associated with reduced slow-wave sleep, increased sleep fragmentation, and upper airway structural alterations, all of which may affect respiratory event patterns and arousals. Notably, excessive daytime sleepiness may be less prominent in older adults despite clinically significant OSA. Emerging data link OSA in older adults to cognitive decline, Alzheimer's disease biomarkers, and heightened risk of cerebrovascular disorders, although research specifically targeting elderly populations remains limited. Positive airway pressure (PAP) therapy may enhance mood, daytime functioning, and certain cognitive outcomes; however, current evidence is constrained by small sample sizes, short follow-up, and adherence challenges. Diagnosis and management of OSA in older adults require age-appropriate clinical interpretation and further longitudinal and interventional studies to elucidate causal relationships and the effects of treatment on neurodegenerative and cerebrovascular outcomes.},
}

@article {pmid42268317,
year = {2026},
author = {Choi, SA and Hong, SH},
title = {MiR-125a C > T, MiR-152 C > T, MiR-938 G > A, and MiR-491 G > A single nucleotide polymorphisms and their influence on genetic susceptibility to type 2 diabetes.},
journal = {Genes & genomics},
volume = {},
number = {},
pages = {},
pmid = {42268317},
issn = {2092-9293},
support = {NRF 2017R1D1A3B03027985//Ministry of Education, Science and Technology/ ; },
abstract = {BACKGROUND: Diabetes mellitus (DM) is a chronic metabolic disorder that carries the risk of severe complications, such as cardiovascular disease, renal impairment, and an increased susceptibility to Alzheimer's disease. Considering these significant health implications, it is crucial to deepen our understanding of this condition. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, play a critical role in various biological processes and, when dysregulated, can contribute to the development of diseases such as diabetes mellitus.

OBJECTIVE: This study aimed to investigate the association between type 2 diabetes mellitus (T2DM) and specific miRNA polymorphisms (miR-125a C > T, miR-152 C > T, miR-938 G > A, and miR-491 G > A) in a Korean population.

METHODS: We examined the distribution of miRNA polymorphisms through genotyping in 238 T2DM patients and 343 healthy controls using polymerase chain reaction-restriction fragment length polymorphism technique.

RESULTS: Our findings indicate that the miR-938 GA genotype and its dominant model were significantly associated with an elevated risk of T2DM. Moreover, specific combinations of genetic variations were linked to either an increased or decreased risk of developing T2DM.

CONCLUSIONS: These results suggest that miRNA polymorphisms may influence an individual's genetic susceptibility to T2DM and offer potential therapeutic targets and diagnostic tools.},
}

@article {pmid42268366,
year = {2026},
author = {Shirvani, H and Pescatello, LS and Eftekhari Moghadam, AR and Arabzadeh, E},
title = {Unlocking Neuroprotection: Exercise-Induced Muscle Secretome (Myokines) as a Therapeutic Avenue Against Alzheimer's Disease Pathogenesis.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42268366},
issn = {1559-1166},
mesh = {Humans ; *Myokines/metabolism ; *Alzheimer Disease/metabolism/therapy ; Animals ; *Exercise ; *Neuroprotection ; Neuroprotective Agents/therapeutic use ; },
abstract = {This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer's disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30-45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy-affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein-including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails-remain speculative and are presented as future research directions rather than established therapeutic interventions.},
}

Humans
*Myokines/metabolism
*Alzheimer Disease/metabolism/therapy
Animals
*Exercise
*Neuroprotection
Neuroprotective Agents/therapeutic use

@article {pmid42268445,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Baghalishahi, M and Shamsara, A},
title = {The protective effects of dexmedetomidine via AMPK/SIRT1 pathway activation in a rat model of alzheimer's disease: evidence from preliminary findings.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268445},
issn = {1573-4978},
mesh = {Animals ; *Dexmedetomidine/pharmacology/metabolism ; *Sirtuin 1/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Male ; Rats ; Rats, Wistar ; Disease Models, Animal ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Streptozocin ; *Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Hippocampus/metabolism/drug effects ; },
abstract = {BACKGROUND: Metabolic dysfunction and impaired energy signaling play critical roles in Alzheimer's disease (AD). The AMP-activated protein kinase (AMPK) / sirtuin-1 (SIRT1) pathway is a key regulator of neuronal energy homeostasis and survival. Dexmedetomidine (Dex), a selective α -2 adrenergic receptor agonist, has shown neuroprotective effects in acute neurological injury and energy homeostasis; however, its efficacy in metabolically driven AD models remains unclear.

METHODS: Forty-two adult male Wistar rats were randomly assigned to seven groups: control, sham, STZ, sham + Dex 25, STZ + Dex 25, STZ + Dex 50, and STZ + Dex 100 (n = 6/group). Sporadic AD was induced by bilateral intracerebroventricular injections of streptozotocin (STZ, 3 mg/kg) on days 1 and 3. Dex was administered intraperitoneally at doses of 25, 50, or 100 µg/kg following STZ injection. Hippocampal neuronal injury was assessed by Nissl staining, and AMPK and SIRT1 protein levels were evaluated using Western blot analysis 30 days after STZ administration.

RESULTS: STZ administration significantly increased neuronal injury in the hippocampal CA1 region and markedly reduced AMPK and SIRT1 expression compared with control and sham groups (p < 0.05-0.001). Dex treatment at all doses significantly attenuated CA1 neuronal damage, with the most pronounced histological protection observed at 25 µg/kg (p < 0.001). In parallel, Dex reversed STZ-induced downregulation of AMPK and SIRT1, with maximal molecular upregulation observed at 100 µg/kg (p < 0.05).

CONCLUSIONS: Dex mitigates STZ-induced hippocampal neurodegeneration, at least in part, through modulation of the AMPK/SIRT1 signaling pathway. These findings support the therapeutic potential of Dex in metabolically driven models of sporadic AD.},
}

Animals
*Dexmedetomidine/pharmacology/metabolism
*Sirtuin 1/metabolism
*Alzheimer Disease/drug therapy/metabolism
Male
Rats
Rats, Wistar
Disease Models, Animal
*AMP-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
Streptozocin
*Neuroprotective Agents/pharmacology
Neurons/drug effects/metabolism
Hippocampus/metabolism/drug effects

@article {pmid42268464,
year = {2026},
author = {Mishra, H and Mishra, MK},
title = {Advances in anti-tau therapeutics for alzheimer's disease: immunotherapy, gene modulation, and combination approaches.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268464},
issn = {1573-4978},
abstract = {Tau protein abnormalities are more detrimental to neurocognitive function and behaviour than amyloid plaque formation in patients affected by Alzheimer's Disease (AD) - the most common cause of dementia worldwide. Pathologically, tau misfolding, neurofibrillary tangle formation, hyper phosphorylation, and dissociation from microtubules lead to synaptic dysfunction and neuron death. With this understanding, tau is now a major therapeutic target; there is a growing research effort to assess immunotherapy, kinase inhibitors, and tau aggregation inhibitors, and evidence suggests that combination therapies may have synergistic effects. Although there are many challenges remaining, including poor late-stage trial efficacy and limited therapeutic access through the blood-brain barrier, the preliminary results from early preclinical and clinical studies suggest that tau pathology can be reduced and neuronal function improved. Additionally, RNA interference, antisense oligonucleotides, and other gene-based therapies are under investigation. Overall, tau-directed treatments show promise for the treatment of AD, with particular optimism about improvements in delivery systems and combination therapies that will lead to substantial therapeutic benefits and improved quality of life for patients with AD.},
}

@article {pmid42268478,
year = {2026},
author = {Khajouei, F and Ghaemi, A and Abnous, K and Taghdisi, SM and Ramezani, M and Alibolandi, M},
title = {CRISPR-Based Gene Therapy for Brain Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42268478},
issn = {1559-1182},
abstract = {Neurological disorders are complex and often very challenging for patients. Many of these conditions result from mutations in genes that are essential for normal function. Most existing treatments only alleviate symptoms, highlighting the urgent need for more effective therapeutic strategies. In the current drug development landscape, gene therapy offers hope as a promising approach. Specifically, CRISPR-Cas9 technology enables precise gene editing across diverse cell types and organisms. An increasing number of research groups are investigating innovative therapies and the molecular mechanisms behind neurological diseases. This review highlights the use of CRISPR-based gene therapies for various brain diseases, including multiple sclerosis, Alzheimer's, Parkinson's disease, epilepsy, stroke, and brain tumors. It consistently recognizes significant challenges in clinical applications, including overcoming the blood-brain barrier (BBB), managing off-target effects, ensuring efficient delivery, and addressing immunogenicity and ethical concerns.},
}

@article {pmid42268484,
year = {2026},
author = {Asadi Anar, M and Fathollahi, MA and Zare, F and Farrokhi, Z and Habibzadeh, E and Hasany, S and Mirmazloumi, M and Arab Bafrani, M and Abedian Kenari, F and Falahati, M and Khorsand, K and Zakavi, A and Asadollah Salmanpour, Y and Yadegarifard, E and Khosravi, F and Goudarzi, P},
title = {Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42268484},
issn = {1573-7365},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by profound disturbances in cerebral energy metabolism. Mitochondrial dysfunction has long been implicated in AD pathophysiology; however, the specific contribution of mitochondrial enzymes in human disease remains fragmented across heterogeneous studies. Enzymes regulating carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, and redox balance represent key metabolic control points whose dysfunction may contribute to neuronal vulnerability. To systematically synthesize human evidence on mitochondrial enzyme alterations in Alzheimer's disease and to evaluate the feasibility of quantitative meta-analysis based on current reporting practices. A systematic literature search was conducted in PubMed, Scopus, and Web of Science from database inception through January 2026 in accordance with PRISMA 2020 guidelines. Studies were included if they investigated mitochondrial enzymes in human postmortem brain tissue, human-derived cellular models, or peripheral biospecimens. Risk of bias was assessed using the ROBINS-I tool. The feasibility of meta-analysis was evaluated based on the availability and comparability of group-level summary statistics. Fifteen studies met the eligibility criteria and were included in the final synthesis. Mitochondrial enzymes involved in carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, redox regulation, and neurotransmitter-linked mitochondrial metabolism were the most frequently investigated targets. Direct enzyme-activity evidence most consistently implicated selected metabolic control points, particularly PDHC and αKGDHC, whereas additional studies supported mitochondrial impairment through protein or post-translational modification changes, respiratory dysfunction, redox alterations, or RNA-regulatory mechanisms. Quantitative meta-analysis was not feasible due to heterogeneous assay methodologies, variable normalization strategies, and inconsistent reporting of group-level summary statistics. Human evidence consistently implicates mitochondrial enzyme dysfunction as a central metabolic feature of Alzheimer's disease. However, progress toward cumulative quantitative synthesis remains limited by methodological heterogeneity and incomplete reporting of enzyme activity outcomes. Standardized measurement and reporting of mitochondrial enzyme alterations will be essential to advance mechanistic understanding and enable future meta-analytic integration.},
}

@article {pmid42268486,
year = {2026},
author = {Hashem, S and Yamashiro, S and Joe, E and Chui, H and Marmarelis, V},
title = {PRBS Gas Challenges Reveal Impaired Chemoreflex and Cholinergic Dynamics in MCI.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {42268486},
issn = {1573-9686},
support = {R01-AG058162/AG/NIA NIH HHS/United States ; },
abstract = {PURPOSE: This study investigates the dynamic regulation of cerebral oxygenation in individuals with mild cognitive impairment (MCI) compared to healthy controls, using a novel pseudorandom binary sequence (PRBS) gas challenge. Traditional assessments often overlook frequency-dependent features of cerebrovascular control; this work aims to uncover latent deficits through broadband perturbations and nonparametric dynamic modeling.

METHODS: Seventeen ApoE4-negative participants (9 controls, 8 MCI) underwent a three-session supine protocol involving PRBS-modulated inhalation of hypoxic and hypercapnic gas mixtures. Physiological signals-including near-infrared spectroscopy (TOI), arterial pressure (ABP), and end-tidal CO2 (PETCO2)-were recorded. Laguerre-based Volterra modeling and Principal Dynamic Mode (PDM) decomposition were used to analyze the dynamic response of cerebral oxygenation to ABP and CO2 stimuli. Group differences were statistically assessed using Welch's t-tests and repeated measures ANOVA.

RESULTS: Controls showed significant increases in ventilation and TOI from baseline to stimulation (p < 0.01), while MCI did not. Gain of the first CO2 PDM increased in controls during PRBS (p = 0.016) but decreased in MCI. A low-frequency ABP-derived PDM (∼  0.014 Hz), consistent with endothelial-dependent vasodilation, was elevated only in controls during stimulation. Persistent differences in spectral recovery, kernel profiles, and PDM Gains suggested impaired baroreflex and chemoreflex regulation, and possible disruption of cholinergic-linked neurovascular coupling in MCI.

CONCLUSION: PRBS gas modulation combined with dynamic modeling revealed subtle but significant cerebrovascular control impairments in MCI. This methodology enables mechanistic insights into early pathophysiology and may aid future physiomarker development.},
}

@article {pmid42268489,
year = {2026},
author = {Palabiyik, AA and Palabiyik, E},
title = {Unravelıng non-canonıcal Wnt sıgnalıng ın neural development and dısorders: a revıew of Wnt/PCP and Wnt/ca[[2+]] pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268489},
issn = {1573-4978},
abstract = {Non-canonical Wnt signaling pathways, particularly the Planar Cell Polarity (Wnt/PCP) and Wnt/Ca[2+] branches, play critical roles in regulating neural development and maintaining cellular homeostasis within the nervous system. This review provides a comprehensive evaluation of the molecular and cellular functions of these pathways, with a focus on their involvement in cytoskeletal dynamics, cellular polarity, and calcium signaling. Non-canonical Wnt signaling is essential for key neurodevelopmental processes, including neural tube closure, neuronal migration, axon guidance, and synaptic plasticity, while its dysregulation contributes to the pathogenesis of both neurodevelopmental and neurodegenerative disorders such as autism spectrum disorder, spina bifida, Alzheimer's disease, and Parkinson's disease. Particular emphasis is placed on the role of Dishevelled (DVL) as a shared intracellular signaling mediator across canonical and non-canonical Wnt pathways, as well as on the context-dependent activation of downstream effectors including Rho GTPases, protein kinase C (PKC), calcium/calmodulin-dependent kinase II (CaMKII), and nuclear factor of activated T-cells (NFAT). In addition, emerging experimental platforms, including CRISPR/Cas9 gene editing and human brain organoids, are highlighted for their utility in dissecting pathway-specific mechanisms and advancing translational applications. Overall, this review underscores the importance of non-canonical Wnt signaling as a dynamic and context-dependent regulatory network and discusses its potential as a target for precision-based therapeutic strategies in neurological disorders.},
}

@article {pmid42268557,
year = {2026},
author = {Galán-Ganga, M and Rodríguez-Navarro, I and Zaballa, S and Ramón-Lainez, A and Gómez-Rivada, N and Peters, C and Fernández-Irigoyen, J and Santamaría, E and Rabadán, MÁ and Alberch, J and Rodríguez, MJ and Del Toro, D and Giralt, A},
title = {Targeted neuronal reprogramming rescues memory and neural synchrony in Alzheimer's disease.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42268557},
issn = {2662-8651},
support = {CIVP21A7024//Fundación Ramón Areces/ ; CNS2022 - 135391//Ministerio de Ciencia e Innovación/ ; PID2024-157024OB-I00//Ministerio de Ciencia e Innovación/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and represents a major societal burden. Aging is the strongest risk factor for AD, and partial cellular reprogramming using Yamanaka factors (YFs) has recently emerged as a strategy to counteract age-associated dysfunction. However, the mechanisms by which partial reprogramming ameliorates AD-related phenotypes remain poorly defined. Here, we investigated whether targeted and intermittent expression of YFs in hippocampal neurons restores cognitive function and neural network integrity in the P301S mouse model of tauopathy. We first show that controlled YFs expression in hippocampal neurons increases excitatory synaptic transmission and enhances neural synchrony in GCaMP6-expressing neuronal networks. We then induced intermittent, neuron-specific YFs expression for six months in adult control and P301S mice. This intervention led to a sex-dependent improvement in cognitive and emotional behaviors in P301S mice, accompanied by a reduction in Tau pathology and partial restoration of epigenetic aging markers. At the molecular level, reprogramming restored the composition and signaling of N-methyl-D-aspartate receptor (NMDAR) macro-complexes, including key subunits and AD-associated risk factors such as proline-rich tyrosine kinase 2 (PYK2/PTK2B). Importantly, impaired hippocampal neural synchrony observed in P301S mice was also rescued. Together, these findings demonstrate that targeted, partial in vivo neuronal reprogramming reverses behavioral and network-level deficits in a mouse model of AD and identify NMDAR-associated signaling as a potential mechanistic mediator of this effect.},
}

@article {pmid42268602,
year = {2026},
author = {Moore, GJ and Bose, N and Henter, ID and Manji, HK},
title = {The 25-Year Evolution of Lithium as a Disease-Modifying Agent in Dementia: A Narrative Review.},
journal = {JAMA psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamapsychiatry.2026.1296},
pmid = {42268602},
issn = {2168-6238},
abstract = {IMPORTANCE: Lithium, a long-established cornerstone therapy for bipolar disorder, is a biologically plausible disease-modifying agent for neurodegenerative disorders, including mild cognitive impairment (MCI) and Alzheimer disease (AD).

OBSERVATIONS: Rather than targeting a single pathology like amyloid or tau, lithium acts across multiple cellular resilience pathways. Chronic lithium exposure induces the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), enhances brain-derived neurotrophic factor (BDNF) signaling, inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes mitochondrial function, and reduces oxidative stress. These convergent mechanisms promote neuronal survival and synaptic integrity. In humans, proton magnetic resonance spectroscopy studies found that lithium increased N-acetylaspartate levels, consistent with improved neuronal viability, and structural magnetic resonance imaging (MRI) studies found that lithium preserved gray matter and/or reversed illness-related atrophy in hippocampal and corticolimbic regions. In addition, extensive evidence demonstrates that low-dose lithium (approximately 0.3mM)-significantly lower than traditional psychiatric doses (0.6-1.0mM)-exerts robust neurotrophic and neuroprotective effects. Preclinical models have found that these concentrations stimulate hippocampal neurogenesis, promote structural plasticity, and protect against proteotoxic injury. Furthermore, epidemiological studies have associated cumulative lithium exposure with reduced dementia risk, and early randomized clinical trials in MCI suggest cognitive stabilization and favorable tau biomarker changes at low, well-tolerated doses. The recent repletion hypothesis suggests that lithium may also function as a physiological trace element, but these findings await independent replication.

CONCLUSIONS AND RELEVANCE: These convergent data support a prospective clinical trial of low-dose lithium orotate to slow disease progression in MCI. Such an approach would prioritize established neuroprotective mechanisms while potentially mitigating the kidney and thyroid risks associated with higher-dose carbonate formulations. If low-dose lithium can indeed meaningfully alter disease trajectory, it would represent a much-needed, accessible, and inexpensive treatment that may be especially relevant in low- and middle-income countries.},
}

@article {pmid42268632,
year = {2026},
author = {Casaletto, KB and Dubal, DB},
title = {Female Clinical Resilience Despite Pathologic Risk in Alzheimer Disease.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.9351},
pmid = {42268632},
issn = {1538-3598},
}

@article {pmid42269217,
year = {2026},
author = {Chae, HJ and Kwon, H and Son, SR and Moon, S and Park, AY and Bae, HJ and Jang, DS and Kim, DH},
title = {Fukinolic acid facilitates toxic amyloid-β oligomerization and exacerbates synaptic dysfunction.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119619},
doi = {10.1016/j.biopha.2026.119619},
pmid = {42269217},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) aggregates that induce synaptic dysfunction and neuronal loss. Among the various Aβ species, soluble oligomers are considered the most neurotoxic forms and play a critical role in AD progression. Fukinolic acid (FA), a polyphenolic compound isolated from medicinal plants, has been reported to possess antioxidant and anti-inflammatory activities; however, its effects on Aβ aggregation have not been investigated. In the present study, we investigated whether FA modulates Aβ aggregation and synaptic dysfunction. Molecular docking analysis suggested that FA directly interacts with Aβ monomers at aggregation-prone regions. Consistent with this prediction, FA facilitated the formation of toxic Aβ oligomers and enhanced Aβ-induced neuronal cytotoxicity. The potentiation of Aβ toxicity by FA was abolished by an N-methyl-D-aspartate (NMDA) receptor antagonist, indicating the involvement of NMDA receptor-dependent signaling. Electrophysiological recordings showed that FA exacerbated Aβ-induced long-term potentiation (LTP) impairment in hippocampal slices without affecting basal synaptic transmission. In addition, FA administration increased Aβ deposition and reduced neuronal viability in the hippocampus of 5XFAD mice. FA treatment showed non-significant trends toward reduced hippocampal LTP and spontaneous alternation in the Y-maze test, indicating that further studies are required to determine whether FA affects synaptic and cognitive function in vivo. These findings suggest that FA promotes toxic Aβ oligomer formation and may aggravate Aβ-associated synaptic impairment through NMDA receptor-dependent mechanisms, highlighting the importance of evaluating the effects of natural compounds on Aβ pathology in AD.},
}

@article {pmid42269220,
year = {2026},
author = {Müller, WEG and Perovic-Ottstadt, S and Dobmeyer, R and Neufurth, M and Nassabi, H and Muñoz-Espí, R and Ushijima, H and Schröder, HC and Wang, X},
title = {Prevention of NMDA receptor sensitization by neurotoxic β-amyloid through polyphosphate coacervation.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119578},
doi = {10.1016/j.biopha.2026.119578},
pmid = {42269220},
issn = {1950-6007},
abstract = {Alzheimer's disease is characterized by amyloid-β (Aβ)-induced synaptic dysfunction and N-methyl-d-aspartate (NMDA) receptor-dependent calcium dysregulation, and inorganic polyphosphate (polyP), a platelet-enriched polymer released upon platelet activation, has emerged as a potential modulator of neuronal survival. Primary rat neuronal cultures and PC12 pheochromocytoma cells were exposed to the neurotoxic Aβ fragment Aβ(25-35), following a 2-5 day pre-incubation to induce its toxic conformation; neuronal apoptosis, NMDA receptor-mediated calcium influx, and the mechanistic basis of polyP action were assessed in the presence of sodium polyphosphate (Na-polyP), including experiments with calcium-chelating polyP coacervates formed in combination with serotonin, and the release kinetics of three polyP-based brain-targeted formulations were characterized. Pre-incubated Aβ(25-35) at 10 µM induced apoptotic neuronal death within 3 days, whereas coincubation with Na-polyP (50 µg/mL) abolished Aβ-induced neurotoxicity and significantly attenuated glutamate-evoked NMDA receptor-dependent calcium influx; mechanistic analyses demonstrated that Na-polyP forms calcium-chelating coacervates, promoted by serotonin at physiological Ca[2+] concentrations, and that polyP nanogels, nanoparticles and micelle-based formulations exhibit controlled release profiles. These data identify calcium chelation via polyP coacervate formation as a key mechanism underlying protection against Aβ-induced NMDA receptor sensitization and neuronal death, and suggest that polyP-based strategies may provide a mechanistically grounded approach for therapeutic intervention in Alzheimer's disease.},
}

@article {pmid42269324,
year = {2026},
author = {Xu, X and Li, L and Huang, W and Yang, Y and Li, X and Wang, P and Zhao, M and Zhang, H and Yuan, C},
title = {Bidirectional causal relationships between plasma proteins, neuroimaging metrics and risk of Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100619},
doi = {10.1016/j.tjpad.2026.100619},
pmid = {42269324},
issn = {2426-0266},
abstract = {BACKGROUND: Changes in neuroimaging metrics are among the first detectable pathophysiological alterations in Alzheimer's disease (AD). Proteins are closely linked to fluctuations in neuroimaging metrics. Therefore, the analysis of the proteomic signature associated with neuroimaging metrics holds significant promise for uncovering therapeutic targets that contribute to AD.

METHODS: GWAS data concerning the Brain Imaging Data Structure (BIDs). The AD cohort comprised a total of 401,661 individuals diagnosed with AD, alongside 10,520 control participants. For a bidirectional MR analysis involving neuroimaging metrics, proteomics, and AD, the methods utilized included inverse variance weighted (IVW), MR Egger, weighted median, weighted mode, and the Wald ratio approaches.

RESULTS: We identified 12 neuroimaging metrics that demonstrate significant relevance to AD (thickness of the left total hemisphere, volume of the right thalamus, and et al.). These metrics are structural magnetic resonance imaging (MRI) biomarkers that remain stable throughout the entire course of AD, from the preclinical stage through mild cognitive impairment (MCI) to dementia. Additionally, we found a substantial number of 1633 proteins that also show a noteworthy causal relationship with AD. Functional enrichment analysis indicated that these proteins were predominantly focused within various pathways linked to AD, encompassing those involved in the synaptic vesicle cycle, synaptic membranes, neurotransmitter release, and the activity of GABA receptors. In addition, our research indicates that the significant relationships observed between the identified proteins and AD are influenced by neuroimaging metrics. Notably, we found that these neuroimaging metrics play a crucial role in mediating a substantial 67% of the inverse relationship that exists between PTPRC and the phenotypic characteristics associated with AD.

CONCLUSIONS: This study successfully establishes a connection between proteomic and neuroimaging metrics, as well as the AD that influence them. By creating this relationship, the research offers important information that aids in comprehending the intricate mechanisms involved in AD.},
}

@article {pmid42269375,
year = {2026},
author = {Dai, Y and Zhao, Z and Song, Y and Li, C and He, X and Wang, Y and Xu, ZD and Yang, Y},
title = {Galanin receptor 2: A multifunctional modulator in neurological diseases - Structure, mechanisms, and therapeutic prospects.},
journal = {Neuropeptides},
volume = {118},
number = {},
pages = {102634},
doi = {10.1016/j.npep.2026.102634},
pmid = {42269375},
issn = {1532-2785},
abstract = {Galanin receptor 2 (GALR2), as a subtype of neuropeptide galanin receptor, is predominantly expressed in the central and peripheral nervous systems. Accumulating evidence suggests that GALR2 is involved in the pathogenesis of depression, Alzheimer's disease, epilepsy, neuropathic pain, multiple sclerosis, as well as in neurological tumors. Here, we summarize the current knowledge on the molecular architecture, signal transduction mechanisms, and diverse biological functions of GALR2. In addition, we also discuss the involvement of GALR2 in neurological diseases, with a particular emphasis on evaluating its potential as a novel and viable therapeutic target for future drug development.},
}

@article {pmid42269785,
year = {2026},
author = {Aranda-Abreu, GE and Rojas-Durán, RD and Hernández-Aguilar, HE and Herrera-Covarrubias, D and Tlapa-Monge, LR and Mestizo-Gutiérrez, SL},
title = {Alternative Splicing in Alzheimer's Disease: Driver, Modifier, or Consequence of Neurodegeneration.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112211},
doi = {10.1016/j.mad.2026.112211},
pmid = {42269785},
issn = {1872-6216},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder in which the molecular mechanisms driving onset and progression remain incompletely understood. Emerging evidence highlights RNA splicing as a central regulatory axis shaping neuronal function and vulnerability. In this review, we examine how disruptions in alternative splicing contribute to AD pathogenesis by altering transcript isoform diversity across key genes, including APP, MAPT, PSEN1/2, and BACE1. We discuss how aging, oxidative stress, neuroinflammation, and cellular stress responses converge to impair spliceosomal fidelity and RNA-binding protein function. These alterations lead to isoform imbalance, protein dysfunction, and synaptic impairment, ultimately promoting neurodegeneration. Importantly, we critically address whether splicing dysregulation represents a primary driver or a downstream consequence of disease. Finally, we explore emerging therapeutic strategies targeting RNA processing, including antisense oligonucleotides and RNA-based technologies, highlighting their potential to restore transcriptomic balance and modify disease progression.},
}

@article {pmid42269809,
year = {2026},
author = {Yao, M and Liu, A and Song, J and Xing, L and Zi, M and Li, H},
title = {Cerebral hypoperfusion and the vascular-metabolic-immune-glymphatic network in Alzheimer's disease: mechanisms, diagnosis, and therapy.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.001},
pmid = {42269809},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strategies have dominated this field for over three decades. Although recent anti-Aβ antibodies have shown modest promise, their limited clinical benefits coupled with safety concerns underscore the necessity of re-evaluating the pathological mechanisms underlying AD. Cerebral hypoperfusion (CH), a detectable alteration emerging in the preclinical stage of AD, has garnered increasing attention for its potential driving role in disease pathogenesis. This review proposes a "vascular-metabolic-immune-glymphatic" (VMIG) pathological network model originating from CH: CH induces pericyte damage, astrocyte end-feet impairment, and extracellular matrix degradation, thereby resulting in neurovascular unit dysfunction; reduces oxygen and glucose delivery, precipitating mitochondrial energy failure and reactive oxygen species overproduction, which in turn initiates neuroinflammatory cascades; and attenuates arterial pulsation-driven flow while disrupting perivascular space architecture, culminating in glymphatic system clearance dysfunction. These mechanisms are intricately interconnected, establishing a self-perpetuating pathological loop. Building upon the VMIG framework, this review integrates multimodal neuroimaging techniques (ASL-MRI, Aβ/tau-PET, DTI-ALPS) with peripheral biomarkers (VEGF/Ang-2, sTREM2/GFAP, sPDGFRβ/Aβ42 ratio) to establish a comprehensive system for early diagnosis and stratified assessment of AD. Furthermore, we advocate for temporally sequenced combinatorial therapeutic strategies targeting the pathological network and discuss the translational potential of nanoparticle-based co-delivery systems. The VMIG model offers an integrative framework for understanding the multi-system dysregulation inherent to AD, facilitating a paradigm shift from single-target intervention toward network-based restoration.},
}

@article {pmid42269855,
year = {2026},
author = {Mangalmurti, A and Bonheur, A and Lukens, JR},
title = {Microglial ITAM & ITIM signaling in neurodegenerative disease and brain aging.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169910},
doi = {10.1016/j.jmb.2026.169910},
pmid = {42269855},
issn = {1089-8638},
abstract = {Innate immunity within the central nervous system (CNS) plays key roles in shaping both healthy brain aging and vulnerability to neurodegenerative disease. Microglia, the tissue-resident macrophages of the CNS, play a key role in mediating the innate immune responses to age-associated pathologies. A growing body of literature details the roles of microglia in responding to white matter degeneration, misfolded proteins, and cell death. These functions depend on cell-surface receptors that enable microglia to sample and react to changes in their environment. Recent studies highlight the importance of receptors associated with immunoreceptor tyrosine-based activation and inhibitory motifs (ITAMs/ITIMs) in pathological brain aging. In this review, we describe how ITAM/ITIM-associated receptors and their downstream signaling pathways shape microglial responses to neurodegenerative disease and aging. A deeper understanding of microglial activation and resolution may provide tools to harness these cells' capacity to maintain and extend neurological healthspan.},
}

@article {pmid42269957,
year = {2026},
author = {Salehinejad, MA and Jouzdani, AF and Bandeira, ID and Bender, S and Bikson, M and Castelo-Branco, M and Kadosh, RC and Costanzo, F and Croarkin, PE and Desarkar, P and Dyke, K and Eickhoff, S and Fitzgerald, PB and Hartwigsen, G and Koenig, J and Martino, D and Menghini, D and Sadat Mirfazeli, F and Moliadze, V and Nitsche, MA and Oberman, LM and Siniatchkin, M and Vaziri, Z and Vicario, CM and Vöckel, J and Wischnewski, M and Wolters, CH and Zangen, A and Zaehle, T and Zomorrodi, R and Brunoni, AR},
title = {Global prevalence and disability burden of brain disorders: Impact of neurological, mental, and substance use disorders.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106808},
doi = {10.1016/j.neubiorev.2026.106808},
pmid = {42269957},
issn = {1873-7528},
abstract = {Brain disorders-encompassing neurological, mental, and substance use disorders-account for 10 of the top 25 causes of disability worldwide in 2021. Despite such an impact, they have not been centrally analyzed in prior Global Burden of Disease (GBD) studies. This review synthesizes the latest disability-focused GBD study to quantify the prevalence and disability burden of 35 conditions from 2010 to 2021, a period marking the first decline in global health outcomes in three decades. It further incorporates disability metrics from 2021 to 2023 to contextualize post-pandemic trends. The review covers the prevalence and disability burden of neurological, mental, and substance use disorders along with COVID-19 using DALYs and YLDs metrics. From 2010 to 2021, Parkinson's, Alzheimer's, and motor neuron diseases (in neurological disorders), major depressive, anxiety, and eating disorders (in mental disorders), and opioid and drug use disorders (in substance use disorders) showed the greatest increases in age-adjusted prevalence rates across all sexes. In 2021, neurological disorders were the primary cause of DALYs, while depressive and anxiety disorders ranked as the 2[nd] and 6[th] leading causes of global YLDs. Alzheimer's disease/dementias, Parkinson's disease, autism spectrum disorder, depressive and anxiety disorders, and opioid and drug use disorders show the largest increases in burden within their respective categories between 2010 and 2021. In the 2021-2023 extension analysis, disability data showed increases in prevalence and disability of several brain disorders, mostly anxiety disorders, while the COVID-19 disability burden declined markedly by 2023. Sex-specific burden metrics, key insights from each disorder, and limitations/confounds are discussed.},
}

@article {pmid42269977,
year = {2026},
author = {Wan, H and Chen, Y and Zhang, X and Yu, Z and Zheng, K and Shao, X and Bi, M and Jiang, B and Wang, Z},
title = {Large-scale EEG network alterations in late-onset epilepsy of unknown etiology: A comparative study with Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107483},
doi = {10.1016/j.nbd.2026.107483},
pmid = {42269977},
issn = {1095-953X},
abstract = {Late-onset epilepsy of unknown etiology (LOEU) is frequently accompanied by cognitive impairment and has been increasingly linked to Alzheimer's disease (AD), prompting questions about overlapping versus distinct pathophysiological mechanisms. While both conditions have been associated with cerebral small vessel disease (CSVD) and large-scale functional network dysfunction, the shared and disorder-specific network substrates underlying cognitive decline remain incompletely characterized. In this prospective, two-center cohort study, we used biomarker-supported AD as a clinical reference point to investigate network alterations in LOEU. We systematically assessed CSVD burden and performed resting-state electroencephalography (EEG)-based functional connectivity analysis in 60 patients with LOEU, 65 patients with AD, and 60 cognitively healthy controls. Functional connectivity was quantified using the weighted phase lag index (wPLI). Compared with healthy controls, both patient groups exhibited higher CSVD burden and shared significant alpha-band desynchronization, whereas significant theta-band hypersynchronization and beta-band desynchronization were exclusive to AD. Furthermore, multivariate analyses revealed distinct substrates underlying cognitive decline. In LOEU, cognitive impairment was independently associated with both vascular burden (specifically white matter hyperintensities) and global alpha-band desynchronization. In contrast, cognitive decline in AD was exclusively associated with specific oscillatory abnormalities (concurrent theta-band hypersynchronization and alpha-band desynchronization). These findings indicate that while alpha-band disruption serves as a shared downstream network manifestation, cognitive decline in LOEU possesses a unique, vascular-associated pathophysiological profile distinct from Alzheimer's-type neurodegeneration. Overall, these results highlight the value of integrating EEG and structural markers to decouple shared and disorder-specific mechanisms, providing functional insights to further inform the clinical evaluation of LOEU.},
}

@article {pmid42270085,
year = {2026},
author = {Hawksworth, JI and Kirkby-Geddes, E and Thom, S and O'Neill, J and Ikwue, A and Wood, L and Outeiro, TF and Erskine, D},
title = {Lewy Bodies Are Not Associated With Neuronal or Synaptic Loss in Dementia With Lewy Bodies.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {3},
pages = {e70085},
doi = {10.1111/nan.70085},
pmid = {42270085},
issn = {1365-2990},
support = {ARUK-SRF2022A-006//Alzheimer's Research UK/ ; SFB1286B8//Deutsche Forschungsgemeinschaft/ ; //NIHR Newcastle Biomedical Research Centre/ ; },
mesh = {Humans ; *Lewy Body Disease/pathology/metabolism ; *Neurons/pathology/metabolism ; *Synapses/pathology/metabolism ; Female ; Aged, 80 and over ; Male ; *Lewy Bodies/pathology/metabolism ; Aged ; *Gyrus Cinguli/pathology/metabolism ; alpha-Synuclein/metabolism ; Temporal Lobe/pathology/metabolism ; },
abstract = {AIMS: The misfolding and accumulation of the protein α-synuclein (αSyn) into cytoplasmic inclusions termed Lewy bodies (LBs) and Lewy neurites is the defining neuropathological feature of LB diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The loss of neurons and/or synapses has been postulated to underlie the clinical syndrome of DLB. The present study sought to elucidate the relationship between LB burden and neuronal and synaptic loss in DLB.

METHODS: Post-mortem brain tissue from the cingulate gyrus and inferior temporal gyrus, two regions vulnerable to LB pathology, was obtained from DLB (N = 20) and control cases (N = 20). Formalin-fixed paraffin-embedded tissue was stained to quantify LB, Alzheimer-type pathology and a neuronal marker. Frozen tissue from the contralateral hemisphere was processed for immunoblotting to compare the abundance of synaptic markers across cases.

RESULTS: Across both regions, no evidence of reduced total neuronal density was observed, but a modest reduction in parvalbumin interneurons was observed in the cingulate gyrus, and there were only modest reductions in some synaptic markers in DLB. LB burden was markedly variable across DLB cases but was not associated with any synaptic marker abundance or neuronal density.

CONCLUSIONS: Taken together, these findings do not support an association between LB density and neuronal or synaptic loss in DLB, even in regions with particularly high burdens of LBs, such as the cingulate gyrus. These findings suggest that the link between αSyn proteinopathy and disease requires further investigation.},
}

Humans
*Lewy Body Disease/pathology/metabolism
*Neurons/pathology/metabolism
*Synapses/pathology/metabolism
Female
Aged, 80 and over
Male
*Lewy Bodies/pathology/metabolism
Aged
*Gyrus Cinguli/pathology/metabolism
alpha-Synuclein/metabolism
Temporal Lobe/pathology/metabolism

@article {pmid42270143,
year = {2026},
author = {Semiz, M and Millien, E and Simoes Loureiro, I},
title = {Comparing approaches to treating anomia in early Alzheimer's disease: Network model-based method vs. embodied cognition method.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/09602011.2026.2685294},
pmid = {42270143},
issn = {1464-0694},
abstract = {Semantic memory is affected early on in Alzheimer's disease (AD), leading to language difficulties such as anomia. Defined as the inability to find words during speech, anomia constitutes a real obstacle to the quality of life of AD patients. The aim of this research is to study the benefits of two treatment methods: the ESFA (Elaborated Semantic Feature Analysis) method, based on abstractive network models of semantic memory, and the TERM (Treatment by Embodied Reactivation of Memory) method, a new sensorimotor stimulations therapy based on the theory of embodied cognition. 19 patients with early-stage AD (MMSE ≥20/30) were distributed into two groups: ESFA group (N = 10, 7 women and 3 men; mean age = 82.7, SD = 4.52) and TERM group (N = 9, 8 women and 1 man; mean age = 81.78, SD = 7.26). Groups were equal, and comparisons were possible. While the ESFA method allows a broad improvement in both trained (W = -2.809; p = .005) and untrained (W = -2.194; p = .028) items, the TERM method seems to lead to an item-centered effect (W = -2.668; p = .008). Moreover, only with the TERM method, the benefits seem to be maintained (W = -1.715; p = .086). Further studies are still needed to further investigate the benefits of these two interesting methods.},
}

@article {pmid42270582,
year = {2026},
author = {Gui, Y and Chen, Y and Guo, Q and Luo, Y and Yang, F and Mahaman, YAR and Wang, JZ and Liu, R and Luo, H and Shu, X and Wang, X and Huang, F},
title = {Npas4 is involved in synaptic and cognitive function by regulating the transcription of Neuroligin-1 and N-cadherin.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03949-z},
pmid = {42270582},
issn = {2158-3188},
support = {32000688//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Ischemic injury has been reported to induce mild to severe permanent deficits. Nevertheless, its recovery is often dynamic, depending on the plasticity of the injured neurons. The current study found that during the early stage of cerebral ischemia (1 h), Npas4 expression was increased in the hippocampus of mice, thereby transcriptionally regulated the expression of Neuroligin-1 and N-cadherin to enhance long-term potentiation. Knocking down of Npas4 reduced the level of Neuroligin-1 and N-cadherin, sequentially prevented the enhanced neural plasticity in the early cerebral ischemia. Furthermore, the downregulation of Neuroligin-1 and N-cadherin also impeded the ischemia-induced enhancement in neural plasticity without affecting the expression of Npas4. Overexpression of Npas4 in the primary neurons increased the number of VAMP2-labeled synaptic vesicles, while interfering the expression of Neuroligin-1 and N-cadherin in the primary neurons with siRNA reduced the increase of VAMP2-labeled synaptic vesicles without affecting the Npas4 expression. Interestingly, the transcriptional level of Npas4, Neuroligin-1, and N-cadherin declined in multiple brain regions of Alzheimer's disease (AD) patients and 3 × TG AD mice. Moreover, overexpression of Npas4 increased the expression of Neuroligin-1 and N-cadherin, ameliorated the synaptic plasticity impairment of 3 × TG mice, and enhanced the cognitive function. These findings suggest a previously undiscovered biological mechanism of neural plasticity, driven by Npas4 upregulation of Neuroligin-1 and N-cadherin, which partially explain why the compensatory increase in Npas4 in the early stages of ischemic injury and the lack of Npas4 in AD progression, highlighting potential therapeutic strategies for cognitive deficits.},
}

@article {pmid42270587,
year = {2026},
author = {Shimonty, A and Bonewald, LF},
title = {Sex specific effects of irisin on the skeleton.},
journal = {Bone research},
volume = {14},
number = {1},
pages = {},
pmid = {42270587},
issn = {2095-4700},
abstract = {Irisin, the circulating protein derived from cleavage of fibronectin type III domain containing protein 5 (FNDC5) has attracted considerable attention regarding its positive effects on a number of organs/tissues such as fat, brain, and heart. However, effects on bone can appear to be either positive or negative depending on context and sex. Sex differences have also been described in Alzheimer's disease also emphasizing sex differences in response to irisin. Here in this review, we outline and focus on the effects of irisin on osteoblasts, osteoclasts, and osteocytes, murine models, and human studies. The consideration of sex effects is necessary especially in the context of irisin serving as a therapeutic.},
}

@article {pmid42270761,
year = {2026},
author = {Ma, T and Liu, J and Liang, D and Ebelt, S and Steenland, K and Levey, AI and Lah, JJ and Wingo, AP and Wingo, TS and Hüls, A},
title = {Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42270761},
issn = {1476-5578},
support = {U01 AG088425/AG/NIA NIH HHS/United States ; R01AG087250//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30 AG066511/AG/NIA NIH HHS/United States ; U01 AG046161/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; R01 AG070937/AG/NIA NIH HHS/United States ; I01 BX003853/BX/BLRD VA/United States ; I01 BX005686/BX/BLRD VA/United States ; IK4 BX005219/BX/BLRD VA/United States ; R01 AG056533/AG/NIA NIH HHS/United States ; R01 AG072120/AG/NIA NIH HHS/United States ; R01 AG075827/AG/NIA NIH HHS/United States ; R01 AG056533/AG/NIA NIH HHS/United States ; R01 AG072120/AG/NIA NIH HHS/United States ; R01 AG075827/AG/NIA NIH HHS/United States ; R01 AG079170/AG/NIA NIH HHS/United States ; U01 AG088425/AG/NIA NIH HHS/United States ; },
abstract = {Fine particulate matter (PM2.5) is a known risk factor for Alzheimer's disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While studies have linked PM2.5 exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM2.5 and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce. Genome-wide DNAm profiles (Illumina EPIC BeadChips) in whole blood and CSF Aβ42 concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM2.5 exposure for the year preceding participants' blood collection was estimated. A multi-stage analytical pipeline, incorporating single-mediator analysis, high-dimensional mediation analysis, and causal mediation analysis, was applied. Nine CpG sites were identified as noteworthy mediators of the relationship between PM2.5 and decreased CSF Aβ42 concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from -0.015--0.029 per 1 ug/m[3] increase in PM2.5 exposure. The proportion mediated ranging from 14-43%. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM2.5 exposure and CSF Aβ42 concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM2.5 toxicity in the pre-clinical stages of AD.},
}

@article {pmid42270765,
year = {2026},
author = {Zheng, YY and Feng, KG and Xie, X},
title = {A modifiable driver of dementia: cognitive impairment in primary aldosteronism.},
journal = {Hypertension research : official journal of the Japanese Society of Hypertension},
volume = {},
number = {},
pages = {},
pmid = {42270765},
issn = {1348-4214},
abstract = {Primary aldosteronism (PA) is the most common endocrine cause of hypertension, yet emerging longitudinal data indicate that its injurious effects extend to the brain. A nationwide Korean cohort study demonstrated that patients with PA exhibit a significantly higher incidence of all-cause dementia than matched individuals with essential hypertension, independent of blood pressure. However, this association was attenuated for Alzheimer's disease after multivariable adjustment, whereas vascular dementia remained significantly associated with PA. Aldosterone activates mineralocorticoid receptors (MRs) in the brain, triggering oxidative stress, blood-brain-barrier leakage and neuro-inflammation that damage hippocampal and prefrontal networks, leading to deficits in executive function, language and attention. Notably, these effects are amplified by dietary salt intake, and experimental evidence suggests that aldosterone-induced end-organ damage requires a high-salt milieu. In animal models, chronic aldosterone exposure reproduces these cognitive impairments, whereas MR blockade or adrenalectomy reverses learning and memory deficits. However, current PA guidelines omit recommendations for cognitive screening or intervention, rendering this potentially reversible aetiology largely overlooked. Here we systematically synthesize the pleiotropic mechanisms of aldosterone signalling in neurons, glia and cerebral vessels; integrate cross-sectional, prospective and interventional clinical evidence to quantify the strength of the PA-dementia association; and compare the differential cognitive outcomes of surgery versus pharmacotherapy. We also discuss emerging aldosterone synthase inhibitors as a novel therapeutic strategy that eliminates ligand production rather than merely blocking receptor signalling. Finally, we propose a risk-prediction framework that incorporates neuroimaging and fluid biomarkers, and call for a transdisciplinary clinical pathway to enable early recognition and precision intervention.},
}

@article {pmid42270783,
year = {2026},
author = {Aslan, D and Alaca, N and Elmas, MA and Özbeyli, D and Arbak, S and Can, A and Onat, F},
title = {Combined effects of tactile stimulation and aerobic exercise on BDNF-related pathways and neurofunctional outcomes in an early-stage 5xFAD mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54728-1},
pmid = {42270783},
issn = {2045-2322},
support = {123S251//Scientific and Technological Research Council of Türkiye (TÜBİTAK-1002)/ ; 123S251//Scientific and Technological Research Council of Türkiye (TÜBİTAK-1002)/ ; 123S251//Scientific and Technological Research Council of Türkiye (TÜBİTAK-1002)/ ; 123S251//Scientific and Technological Research Council of Türkiye (TÜBİTAK-1002)/ ; 123S251//Scientific and Technological Research Council of Türkiye (TÜBİTAK-1002)/ ; 123S251//Scientific and Technological Research Council of Türkiye (TÜBİTAK-1002)/ ; TYL-2023-66//Acibadem University Scientific Research Projects Coordination Unit (ABAPKO)/ ; TYL-2023-66//Acibadem University Scientific Research Projects Coordination Unit (ABAPKO)/ ; TYL-2023-66//Acibadem University Scientific Research Projects Coordination Unit (ABAPKO)/ ; TYL-2023-66//Acibadem University Scientific Research Projects Coordination Unit (ABAPKO)/ ; TYL-2023-66//Acibadem University Scientific Research Projects Coordination Unit (ABAPKO)/ ; TYL-2023-66//Acibadem University Scientific Research Projects Coordination Unit (ABAPKO)/ ; },
abstract = {Alzheimer's disease (AD) lacks effective early-stage non-pharmacological interventions capable of simultaneously targeting neurotrophic signaling and neurofunctional decline. This study examined the early-stage effects of tactile stimulation (TS), aerobic exercise (Ex), and their combination (TS + Ex) on behavioral, molecular, and histopathological outcomes in 5xFAD mouse model of AD. Twenty-eight male transgenic 5xFAD mice (7-8 weeks old) were randomly assigned to four groups: control (n = 7), TS (n = 7), Ex (n = 7), and TS + Ex (n = 7). Interventions were applied for eight weeks, 5 days per week, with daily 30-minute sessions. Behavioral assessments were conducted, and biochemical analyses measured brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), fibroblast growth factor-2 (FGF-2), irisin, lactate, total antioxidant status (TAS), total oxidant status (TOS), and myeloperoxidase (MPO) levels in brain, muscle, skin, and serum tissues. Histological, immunofluorescent, and ultrastructural evaluations were performed in the hippocampus. Compared to control, the TS + Ex group showed significant improvements in motor performance, neurotrophic factor levels, irisin and lactate concentrations, and antioxidant capacity in 5xFAD mice (p = 0.05-<0.001, partial η[2]=0.498-0.902). Additionally, increased doublecortin expression (p = 0.032, partial η[2]=0.571) and improved histopathological architecture were observed. Aerobic exercise alone improved motor function, anxiety-related behaviors, modulated several biochemical and histological outcomes compared with the control (p = 0.05 - 0.004, partial η[2]=0.332-0.498). TS alone produced limited effects, with notable increases only in hippocampal BDNF (p < 0.001, partial η[2]=0.712) and lactate levels (p = 0.015, partial η[2]=0.605) compared with the control group. The combination of TS and Ex may exert synergistic neuroprotective effects, suggesting that multimodal non-pharmacological strategies could represent promising early-stage interventions for mitigating AD-related pathology.},
}

@article {pmid42270887,
year = {2026},
author = {Sun, Z and Lee, Y and Walker, CK and Karch, CM and Yoo, AS},
title = {Three-dimensional direct neuronal reprogramming for modeling Alzheimer's disease neuropathology.},
journal = {Nature protocols},
volume = {},
number = {},
pages = {},
pmid = {42270887},
issn = {1750-2799},
abstract = {Late-onset Alzheimer's disease (LOAD) accounts for over 95% of Alzheimer's disease (AD) cases. However, modeling the age-dependent neuropathological hallmarks of LOAD has remained a major challenge. We recently developed a patient-based, three-dimensional (3D) neuronal culture system that endogenously recapitulates key neuropathological features of AD, including extracellular Aβ deposition, tau dysregulation and spontaneous neuronal death. This platform uses high-efficiency, microRNA- and chromatin-based direct somatic reprogramming of fibroblasts from patients with autosomal dominant AD or LOAD to cortical neurons in 3D thin gel (3D-CNs) or self-assembled neuronal spheroids. Here we provide stepwise instructions for generating 3D-CNs and cortical spheroids via neuronal reprogramming of patient fibroblasts, along with methods for analyzing downstream AD neuropathology. Within 3 weeks, fibroblasts are reprogrammed into neurons under either thin-gel or spheroid conditions. By 4 weeks, key AD neuropathology, such as Aβ deposition, tau dysregulation, and neuronal death, can be detected in AD neurons. This system provides an age-relevant, patient-specific neuronal model for investigating molecular events underlying AD-associated neurodegeneration and evaluating compounds or gene targets in the context of potential personalized therapeutic interventions. Successful implementation of this protocol requires prior experience in mammalian cell culture, plasmid preparation, lentiviral production and standard confocal imaging techniques.},
}

@article {pmid42270927,
year = {2026},
author = {Polk, SE and Clark, LR and Basche, K and Kleineidam, L and Glanz, W and Butryn, M and Perneczky, R and Buerger, K and Fliessbach, K and Laske, C and Spottke, A and Schneider, A and Wiltfang, J and Teipel, S and Bartels, C and Rostamzadeh, A and Janowitz, D and Rauchmann, BS and Kilimann, I and Sodenkamp, S and Coenjaerts, M and Brosseron, F and Wagner, M and Frommann, I and Stark, M and Schmid, M and Schott, BH and Johnson, SC and Jessen, F and Düzel, E and Berron, D},
title = {Smartphone-based detection of subtle memory decline in prodromal Alzheimer's disease.},
journal = {NPJ digital medicine},
volume = {9},
number = {1},
pages = {},
pmid = {42270927},
issn = {2398-6352},
abstract = {The slow progression of Alzheimer's disease (AD) poses a challenge for the quantification of early disease-driven cognitive decline. Here, we show that frequently administered remote and unsupervised digital cognitive assessments can detect differences in cognitive decline within 30 weeks in early AD. The sample comprised 202 individuals (52-85 years old) recruited from longitudinal observational studies, who were cognitively unimpaired (CU, n = 152) or had a diagnosis of mild cognitive impairment (MCI, n = 50). Participants self-administered remote tasks testing memory precision for objects and scenes, associative memory, and familiarity-dependent memory. The MCI group showed greater decline than the CU group in the familiarity-dependent task, while stratifying the MCI group by beta-amyloid (Aβ) status (n = 21 Aβ-; n = 24 Aβ+) revealed greater change in memory precision for objects and familiarity-dependent memory in the MCI Aβ+ group. A 30-week change in the remote familiarity-dependent task was correlated with a multi-year change in annual in-person neuropsychological assessments. In conclusion, frequent remote cognitive testing is a promising tool to feasibly capture and monitor subtle and short-term cognitive decline.},
}

@article {pmid42270947,
year = {2026},
author = {Mandal, P and Trushina, E and Arnold, M and Kaddurah-Daouk, R and Baloni, P},
title = {Mitochondrial bioenergetic signatures differentiate asymptomatic from symptomatic Alzheimer's disease.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10474-8},
pmid = {42270947},
issn = {2399-3642},
support = {4RF1AG055549-03//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 4RF1AG055549-03//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG061359, U19AG063744, R01AG069901, U19AG074879, U01AG088562, R01AG081322//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG063744, U01AG061359, R01AG081322//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Asymptomatic Alzheimer's disease (AsymAD) refers to individuals who, despite exhibiting amyloid-β plaques and tau pathology comparable to Alzheimer's disease (AD), maintain cognitive performance similar to cognitively normal individuals. The resilience mechanism in AsymAD individuals remains understudied. We performed a systematic analysis comparing AsymAD and AD across multiple cohorts (ROSMAP, Banner and Mount Sinai), brain regions (BA6, BA9, BA36 and BA37) and neuronal and glial cell types using proteomics and transcriptomics data. AsymAD brains exhibited preserved mitochondrial bioenergetics, characterized by enhanced oxidative phosphorylation, electron transport chain activity, fatty acid and lipid metabolism, and branched-chain amino acid utilization. Pathways regulating mitochondrial complex biogenesis and calcium homeostasis were also upregulated. Key mitochondrial proteins such as MRPL47, CPT2, BCAT2, and IDH2, were consistently upregulated in AsymAD. At the cellular level, excitatory neurons, including superficial, mid-layer, and deep-layer subtypes, exhibited the most preserved mitochondrial function, whereas vulnerable inhibitory subtypes, including PVALB and SST neurons, showed increased cellular abundance and bioenergetic activity. In contrast, microglia and oligodendrocytes proportions were reduced in AsymAD relative to AD. Our findings identify preserved mitochondrial bioenergetics in AsymAD and suggest that enhancing NADH metabolism via NAD+ precursor-based interventions may potentially help in maintaining cognitive function despite amyloid and tau pathology.},
}

@article {pmid42270967,
year = {2026},
author = {Merza, J and Alsaqati, M and Wills, C and Waddell, PG and Ashton, M},
title = {The Synthesis and Biological Activity of Series of New Polyfunctional Pyrroles with the Potential to Modulate Neuronal Viability.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {42270967},
issn = {1559-0283},
abstract = {The polyfunctional pyrrole 3,5-dichloro-1H-pyrrole-2,4-dicarbaldehyde (2) was reacted with malononitrile and Meldrum's acid in a regioselective manner to yield derivatives (4, 5, 6, 8, 9, and 10). Compound 8 was isolated and its structure was characterised by crystallography and 1 and 2D-[1]H, [13]C-NMR spectroscopy. The biological effects of these derivatives were evaluated on differentiated SH-SY5Y human neuroblastoma cells, under control conditions and following Aβ exposure as an in vitro model of Alzheimer's disease. MTT assays were performed to assess neuronal viability, and Annexin V staining was used to quantify apoptosis. Compounds 2 and 8 significantly increased cell viability in control differentiated neurons, suggesting a neurotrophic or protective effect. However, in Aβ-treated cells, all tested compounds, namely 5, 6, 8 and 2, reduced viability, indicating a possible interaction between our derivatives and Aβ-induced neurotoxicity. These findings reveal that certain polyfunctional pyrrole derivatives can differentially modulate neuronal survival depending on the cellular environment. This suggests that the neuronal cell death induced by Aβ in Alzheimer's patients can be enhanced in the presence of those compounds. Since pyrrole scaffolds are present both in biologically essential molecules and in various environmental compounds, this dual action suggests their potential relevance in understanding the mechanisms of neurodegeneration and highlights the need for further mechanistic and translational studies to explore their impact on neurodegenerative disorders, including Alzheimer's.},
}

@article {pmid42271047,
year = {2026},
author = {d'Oleire Uquillas, F and Sefik, E and Seidlitz, J and Daniel Hertz, E and Romero-Garcia, R and Warrier, V and Bethlehem, RAI and Alexander-Bloch, AF and Cohen, JD and Wang, SS and Sepulcre, J and Vannini, P and Gomez, J},
title = {Cerebellar aging is spatially heterogeneous and supports cognitive resilience in later life.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42271047},
issn = {1546-1726},
support = {CAREER 2337373//National Science Foundation (NSF)/ ; GRFP 2021314805//National Science Foundation (NSF)/ ; 20210323//Ford Foundation/ ; N00014-22-12002//United States Department of Defense | United States Navy | Office of Naval Research (ONR)/ ; },
abstract = {The cerebellum contains most of the brain's neurons and supports many functions, yet how it changes with age remains unclear. Here we used three brain imaging studies spanning 47,000 adults and examined how different parts of the cerebellum age and their relation to cognition. We characterized cerebellar aging using volumetry and the T1-weighted/T2-weighted ratio, and corroborated these findings with quantitative magnetic resonance imaging in an independent sample. We show a spatially heterogeneous pattern of aging in which specific association and motor-related regions show steeper relationships with age than other lobules. Greater cerebellar volume was associated with higher cognitive scores with increasing age, suggesting that cerebellar structure may provide brain reserve that helps maintain function despite aging. In patients with Alzheimer's disease, cerebellar volume was linked to cognition in individuals with lower amyloid burden, especially in those carrying two copies of the APOE-ε4 risk gene. This supports a threshold-reserve model, in which the cerebellum helps sustain cognition until pathology becomes widespread. These results show that the cerebellum has an active role in healthy cognitive aging and resilience.},
}

@article {pmid42271113,
year = {2026},
author = {Carlisle, TC and Holden, SK and Sillau, S and Unger, JR and Lafreniere, M and Bettcher, BM and Molden, J and Nachiappan, M and Tanabe, J and Nair, KV and Pelak, VS},
title = {Descriptive Analysis of Retrospective Observational Real-World Evidence of a Monoclonal Anti-Amyloid Therapy Program in a Wide Catchment Specialty Memory Clinic.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42271113},
issn = {2193-8253},
support = {U24 NS133991/NS/NINDS NIH HHS/United States ; },
abstract = {INTRODUCTION: Anti-amyloid therapy (AAT) protocol complexity may widen specialty dementia care access gaps. The University of Colorado (CU) Advanced Therapy in Neurodegenerative Disorders (ATND) Clinic is within the CU-Memory Disorders Clinic (CU-MDC). The aim of this study is to report initial CU-ATND real-world evidence (RWE).

METHODS: Patients who completed CU-ATND Clinic intake paperwork were included (n = 123) and compared to CU-MDC (n = 1100) seen between April 2024 to June 2025. Demographic information was included for both clinics. Retrospective observational data on CU-ATND Clinic patients including work-up, decisions about pursing AAT, and adverse events at the time of data extraction was described.

RESULTS: AAT status included patient declined (37.4%) or deferred (8.1%), clinically excluded (14.6%), undergoing work-up (8.1%), consented for infusions (26.0%), completed infusions (0.8%), and stopped infusions (4.1%). CU-ATND Clinic patients had a median age of 73 years and were 50.4% women with the majority white and urban-dwelling similar to the CU-MDC. AAT candidacy steps and decision duration varied. AAT-related adverse events were managed without extended inpatient admission or persistent effects.

CONCLUSION: Many care disparities were present prior to CU-ATND referral. The CU-ATND RWE highlights successes and provides insight into barriers impacting access.},
}

@article {pmid42271162,
year = {2026},
author = {Hosp, JA and Reisert, M and Schröter, N and Kellner, E and Mast, H and Rijntjes, M and Hellwig, S and Frings, L and Wiendl, H and Urbach, H and Rau, A},
title = {The degenerome-a novel streamline-wise approach for white matter integrity in neurodegeneration.},
journal = {NPJ Parkinson's disease},
volume = {12},
number = {1},
pages = {},
pmid = {42271162},
issn = {2373-8057},
support = {Priority Programme SPP2177; grant RA 3495//Deutsche Forschungsgemeinschaft/ ; Priority Programme SPP2177; grant RA 3495//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Neurodegenerative diseases impair both gray matter and long-range white-matter pathways. Existing diffusion MRI approaches are either local or depend on predefined parcellations, limiting their ability to capture distributed network disruption. We introduce a streamline-wise framework to map axonal degeneration and derive disease-specific fiber "degeneromes" across Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). We analyzed diffusion microstructure imaging and T1-weighted MRI (3 T Siemens Prisma, 2018-2024) in AD (n = 81), PD (n = 177), MSA (n = 50), PSP (n = 35), and healthy controls (n = 26). The intraaxonal volume fraction, estimated via a Bayesian three-compartment model, was mapped along ~20,000 normative streamlines in MNI space using age- and sex-adjusted regression with FDR correction. Streamline-wise mapping revealed disease-specific degeneromes consistent with established pathoanatomical models: AD involved limbic and temporo-occipital pathways, PD showed commissural and posterior association involvement, MSA affected pontocerebellar and corticospinal tracts, and PSP involved the dentato-rubro-thalamic tract and superior cerebellar peduncle. These signatures supported group-level differentiation, and streamline-wise z-scores enabled intuitive single-patient visualization. Fiber degeneromes offer a connectome-informed biomarker with strong biological plausibility, discriminatory potential across neurodegenerative entities, and a clear route toward clinical single-patient reporting.},
}

@article {pmid42271173,
year = {2026},
author = {Ramezan, M and Demetriou, A and Burke, SN and Nalvarte, I and Shin, AC},
title = {Sex differences in brain glucose metabolism and Alzheimer's disease risk and progression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71491},
doi = {10.1002/alz.71491},
pmid = {42271173},
issn = {1552-5279},
abstract = {Sex differences are increasingly recognized as central to the biology of Alzheimer's disease (AD), yet the mechanisms through which they shape brain metabolism and disease vulnerability remain incompletely understood. Brain glucose hypometabolism is a core hallmark of AD and emerges decades before clinical decline, but accumulating evidence indicates that its causes, timing, and functional consequences differ between women and men. In this review, we synthesize findings from neuroimaging, molecular, and cellular studies to examine how sex-dependent regulation of glucose transport, glycolysis, and mitochondrial function interacts with aging and AD pathology. We highlight reinforcing evidence for a steeper and more pathology-linked decline in mitochondrial glucose metabolism in females, particularly in the context of menopause and apolipoprotein E (APOE) ε4 genotype. We identify major knowledge gaps at the level of cell type, brain region, and disease stage, and outline priorities for sex-informed, mechanistically anchored research to enable metabolic-precision interventions for AD risk and progression.},
}

@article {pmid42271174,
year = {2026},
author = {Sdougkou, K and Rekka, E and Papagiannopoulou, D},
title = {Synthesis and Evaluation of Novel Cinnamic Acid Hybrids With Antiacetylcholinesterase, Antioxidant, and Anti-Inflammatory Properties.},
journal = {ChemMedChem},
volume = {21},
number = {11},
pages = {e70343},
doi = {10.1002/cmdc.70343},
pmid = {42271174},
issn = {1860-7187},
abstract = {Alzheimer's disease, one of the most widespread neurodegenerative disorders, is known for its multifactorial nature that makes it challenging to treat. In the present work, hybrid molecules were designed and synthesized combining the anti-acetylcholinesterase (AChE) activity of donepezil with the antioxidant and/or anti-inflammatory activity of selected cinnamic acids. In particular, the new derivatives were conjugated by Steglich esterification or amidation of suitable benzylpiperazine/piperidine moieties with ferulic, sinapic, 3,4-dimethoxycinnamic acids. All new molecules were evaluated for their activity in terms of AChE inhibition, while molecules that carried a phenolic group were also evaluated for their ability to inhibit lipid peroxidation. A representative group of compounds were studied in vivo for their anti-inflammatory activity with very encouraging results in paw-induced edema in mice. The 3,4-dimethoxycinnamic and sinapic acid esters with a two-carbon linker exhibited the strongest inhibition of AChE with nanomolar values of IC50. In addition, the sinapic esters demonstrated the highest antioxidant and anti-inflammatory activity. Thus, the above results indicate that the new sinapic acid derivatives based on donepezil combine anti-AChE, anti-inflammatory, and antioxidant activities, which warrant their further evaluation as new lead compounds in the treatment of related neurodegenerative diseases.},
}

@article {pmid42271180,
year = {2026},
author = {Cary, GA and Ganesh, SSA and Heath, L and Leal, K and Kampmann, M and Longo, FM and Butler, RR and Levey, AL and Carter, GW and Wiley, J},
title = {Alzheimer's disease biological domain sub-stratification enhances the precision of functional analyses.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71403},
doi = {10.1002/alz.71403},
pmid = {42271180},
issn = {1552-5279},
support = {U54AG065187/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The Target Enablement to Accelerate Therapy Development for AD (TREAT-AD) bioinformatics pipeline employs a rank-and-organize strategy. Disease-associated genes drive enrichment of large AD-linked endophenotypes. However, these biological areas were too large to promote hypothesis development or target identification. Here we delineate subdomains that map to, and enrich, specific biological processes.

METHODS: To refine the biodomains into more focused areas, we built κ networks out of the Gene Ontology terms in the biodomain and employ shared gene annotation between terms to determine edge weights. κ-value filtration enabled us to identify data-driven subdomains, which we employed in an analysis of TREAT-AD harmonized datasets.

RESULTS: The subdomain enrichment highlights core areas of biological impairment within the biodomain space and facilitates a deeper interpretation of large-scale multiomic datasets.

DISCUSSION: The subdomain mapping of AD-risk-associated processes may facilitate an open-source, open-science shareable resource for the comparison of large datasets for the formulation of future hypotheses and identification of therapeutic targets.},
}

@article {pmid42271186,
year = {2026},
author = {Huang, C and Cai, Q and Feng, Z and Zhang, C and Luo, Z and Cheng, X and Wu, H},
title = {Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer-like pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71543},
doi = {10.1002/alz.71543},
pmid = {42271186},
issn = {1552-5279},
support = {2023YFC3605600/2023YFC3605605//the National Key Research and Development Program/ ; 2021-29-1//the Science and Technology Program for Overseas Students in Sichuan Province/ ; 2021YFSY0011//the Sichuan Province Science and Technology Support Program/ ; },
abstract = {INTRODUCTION: Periodontal pathogen Porphyromonas gingivalis is epidemiologically linked to Alzheimer's disease (AD), yet how oral infection disrupts the central circadian clock to drive hippocampal neurodegeneration remains unknown.

METHODS: C57BL/6 mice received oral P. gingivalis for 6 months; hippocampal clock gene oscillations, phosphorylated protein kinase B (p-AKT), glial fibrillary acidic protein (GFAP)/Ionized calcium-binding adapter molecule 1 (Iba1), and amyloid beta (Aβ) load were quantified. C8-D1A astrocytes and BV2 microglia were infected with P. gingivalis ± phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT inhibitor or agonist; Bmal1 (brain and muscle ARNT-like 1)/Clock (circadian locomotor output cycles kaput) were knocked down by lentivirus.

RESULTS: P. gingivalis-induced periodontitis dampened hippocampal Bmal1 rhythms, lowered p-AKT, activated glia, and elevated Aβ and interleukin 1β (IL-1β). In glial cells, P. gingivalis flattened Bmal1 oscillation; PI3K blockade mimicked these effects, whereas AKT agonist restored rhythms and suppressed GFAP/Iba1/IL-1β. Bmal1 knockdown alone triggered glial activation and cytokine release.

DISCUSSION: P. gingivalis oral infection suppresses PI3K/AKT signaling, destabilizing glial circadian clocks and unleashing neuroinflammation that fosters hippocampal AD-like pathology; rescuing PI3K/AKT or clock function may mitigate the oral-brain axis in AD.},
}

@article {pmid42271188,
year = {2026},
author = {Fan, L and Sun, Y and Liu, D and Robb, WH and Pechman, KR and Shashikumar, N and Vyas, Y and Landman, BA and Hohman, TJ and Jefferson, AL},
title = {High-fat diet is associated with accelerated gray matter atrophy in cognitively unimpaired older adults but slower atrophy in individuals with existing mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71548},
doi = {10.1002/alz.71548},
pmid = {42271188},
issn = {1552-5279},
support = {IIRG-08-88733 (ALJ)//by Alzheimer's Association/ ; R01-AG034962 (ALJ)//by Alzheimer's Association/ ; R01-AG056534 (ALJ)//by Alzheimer's Association/ ; K24-AG046373 (ALJ)//by Alzheimer's Association/ ; UL1-TR000445//Vanderbilt Clinical Translational Science Award/ ; UL1-TR002243//Vanderbilt Clinical Translational Science Award/ ; S10-OD023680//Vanderbilt's High-Performance Computer Cluster for Biomedical Research/ ; S10-OD021771//VUIIS Center for Human Imaging/ ; P20-AG068082//Vanderbilt Alzheimer's Disease Research Center/ ; //the Richard Eugene Hickman Alzheimer's Disease Research Endowment/ ; //the Vanderbilt Memory and Alzheimer's Center/ ; },
abstract = {INTRODUCTION: Prior studies showed inconsistent links between dietary fat and Alzheimer's disease (AD) risk. We examined whether dietary fat affected brain atrophy markers differentially based on risk factors like female sex, apolipoprotein ε4 (APOE ε4) status, and cognitive status.

METHODS: Participants from the Vanderbilt Memory and Aging Project, classified as cognitively unimpaired (CU) or with mild cognitive impairment (MCI), were included (n = 758). Linear mixed-effects regression models examined associations between total fat intake (Tfat, times/day) and percentage of energy from fat (Pfat, %) and longitudinal gray matter volumes, as well as interactions.

RESULTS: Over 4.6 ± 3.1 years, Pfat interacted with cognitive status on longitudinal temporal lobe (p = 0.009) and inferior lateral ventricle volume (p = 0.002). Higher Pfat was associated with faster reduction in temporal lobe volume in CU participants (β = 47.2, p = 0.007) but slower enlargement of the inferior lateral ventricle among participants with MCI (β = -22.5, p = 0.006).

DISCUSSION: Different mechanisms may underlie the fat-neurodegeneration relationship across cognitive statuses.},
}

@article {pmid42271192,
year = {2026},
author = {Andrade, V and Kleineidam, L and Wagner-Thelen, H and Ballarini, T and Campos-Martin, R and Martino-Adami, P and Tripathi, KP and Guyonnet, S and Vellas, B and Scherer, M and Maier, W and Pentzek, M and Schmid, M and Riedel-Heller, S and Weyerer, S and Bickel, H and Wiese, B and Egert, S and Wagner, M and Ramírez, A},
title = {Prediction of cognitive outcome and progression to dementia using ω6-PUFA/ω3-PUFA ratio.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71590},
doi = {10.1002/alz.71590},
pmid = {42271192},
issn = {1552-5279},
support = {01EA1372D//European Union Joint Programme Neurodegenerative Disease Research (JPND) German Federal Ministry of Education and Research (BMBF), Diet-Body-Brain (DietBB)/ ; 01EA1410C//European Union Joint Programme Neurodegenerative Disease Research (JPND) German Federal Ministry of Education and Research (BMBF), Diet-Body-Brain (DietBB)/ ; 01EA1410B//European Union Joint Programme Neurodegenerative Disease Research (JPND) German Federal Ministry of Education and Research (BMBF), Diet-Body-Brain (DietBB)/ ; //German Research Network on Dementia (KND)/ ; //German Research Network on Degenerative Dementia (KNDD)/ ; 01GI0102//Health Service Research Initiative/ ; 01GI0420//Health Service Research Initiative/ ; 01GI0422//Health Service Research Initiative/ ; 01GI0423//Health Service Research Initiative/ ; 01GI0429//Health Service Research Initiative/ ; 01GI0431//Health Service Research Initiative/ ; 01GI0433//Health Service Research Initiative/ ; 01GI0434//Health Service Research Initiative/ ; 01GI0710//Health Service Research Initiative/ ; 01GI0711//Health Service Research Initiative/ ; 01GI0712//Health Service Research Initiative/ ; 01GI0713//Health Service Research Initiative/ ; 01GI0714//Health Service Research Initiative/ ; 01GI0715//Health Service Research Initiative/ ; 01GI0716//Health Service Research Initiative/ ; 01GY1322A//Health Service Research Initiative/ ; 01GY1322B//Health Service Research Initiative/ ; 01GY1322C//Health Service Research Initiative/ ; 01GY1322D//Health Service Research Initiative/ ; 01GY1322E//Health Service Research Initiative/ ; 01GY1322F//Health Service Research Initiative/ ; 01GY1322G//Health Service Research Initiative/ ; 01ED1619A//European Union Joint Programme Neurodegenerative Disease Research (JPND) German Federal Ministry of Education and Research (BMBF)/ ; RA 1971/6-1//German Research Foundation (DFG)/ ; RA1971/7-1//German Research Foundation (DFG)/ ; RA 1971/8-1//German Research Foundation (DFG)/ ; 01ED2007A//European Union Joint Programme Neurodegenerative Disease Research (JPND) German Federal Ministry of Education and Research (BMBF), PREADAPT project/ ; },
abstract = {INTRODUCTION: The polyunsaturated fatty acids (PUFAs) omega-6 (ω6) and omega-3 (ω3) are linked to cognitive performance and Alzheimer's-type dementia (DAT), but ω3-PUFA supplementation offers limited benefits. We propose that the ω6-PUFA/ω3-PUFA ratio better explains cognitive decline and DAT risk.

METHODS: PUFA profiles were examined in the AgeCoDe cohort (n = 3327) and MAPT trial (n  = 1679). Cox and linear mixed models evaluated associations of individual PUFAs and the ω6-PUFA/ω3-PUFA ratio with DAT progression and cognitive decline. Mendelian randomization (MR) assessed genetic causal effects. The effect of ω3-PUFA on ω6-PUFA levels was analyzed.

RESULTS: Higher ω6-PUFA/ω3-PUFA ratio increased DAT risk beyond ω3-PUFA levels alone. A baseline high (detrimental) ratio predicted faster cognitive decline, whereas longitudinal improvements slowed decline. MR supported a genetic non-causal link. Higher ω3-PUFA levels correlated with lower ω6-PUFA species.

DISCUSSION: The ω6-PUFA/ω3-PUFA ratio better predicts cognitive decline and DAT progression than individual PUFAs, suggesting that dietary adjustments may help prevent dementia.},
}

@article {pmid42271432,
year = {2026},
author = {Wu, X and Shadrin, A and Blokland, GAM and Guloksuz, S and Andreassen, OA and Linden, DEJ and van der Meer, D},
title = {Shared genetic architecture between Alzheimer's disease and brain morphology.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02105-5},
pmid = {42271432},
issn = {1758-9193},
support = {101057182//the European Union's Horizon Europe program/ ; 164218//Nordforsk/ ; 324499//Research Council of Norway/ ; 324252//Research Council of Norway/ ; },
abstract = {BACKGROUND: A hallmark of Late-onset Alzheimer's disease (LOAD) is brain tissue atrophy across multiple cortical and subcortical regions. However, studies report no significant genetic correlation between LOAD and brain morphology, indicating that the genetic drivers of neurodegeneration are complex. Resolving this shared genetic architecture is key to uncovering the biological mechanisms linking brain morphology to LOAD.

METHODS: We analyzed UK Biobank genotype data (n = 272,513; 57.1 ± 8.0 years; 54.6% female) alongside genome-wide association study summary statistics for LOAD and 89 brain morphological traits. We employed linkage disequilibrium score regression (LDSC), polygenic score (PGS), and Local Analysis of [co]Variant Association (LAVA) to evaluate genetic relationships at the whole-genome and locus level. The extent of polygenic overlap was quantified using bivariate causal mixture modeling (MiXeR), and specific shared loci were identified via conjunctional FDR. Identified loci were mapped to genes and followed by enrichment analyses to characterize the shared biological pathways.

RESULTS: LDSC and regression analyses revealed no significant global genetic correlations between LOAD and brain morphological traits and no associations between PGS and LOAD proxy scores. In contrast, LAVA identified significant local genetic correlations (both positive and negative) across all LOAD-brain trait pairs. MiXeR analysis further revealed a substantial number of shared genetic variants characterized by mixed effect directions, explaining the lack of global correlation. We identified 183 shared loci mapping to 80 distinct genes. Enrichment analyses indicated that these shared genes are involved in biological processes related to cell differentiation, development, and cellular component organization.

CONCLUSIONS: Our findings provide evidence of extensive polygenic overlap between LOAD and brain morphology, revealing that the absence of global genetic correlation stems from mixed local effect directions. These shared genetic architectures implicate pathways in cellular development and differentiation, providing a molecular framework for understanding the link between brain morphology and LOAD.},
}

@article {pmid42271460,
year = {2026},
author = {Nimmo, J and Daskoulidou, N and Van Pottelberge, S and De Muynck, L and Morgan, BP},
title = {Dysregulation of complement at the synapse in P301S mice and human tauopathies.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02347-2},
pmid = {42271460},
issn = {2051-5960},
abstract = {Synapse loss is the best correlate of cognitive decline in neurodegenerative diseases (NDDs). In Alzheimer's disease complement dysregulation, triggered by amyloid-β accumulation, plays a major role in synapse loss, but its contribution in other NDDs where amyloid is absent, most notably tauopathies, is elusive. Aggregation of tau is a prominent co-pathology in many NDDs and is characteristic of classical tauopathies in which amyloid pathology is lacking. Here we explore the effect of tau accumulation on complement dysregulation and its contribution to neuronal damage and synapse loss in a mouse tauopathy model harbouring the familial P301S tau mutation and post-mortem brain samples from human tauopathies. Complement gene and protein expression were analysed in P301S mice at 2, 4 and 6 M of age. Complement dysregulation was evident from qPCR analysis showing increased classical pathway (C4, C2), and complement receptor (C3ar1, Cd11b, Cd11c) gene expression in P301S mice compared to wildtype (WT). C1q protein levels were markedly increased in brain homogenates from P301S mice compared to WT, accompanied by C1q deposition on tau aggregates. Synapse loss was evident for both excitatory and inhibitory synapses and was accompanied by an increased percentage of C1q positive excitatory synapses, unaffected by proximity to tau aggregates. The classic pathway regulator CSMD1 was present on synapses and decreased on C1q positive synapses in P301S mice, implying a loss of protection from complement attack. Observations in human tauopathy brains demonstrated decreased CSMD1-labelled excitatory synapses, consistent with findings in P301S mice. These findings demonstrate that complement dysregulation occurs in areas of tau pathology and may contribute to synapse loss in tauopathies.},
}

@article {pmid42272120,
year = {2026},
author = {Ghosh, P and Mukhopadhyay, S and Sarkar, A and Ghosh, SS and Iyer, PK},
title = {Dual Targeted Far-Red Emissive Small Molecules for Mitochondrial Imaging and Multifunctional Modulation in Alzheimer's Disease.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71341},
doi = {10.1002/adhm.71341},
pmid = {42272120},
issn = {2192-2659},
support = {DST/CRG/2019/002614//Department of Science and Technology (DST), New Delhi, India/ ; 5(1)/2022-NANO//Department of Science and Technology (DST), New Delhi, India/ ; 5/3/8/20/2019-ITR//Department of Science and Technology (DST), New Delhi, India/ ; IGSTC/MPG/PG(PKI)/2011A/48//Max-Planck-Gesellschaft/ ; 1900819//Ministry of Education, Government of India : Prime Minister's Research Fellowship/ ; },
abstract = {Alzheimer's disease (AD), the leading cause of age-related dementia, is a multifactorial neurodegenerative disorder associated with amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, oxidative stress, and mitochondrial dysfunction. The pathological interplay among these processes necessitates multifunctional small molecules capable of both diagnosis and therapeutic intervention. Herein, we report two triphenylamine (TPA)-based aggregation-induced emission (AIE) luminogens, TPA-RPA (triphenylamine-rhodaninepropanoic acid) and TPA-ER (triphenylamine-ethylrhodanine), designed as mitochondria-active anti-amyloid theranostic agents. Among them, TPA-RPA emerged as the lead candidate, exhibiting far-red emission and a pronounced ∼5-fold fluorescence turn-on response upon selective binding to Aβ40 fibrils, enabling sensitive detection of pathogenic aggregates. TPA-RPA effectively inhibited Aβ40 fibrillogenesis, disaggregated preformed fibrils, binds with selective metal ions Fe[3+]/Cu[2+], and suppressed Fe[3+] mediated amyloid aggregation, highlighting its multifunctional anti-amyloid activity. In neuronal cells, TPA-RPA displayed favorable biocompatibility, appreciable mitochondrial localization, and significant protection against Aβ-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction. Comparative studies identified TPA-ER as a useful analog with a stronger but more pronounced oxidative response, while TPA-RPA demonstrated the most balanced overall biological profile, establishing it as a synthetically accessible and mechanistically versatile platform for image-guided intervention in AD, supported by photophysical, cellular, in silico molecular docking analyses, and blood-brain barrier/drug-likeness evaluations.},
}

@article {pmid42272138,
year = {2026},
author = {Yabuki, Y and Shioda, N},
title = {RNA Structural Biology of Neurodegeneration: Phase Separation, Phase Transition, and Proteinopathy.},
journal = {Journal of biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/jb/mvag040},
pmid = {42272138},
issn = {1756-2651},
abstract = {Neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, are becoming increasingly prevalent in super-aging societies. However, the molecular mechanisms by which prion-like proteins undergo aberrant phase transition, aggregation, and propagation during neurodegeneration remain incompletely understood. Although these proteins are capable of undergoing liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the factors that govern their pathological phase transition in vivo remain largely elusive. Notably, many prion-like proteins also possess RNA-binding properties, and accumulating evidence indicates that RNA plays pivotal roles in regulating both LLPS and the subsequent transition to more solid-like states. In this review, we summarize recent advances in the RNA structural biology of neurodegeneration, with particular emphasis on RNA G-quadruplexes (rG4s) as pathological determinants, and discuss emerging mechanisms by which RNA structures promote the phase transition and proteinopathy of prion-like proteins.},
}

@article {pmid42272280,
year = {2026},
author = {Guo, F and Yang, YG and Sun, SQ and Liu, YJ and Zhang, WL and Xin, F},
title = {6-gingerol alleviates Alzheimer's disease in rats through the Pumilio RNA binding family member 1/microRNA-340-5p/pleomorphic adenoma gene like-2/estimated glomerular filtration rate/hypoxia-inducible factor-1alpha/2alpha pathway.},
journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society},
volume = {77},
number = {2},
pages = {197-217},
doi = {10.26402/jpp.2026.2.04},
pmid = {42272280},
issn = {1899-1505},
abstract = {This study explores the modulatory role of Pumilio RNA-binding family member 1 (circ_PUM1) in the neuroprotective mechanisms of 6-gingerol against Alzheimer's disease (AD)-related neuronal injury, providing new insights into circRNA-mediated regulation of neurodegeneration. Variations in circRNA expression indirectly influenced by 6-gingerol (6-GIN) were comprehensively assessed within AD experimental frameworks. The AD phenotype was not absent when hippocampal amyloid-β (Aβ) was introduced into rats, nor when SK-N-SH and SK-SY5Y cells were subjected to Aβ challenge, jointly constructing complementary in vivo and in vitro paradigms for mechanistic exploration. Hippocampal injury was assessed by water content measurement, histological analysis, and TUNEL staining for apoptosis. In cell models, viability, apoptosis, and inflammatory cytokines (interleukin-6, inducible nitric oxide synthase, tumor necrosis factor-α) were quantified. The expression and localization of circ_PUM1 were examined, and its direct interaction with miR-340-5p was confirmed, revealing a regulatory axis potentially mediating the neuroprotective effects of 6-GIN. We found that administration of 6-GIN effectively counteracted Aβ1-42-induced neurotoxicity by alleviating neuronal apoptosis, oxidative injury, and inflammatory responses. These protective effects were evidenced by the reduction of neuronal damage and brain edema scores, decreased secretion of proinflammatory cytokines and lipid peroxidation products malondialdehyde (MDA), as well as the restoration of endogenous antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. Exposure to aβ resulted in a marked downregulation of circ_pum1 expression accompanied by elevated miR-340-5p levels; notably, 6-GIN administration reversed these molecular alterations. Mechanistic analyses further confirmed that miR-340-5p directly binds to the 3'-UTR of pleomorphic adenoma gene like-2 (PLAGL2), thereby regulating the estimated glomerular filtration rate (EGFR)/hypoxia-inducible factor-1α (HIF-1α)/hypoxia-inducible factor-2α (HIF-2α) signaling axis implicated in neuronal survival and metabolic adaptation. Collectively, these findings suggest that circ_PUM1 confers neuroprotection against Alzheimer's disease pathology by sequestering miR-340-5p and activating the PLAGL2/EGFR/HIF-1α-HIF-2α cascade, elucidating a critical pathway through which 6-GIN exerts its therapeutic potential in attenuating Aβ-associated neuronal degeneration. In conclusion: 6-GIN alleviates Aβ-induced apoptosis, oxidative stress, and neuroinflammation in AD through circ_PUM1/miR-340-5p/PLAGL2/EGFR-HIF1/2A signaling pathway.},
}

@article {pmid42272336,
year = {2026},
author = {Cardona, EA and Webber, CJ and Wu, Z and Bolton, BM and Sarinay-Cenik, E and Pierce, JT},
title = {Loss of endogenous tau suppresses APOE4-induced patterned behavioral decline and axon dysmorphia in a C. elegans model of Alzheimer's disease.},
journal = {Disease models & mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1242/dmm.052469},
pmid = {42272336},
issn = {1754-8411},
support = {R01GM122463/GF/NIH HHS/United States ; RF1AG057355/GF/NIH HHS/United States ; R21OD032463/GF/NIH HHS/United States ; //Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin/ ; //George and Karen Casey/ ; //David and Ellen Berman Fellowships for Huntington's Research/ ; //CNS Catalyst Grant/ ; R35GM138340/GF/NIH HHS/United States ; T32 MH106454/GF/NIH HHS/United States ; F-2133-20230405//Welch Foundation/ ; //National Science Foundation Graduate Research Fellowship Program/ ; },
abstract = {Alzheimer's disease (AD) causes a characteristic spatiotemporal pattern of neurodegeneration. The factors that account for this pattern of degeneration, including associated neuronal dysfunction and dysmorphia, are unclear. Previously, we generated a model of AD using the nematode Caenorhabditis elegans with the AD risk variant of apolipoprotein E, APOE4. We showed that the soma of HSN class neurons degenerate in early adult animals. Here, we perform behavioral analyses to deduce the effect of APOE4 on the function of distinct neuronal circuits. We found evidence that APOE4 induces dysfunction of other neurons; this spatiotemporal pattern roughly correlates with endogenous levels of PTL-1, the C. elegans homolog of human MAPT also known as tau. Moreover, deletion of ptl-1 suppressed defects in multiple behaviors, suggesting broad protective effects across the nervous system including the HSN neurons. Lastly, we show that PTL-1 in the touch receptor neurons, where PTL-1 is most abundant, contributes non-cell autonomously for age-related axon dysmorphia and dysfunction of the HSN neurons. Our results suggest that C. elegans may provide a useful in vivo system to study how endogenous tau acts downstream of APOE4 to cause progressive, patterned neurodegenerative phenotypes.},
}

@article {pmid42272485,
year = {2026},
author = {Guo, R and Zhang, L and Song, D and Yu, B and Song, C and Chen, H and Xie, W and Feng, C and Cheng, G and Hu, K and Jiang, J and Qu, Z and Du, H and Zhang, X},
title = {Endogenous iron biomineralization in the mouse spleen of metabolic diseases.},
journal = {Fundamental research},
volume = {6},
number = {3},
pages = {1535-1544},
pmid = {42272485},
issn = {2667-3258},
abstract = {As the most abundant essential trace element in our human bodies, iron plays essential roles in multiple physiological and pathological conditions, including oxygen transport, cancer, diabetes, Alzheimer's and Parkinson's diseases. Although it has been shown that iron can form particles in some bacteria, migrating birds and fish, whether iron biomineralization can also occur in mammals is still debated. Here we demonstrate that iron metabolism abnormalities in diseased mice can directly lead to endogenous iron biomineralization and particle formation in the spleen. Excessive iron accumulation leads to endogenous particle formation with an averaged size of ∼800 nm. In the spleens of severely diabetic mice, they accumulate in the red pulp region, where the red blood cells are recycled. This directly changes the magnetic property of the spleens and results in spleen damage in a gradient high magnetic field. Therefore, our findings not only demonstrate the existence of endogenous iron biomineralization in metabolic diseases, but also set up a direct link among iron accumulation, magnetic property and magnetic responses of animal organs, which may also be applied in other iron metabolism-related diseases including cancer and Alzheimer's disease.},
}

@article {pmid42272624,
year = {2026},
author = {Pham, D and O'Brien, C and Florez-Bhandari, J and Faulstich, N and Ojo, T and Aloi, S and Goodwin, R and Roley, L and Nathaniel, SI and Nathaniel, TI},
title = {Risk factors associated with cancer and metabolic encephalopathy in Alzheimer's disease patients.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1810937},
pmid = {42272624},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) frequently coexists with risk factors that modify its clinical course. The combined presence of cancer and metabolic encephalopathy (ME) in AD represents a particularly vulnerable and understudied phenotype. We investigated whether cancer-associated risk profiles differ between AD patients with and without metabolic encephalopathy.

METHODS: We used multivariate logistic regression to identify clinical, vascular, pulmonary, neurocognitive, psychiatric, and treatment-related factors distinguishing (i) AD patients with metabolic encephalopathy with and without cancer (AD + ME ± C) and (ii) AD patients without metabolic encephalopathy with and without cancer (AD - ME ± C). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were used to identify risk factors and phenotype-specific associations.

RESULTS: Of the total cohort, 10,516 patients had metabolic encephalopathy, and 118,253 did not. Cancer coexistence was present in 146 AD + ME patients and 1,167 AD - ME patients. Among AD + ME patients, cancer was strongly associated with cerebrovascular accident (OR = 3.47, 95% CI 2.16-5.59), secondary dementia (OR = 9.89, 95% CI 3.26-29.98), mild cognitive impairment (OR = 5.20, 95% CI 1.98-13.27), chronic obstructive pulmonary disease (OR = 7.66, 95% CI 5.20-11.29), and SSRI use (OR = 3.27, 95% CI 2.21-4.87). In contrast, memantine, buspirone, and valproate were associated with AD + ME without cancer. Among AD-ME patients, cancer was associated with dyslipidemia, peripheral vascular disease, congestive heart failure, arteriosclerosis, COPD, and cutaneous ulcers, reflecting chronic systemic illness.

CONCLUSION: Metabolic encephalopathy was associated with a different clinical profile in cancer-associated AD. Patients with ME exhibited increased systemic and neurologic vulnerability (e.g., vascular comorbidity and frailty indicators) rather than differences in baseline cognitive severity alone.},
}

@article {pmid42272994,
year = {2026},
author = {Huang, FF and Sun, Y and Hu, Y and Chang, JR and Zhou, Z and Zheng, DKY and Hsu, CL and Samartzis, D and Karppinen, J and Al Zoubi, FM and Fu, SN and Wong, AYL},
title = {Chronic Back Pain Increases Alzheimer's Disease Risk Independent of Gross Brain Structural Alterations: Genetic Evidence from Two Populations.},
journal = {Journal of pain research},
volume = {19},
number = {},
pages = {591448},
pmid = {42272994},
issn = {1178-7090},
abstract = {BACKGROUND: Observational studies suggest chronic musculoskeletal pain (CMP) may be a risk factor for dementia, but confounding factors or reverse causation could obscure these findings. Additionally, whether brain structure imaging measurements mediate this relationship remains unclear. We aimed to investigate their causal association using Mendelian randomization (MR).

METHODS: Genetic instruments derived from genome-wide association studies were employed in a two-sample MR framework. Forward MR analysis examined the genetic effect of CMP on dementia, while reverse MR analysis evaluated the genetic effect of dementia on CMP to assess reverse causation. Primary causal estimates were obtained using the inverse-variance weighted method. Mediation analyses tested brain structural markers as potential mediators. Sensitivity analyses evaluated robustness and horizontal pleiotropy.

RESULTS: Primary inverse-variance weighted analysis suggested genetically predicted chronic back pain (CBP) is associated with an increased risk of Alzheimer's disease (AD) (Odds Ratio 2.287, 95% confidence interval: 1.338 to 3.909, P = 0.002). However, this estimate was characterized by wide confidence intervals, conservative SNP heritability estimates, and null results in MR-Egger sensitivity analyses, indicating potential directional pleiotropy cannot be fully ruled out. No significant causal associations were detected for all-cause, frontotemporal, or vascular dementia. Other CMP subtypes showed no significant genetic effect on any dementia type. There was no evidence of reverse causation. While CBP influenced nine brain structures, these did not mediate the CBP-AD link.

CONCLUSION: Primary MR analyses support a directional association between genetically predicted CBP and increased AD risk. However, due to methodological constraints and wide confidence intervals, the large point estimate of the odds ratio should be interpreted with caution. Structural brain alterations do not appear to mediate this relationship. These findings highlight a potential causal pathway between CBP and AD, but require rigorous validation in independent, adequately powered cohorts before clinical inferences can be drawn.},
}

@article {pmid42273062,
year = {2026},
author = {Uhlmann, WR and Chan, AK and Goldman, JS},
title = {Now is the time: the need to update guidance to expand access to APOE genetic testing.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1808512},
pmid = {42273062},
issn = {2813-3919},
abstract = {Interest in APOE testing has increased due to an aging population, direct-to-consumer testing options, media coverage and FDA approval of anti-amyloid therapies. Previous Alzheimer's disease (AD) guidelines cautioned against APOE testing in asymptomatic individuals. However, updated guidance is warranted due to the changing landscape and research demonstrating low adverse psychological outcomes of APOE testing. With testing for APOE now recommended prior to anti-amyloid therapies, more symptomatic individuals will be identified as having the higher risk ε4 variant. The children and siblings of the symptomatic individuals who test positive will have at least a 50% risk of also having an ε4 and may subsequently seek testing. Since testing for APOE is generally not clinically available to asymptomatic individuals, they may pursue direct-to-consumer genetic testing and, therefore, be tested without a clinician's involvement or counseling. Given limitations and caveats of APOE testing, it is important that patients have access to education, counseling and testing in labs certified for clinical testing. Pre- and post-test education and counseling content for APOE testing, including risk figures, are provided in this Perspective. Both Alzheimer's disease and cardiovascular disease risks associated with APOE should be addressed for all individuals undergoing testing. Given that it has been over a decade since APOE guidance was issued, the time has come for the medical community to discuss the changing landscape, expand APOE genetic testing access to individuals at higher risk, and update guidelines.},
}

@article {pmid42273084,
year = {2026},
author = {Saunders, S and Haider, F and Lanzi, AM and MacWhinney, B and Fromm, D and Chou, CJ and Liu, YC and Chang, YN and Gregory, S and Ritchie, C and Lazarou, I and Nikolopoulos, S and Kompatsiaris, I and Danso, SO and Muniz-Terrera, G and Orozco-Arroyave, JR and Perez-Toro, PA and Cesario, RR and Cesario, M and Luz, S},
title = {The collection of speech data for the assessment of cognition remotely: Balancing ethical and practical challenges.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70341},
pmid = {42273084},
issn = {2352-8729},
abstract = {Speech biomarkers could form a critical step in improving the accessibility, scalability, and early detection of Alzheimer's disease and related dementias. However, ethical and practical challenges remain across regulatory and cultural contexts. In this paper, we briefly review the challenges in adopting speech biomarkers, relate our experiences globally to recent advances in the neurodegenerative field, and consider how speech assessments could be integrated into clinical care. Insights from high- and low- and middle-income countries (Taiwan, Ghana, Colombia, Brazil, Greece, UK, and US) demonstrate the potential impact of speech technology. While there are common benefits, risks, incentives, and hurdles, many aspects are specific to country or region. There is a need for more speech data sets (particularly in languages other than English), standardization in data collection and analysis, stronger collaboration between machine learning and neurodegenerative disease experts, unified privacy regulation, and finally, a consensus on the clinical interpretation of speech biomarker data.},
}

@article {pmid42273161,
year = {2026},
author = {Li, Y and Shao, Y and Zhou, D and Hao, S and Qiu, M and Wang, Z and Xi, Q},
title = {Investigation of the topological properties of brain structural and functional networks in patients with mild cognitive impairment.},
journal = {Quantitative imaging in medicine and surgery},
volume = {16},
number = {6},
pages = {492},
pmid = {42273161},
issn = {2223-4292},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a transitional stage between subjective cognitive decline and Alzheimer's dementia, representing a critical window for intervention. We characterize the small-world properties of brain networks in MCI to identify sensitive biomarkers for early detection and assessment.

METHODS: Thirty-one patients diagnosed with MCI were recruited as the experimental group, while 30 healthy elderly individuals served as the normal control (NC) group. Based on diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI), small-world properties of the brain networks were observed using graph theory analysis. Global and nodal properties were computed to assess differences in brain network topology.

RESULTS: Both structural and functional brain networks in the MCI and NC groups exhibited small-world properties (σ>1), and significant differences were noted in nodal properties such as nodal efficiency, nodal degree centrality, and nodal shortest path length (P<0.05). Importantly, these nodal properties in brain regions were significantly correlated with Montreal Cognitive Assessment (MoCA) scores in patients with MCI (P<0.05).

CONCLUSIONS: Patients with MCI exhibit small-world properties in their brain networks, suggesting preserved efficiency of information transfer. Node property metrics in regions such as the posterior cingulate cortex, prefrontal cortex, and occipital lobe are promising biomarkers for early detection of MCI.},
}

@article {pmid42273366,
year = {2026},
author = {Wu, W and Choi, ES and Liu, L and Thamilselvan, V and Li, L and Rippee-Brooks, MD and Khatkar, K and Li, DY and McGrath, D and Manning, A and Barberan-Soler, S and Lee, I and Zhao, Y and Fang, X and Bao, X},
title = {Disease-associated RNA and protein signatures in iPSC-derived microglia model of Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1799542},
pmid = {42273366},
issn = {1662-4548},
abstract = {INTRODUCTION: Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining neural homeostasis and regulating inflammatory responses in the brain. Increasing evidence suggests that microglial dysfunction contributes to the progression of neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms underlying these alterations remain incompletely understood. This study aimed to characterize disease-associated molecular changes in microglia derived from induced pluripotent stem cells (iPSCs) of sporadic AD patients and healthy donors.

METHODS: iPSC-derived microglia from sporadic AD patients and healthy controls were analyzed using integrated multi-omics approaches, including total RNA sequencing, proteomics, and small non-coding RNA (sncRNA) sequencing. Gene Ontology (GO) analysis was performed to identify dysregulated biological pathways from transcriptomic and proteomic datasets. In addition, a modified T4 polynucleotide kinase (T4 PNK)-based sncRNA sequencing method was used to profile disease-associated sncRNAs and identify previously uncharacterized RNA species.

RESULTS: Comparative analyses revealed significant AD-associated alterations in mRNA, protein, and sncRNA expression profiles in iPSC-derived microglia. GO analysis demonstrated dysregulation of pathways related to extracellular communication, intracellular transport, cytoskeletal organization, and protein-protein interactions. Furthermore, the modified T4 PNK-sncRNA sequencing approach identified multiple disease-associated sncRNAs, including several novel and previously uncharacterized RNA species potentially linked to AD pathology.

DISCUSSION: These findings demonstrate that iPSC-derived microglia provide a valuable model for studying molecular mechanisms associated with sporadic AD. The identified transcriptomic, proteomic, and sncRNA alterations highlight key pathways potentially involved in microglial dysfunction and neurodegeneration. In particular, the discovery of novel disease-associated sncRNAs may provide new insights into AD pathogenesis and reveal potential therapeutic targets for future investigation.},
}

@article {pmid42273367,
year = {2026},
author = {Zhang, D and Zhang, J and Chen, W and Du, G},
title = {GGDA-net: geometry-guided deformable attention network for Alzheimer's disease image classification.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1838681},
pmid = {42273367},
issn = {1662-4548},
abstract = {BACKGROUND: Convolutional neural networks (CNNs) have achieved remarkable success in medical image analysis, including Alzheimer's disease (AD) classification. However, conventional convolution operations rely on fixed sampling patterns, and most existing attention mechanisms primarily focus on feature responses while neglecting spatial sampling geometry, limiting their ability to capture structural variations in brain images.

METHODS: To address these limitations, this paper proposes a Geometry-Guided Deformable Attention Network (GGDA-Net) for medical image classification. The proposed framework integrates Linear Deformable Convolution (LDConv) with a Geometry-Aware (GA) Attention mechanism to jointly model feature semantics and spatial geometry. Specifically, LDConv introduces adaptive spatial sampling through learnable offsets, enabling flexible modeling of geometric deformations in brain structures, while the GA attention exploits the resulting geometric cues to guide the network toward more informative anatomical regions.

RESULTS: The experimental results show that the accuracy rates on the two datasets reached 99.38 and 99.16% respectively, which are superior to the existing most advanced algorithms. At the same time, the model maintains a compact size and has a relatively low computational complexity. These results highlight the effectiveness of feature learning based on geometric perception in medical image analysis and Alzheimer's disease diagnosis.},
}

@article {pmid42273369,
year = {2026},
author = {Offerdahl, JEV and Mor, DE},
title = {Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1846384},
pmid = {42273369},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders (ND) globally, disproportionately affecting the elderly population. Traditionally viewed as distinct diseases, AD is defined by symptoms of cognitive impairment and dementia with amyloid-β and tau protein pathologies, while PD is defined by motor symptoms and eventual dementia with α-synuclein (α-syn) protein pathology. However, these pathologies are not unique to either disease, with a large fraction of AD patients displaying α-syn inclusions and PD patients displaying abnormal tau. Emerging evidence indicates that pathological tau and α-syn not only frequently coexist in AD and PD, but may engage in synergistic interactions that promote mitochondrial dysfunction, accelerate neurodegeneration, and worsen cognitive decline in both disorders. This review aims to provide both the prevailing views of AD and PD, as well as a detailed discussion of their commonalities with a focus on how tau and α-syn toxicities intersect at the mitochondrial level. Common features of mitochondrial impairment in AD and PD are discussed, including complex I deficiency, oxidative stress, impaired axonal transport, altered mitochondrial dynamics, and mitochondrial DNA damage. While prior reviews have often examined AD and PD independently, this review specifically focuses on the convergent and potentially synergistic interactions between tau and α-syn at the level of mitochondrial dysfunction, highlighting a shared mechanistic framework that may inform unified therapeutic strategies. By studying and understanding the mutual mechanisms underlying neurodegeneration in AD and PD, common treatment strategies can be identified.},
}

@article {pmid42273644,
year = {2026},
author = {Zargarbashi, S and Dominguez, C and Peters, M and Yousefi, A and Munday, S and Wang, Y and Chatterjee, S and Hudson, AJ and Gordon, R and Mellor, CJ and Xu, L and Rahmani, M and Ying, C},
title = {Label-free optical observation of disordered-to-ordered transitions in single intrinsically disordered proteins.},
journal = {Npj biosensing},
volume = {3},
number = {1},
pages = {33},
pmid = {42273644},
issn = {3004-8656},
abstract = {Intrinsically disordered proteins (IDPs) and structured proteins with intrinsically disordered regions (IDRs) lack a definitive tertiary structure and contribute to the onset of diseases such as Alzheimer's and cancer. To date, experimental observation of single, label-free IDPs/IDRs poses a significant challenge due to their structural heterogeneity, limiting ensemble techniques from fully capturing their properties, whilst single-molecule measurements require site-specific modifications or non-physiological conditions, perturbing their native biophysics. Here, we demonstrate the first experimental observation of unmodified IDP/IDR conformational dynamics at the single-molecule level, achieved by optical trapping and investigation of individual IDPs/IDRs using nanoaperture optical tweezers. Our results reveal that IDPs/IDRs exhibit significantly larger conformational variations compared to globular proteins of similar size. We demonstrate that phosphorylation of native tau-441 by glycogen synthase kinase 3-beta (GSK3β-tau) induces compaction and reduced conformational dynamics. We further observed a disorder-to-order transition during the binding of the N-terminal region of the Src-associated protein in mitosis of 68 kDa (Sam68) to G8.5 RNA. These findings present nanoaperture optical tweezers as a powerful approach to advance our understanding of IDPs/IDRs and further decode their roles in associated diseases.},
}

@article {pmid42273749,
year = {2026},
author = {Shila, SR and Almatarneh, MH and Suha, HN and Hossain, I and Abdalla, S and Bari, MAU and Poirier, RA and Uddin, KM},
title = {Structure-Based Design of Isoxazolidine RIPK1 Inhibitors for Neuroinflammation.},
journal = {Journal of computational chemistry},
volume = {47},
number = {16},
pages = {e70411},
doi = {10.1002/jcc.70411},
pmid = {42273749},
issn = {1096-987X},
support = {IMSIU-DDRSP2601//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and neuronal loss. Aberrant activation of receptor-interacting protein kinase 1 (RIPK1) plays a critical role in neuroinflammation and programmed neuronal death, making it an attractive therapeutic target. In this computational study, 16 isoxazolidine derivatives (1-16) were evaluated alongside seven reference inhibitors to identify potential RIPK1 blockers. Molecular docking analyses revealed that compound 7 exhibited the highest binding affinity toward RIPK1 (PDB ID: 7XMK), with a binding energy of -9.0 kcal mol[-1], outperforming established inhibitors and demonstrating broad activity against AD-related targets. Density functional theory calculations showed a HOMO-LUMO energy gap of 5.209 eV, indicating favorable electronic stability. Compound 7 complied with Lipinski's rule of five and Veber's criteria and displayed excellent predictive ADMET properties, including high human intestinal absorption (HIA = 1.0), strong blood-brain barrier permeability (BBB = 0.991), and low predicted toxicity. Molecular dynamics (MD) simulations conducted over 100 ns at temperatures ranging from 300 to 320 K confirmed the stability of the RIPK1-compound 7 complex. The root-mean-square deviation (RMSD) values ranged from 5.2 to 14.0 Å (0.52-1.40 nm), indicating acceptable structural fluctuations throughout the simulation. Additionally, the radius of gyration (Rg) ranged from 2.8 to 3.8 nm, indicating that the complex maintained a relatively stable, compact conformation throughout the simulation. Principal component analysis further supported these findings, yielding cosine similarity values of 0.86-0.95. Collectively, these results highlight compound 7 as a promising RIPK1 inhibitor with favorable pharmacokinetic, electronic, and dynamic properties, underscoring its potential as a therapeutic candidate for AD.},
}

@article {pmid42273784,
year = {2026},
author = {Koops, EA and Giudicessi, A and Baena, A and Martinez, L and Bonillas-Felix, N and Medrano, R and Dutta, J and Gonzalez, I and Alvarez, S and Aguillon, D and Quiroz, YT and Jacobs, HIL},
title = {Vulnerability of the locus coeruleus-entorhinal cortex white matter tract in autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71587},
pmid = {42273784},
issn = {1552-5279},
support = {23AARF-1026796/ALZ/Alzheimer's Association/United States ; R01AG062559/AG/NIA NIH HHS/United States ; R01AG068062/AG/NIA NIH HHS/United States ; R01AG082006/AG/NIA NIH HHS/United States ; R21AG074220/AG/NIA NIH HHS/United States ; R01AG054671/AG/NIA NIH HHS/United States ; RF1AG077627/AG/NIA NIH HHS/United States ; 1F31NS134277-01A1/NS/NINDS NIH HHS/United States ; //Massachusetts General Hospital (MGH) Executive Committee on Research/ ; },
abstract = {INTRODUCTION: Locus coeruleus (LC) structural integrity declines early in sporadic and autosomal dominant Alzheimer's disease (AD). We examined LC-entorhinal cortex (LC-EC) tract integrity and its association with amyloid and tau pathology and memory in autosomal dominant AD (ADAD).

METHODS: We examined associations between diffusion-weighted imaging-derived LC-EC tract characteristics and age, sex, amyloid (Pittsburgh Compound B [PiB]), entorhinal tau ([[18]F]-flortaucipir [[18]F-FTP] positron emission tomography [PET]), and memory in PSEN1-E280A mutation carriers (n = 30) and non-carriers (n = 33).

RESULTS: LC-EC tract integrity was lower in females and older individuals in both non-carriers and carriers. In mutation carriers, lower tract integrity was associated with higher entorhinal tau and poorer memory, with tau and amyloid mediating the tract-memory relationship in the entire sample but not in unimpaired carriers.

DISCUSSION: These findings highlight the LC-EC tract as an early disease vulnerability marker in ADAD, with tract disruption associated with memory decline across disease stages, a relationship further mediated by entorhinal tau pathology as disease progresses.},
}

@article {pmid42273802,
year = {2026},
author = {Raket, LL and Lu, M and Evans, CD and Zimmer, JA and Sparks, J and Collins, EC and Shcherbinin, S and Wang, H and Nery, ESM and Epelbaum, S and Dell'Agnello, G and Brooks, DA and Sims, JR and Mintun, MA},
title = {Donanemab treatment effect by baseline tau burden and disease severity: Observations from the TRAILBLAZER-ALZ 2 trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71577},
pmid = {42273802},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
abstract = {INTRODUCTION: Clinical trials indicate that disease-modifying therapies can slow clinical decline in Alzheimer's disease (AD), with earlier initiation associated with greater slowing.

METHODS: In the TRAILBLAZER-ALZ 2 trial, the treatment effect of donanemab on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score was assessed across disease stages defined by baseline tau PET, plasma P-tau217 levels, or predicted disease progression.

RESULTS: Donanemab-mediated slowing of disease progression occurred across baseline tau PET and plasma P-tau217 levels. Participants with lower baseline tau PET and P-tau217 showed greater slowing with donanemab versus placebo. Modeling CDR-SB scores indicated that earlier treatment (at the 25[th] percentile of baseline Predicted disease progression) delayed disease progression by 60% over 76 weeks, compared to 33% and 17% at the 50[th] and 75[th] percentiles.

DISCUSSION: Donanemab benefited participants with early symptomatic AD across clinical and pathological severities, with the greatest slowing in those treated earlier.

CLINICALTRIALS: gov Identifier: NCT04437511.},
}

@article {pmid42273832,
year = {2026},
author = {Dhanam, S and Sanderson-Cimino, M and Taylor, JC and Paolillo, EW and Fregly, R and Kwang, W and Maruff, P and Wise, A and Heuer, HW and Forsberg, LK and Kramer, JH and Boeve, BF and Rosen, HJ and Mackin, RS and Weiner, MW and Nosheny, RL and Boxer, AL and Staffaroni, AM and , },
title = {Remote, self-administered, smartphone cognitive testing in a registry-based cohort: Feasibility, reliability, and validity findings.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71580},
pmid = {42273832},
issn = {1552-5279},
support = {AG077557/NH/NIH HHS/United States ; R33AG062867/NH/NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; //Bluefield Project to Cure FTD/ ; //The Rainwater Charitable Foundation/ ; },
abstract = {BACKGROUND: Remote, smartphone-based cognitive testing may improve access to cognitive assessments for Alzheimer's disease and related dementias. We evaluated the feasibility, reliability, and validity of unsupervised smartphone-based cognitive tests in a registry-based cohort.

METHODS: Adults without a record of cognitive impairment (N = 1815; ages 18-92) were recruited from the University of California, San Francisco (UCSF) Brain Health Registry to complete three unsupervised smartphone cognitive testing sessions within 2 weeks. Reliability was assessed with correlations between sessions. Linear regression models tested associations of smartphone tasks with demographics, self- and informant-rated cognitive concerns, and web-based cognitive testing (Cogstate Brief Battery).

RESULTS: Adherence was high (82.2%) and usability favorable. Test-retest reliability was moderate to strong (ρ's = 0.61-0.85, all p's < 0.001). Lower smartphone scores were associated with older age, lower education, cognitive concerns, and worse Cogstate performance.

DISCUSSION: Findings support the feasibility, reliability, and validity of remote digital assessments in adults without a record of cognitive impairment.},
}

@article {pmid42273871,
year = {2026},
author = {Xiao, C and Ard, T and Blazhenets, G and La Joie, R and Pappas, I and Toga, AW and , and , },
title = {Association of cognitive impairment and APOE ε4 with Centiloids in Hispanic and non-Hispanic White cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71586},
pmid = {42273871},
issn = {1552-5279},
support = {SG-20-678486-GAAIN2/ALZ/Alzheimer's Association/United States ; },
abstract = {INTRODUCTION: Weak associations of apolipoprotein E (APOE) ε4 with cognitive impairment have been reported in Hispanic cohorts. To determine if APOE ε4 associates with brain amyloid load differently in Hispanic and non-Hispanic White (NHW) cohorts, we analyzed reported Centiloid values from studies that conducted amyloid positron emission tomography.

METHODS: This meta-analysis included 17,017 participants (8.4% Hispanic) from five source studies. Analysis of covariance and logistic regression models adjusting for age, sex, education, and cognitive score were applied.

RESULTS: Although cognitive impairment and APOE ε4 were associated with higher Centiloids in both Hispanic and NHW cohorts, cognitively impaired and APOE ε4 positive Hispanic participants had lower Centiloids than NHW participants with the same conditions.

DISCUSSION: APOE ε4 may have a weaker influence on brain amyloid load in Hispanic cohorts. Further comparative analyses are necessary for Alzheimer's disease anti-amyloid treatments to be widely applicable to Hispanic populations.},
}

@article {pmid42273872,
year = {2026},
author = {Wang, Z and Hossain, D and Wang, JJ and Subramaniam, VR and Zhang, B and Wang, M and Huang, KL},
title = {Allele specific expression in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71558},
pmid = {42273872},
issn = {1552-5279},
support = {UL1TR004419//Clinical and Translational Science Awards (CTSA)/ ; S10OD026880//Office of Research Infrastructure of the National Institutes of Health/ ; S10OD030463//Office of Research Infrastructure of the National Institutes of Health/ ; R35GM138113/GM/NIGMS NIH HHS/United States ; 2R35GM138113/GM/NIGMS NIH HHS/United States ; R21AG077168/AG/NIA NIH HHS/United States ; RF1AG077828/AG/NIA NIH HHS/United States ; AARG-22-928419/ALZ/Alzheimer's Association/United States ; },
abstract = {INTRODUCTION: Allele-specific expression (ASE), preferential expression of one allele at a heterozygous locus, is implicated in various brain diseases but remains largely uncharacterized in Alzheimer's disease (AD).

METHODS: We performed a genome-wide characterization of ASE variants across seven brain regions of 2,231 AD and Control patients from Mount Sinai Brain Bank (MSBB) and Religious Orders Study/Memory and Aging Project (ROSMAP) cohorts and investigated cell-type-specific activity via single-cell analysis.

RESULTS: We identified 56,136 unique ASE variants that were enriched in imprinted chromosomal regions, e.g., chr6, chr14q32, and chr15q11. ASE variants were also found in exons of known AD-associated genes, including apolipoprotein E (APOE), CLU, CTSB, and HLA-DRB1. Forty variants exhibited AD-associated ASE, and the affected genes, including SLC12A5, SYT13, and TOMM7, were predominantly downregulated in multiple cell types, including astrocytes, excitatory neurons, and oligodendrocytes.

DISCUSSION: We provided a detailed landscape of ASE in AD, uncovering novel functional variants and highlighting their potential cell-type-specific contributions to disease pathogenesis.},
}

@article {pmid42273876,
year = {2026},
author = {David, MCB and Mallas, EJ and Kolanko, MA and Del Giovane, M and Kurtin, DL and Nilforooshan, R and Zimmerman, KA and Bonet Olivares, C and Lally, PJ and , and Sharp, DJ and Malhotra, PA and Scott, G},
title = {Cortical synchrony is reduced in Alzheimer's disease and relates to arousal state.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71547},
doi = {10.1002/alz.71547},
pmid = {42273876},
issn = {1552-5279},
support = {/MRC_/Medical Research Council/United Kingdom ; /ALZS_/Alzheimer's Society/United Kingdom ; //National Institute for Health and Care Research/ ; },
abstract = {INTRODUCTION: The brain is a complex dynamical system, influenced by arousal state. Cortical synchrony supports information processing and is disrupted in Alzheimer's disease (AD). Locus coeruleus (LC) integrity and pupillometry index arousal system structure and function.

METHODS: Sixty-four AD and 26 controls underwent resting-state pupillometry-fMRI. Neuromelanin MRI and Addenbrooke's Cognitive Examination were conducted. Mean and standard deviation of blood oxygen level dependent (BOLD) phase coherence yielded synchrony and metastability, respectively. Leading Eigenvector Dynamics Analysis (LEiDA) produced coherence-based states.

RESULTS: AD had reduced global synchrony [b = -0.90, p < 0.001], metastability [b = -0.61, p < 0.01], LEiDA "global coherence state" occupancy [b = -0.06, p < 0.01], and LC integrity [b = -0.37, p = 0.01]. Synchrony [b = 0.19, p = 0.01] and LC integrity [b = 0.17, p < 0.01] related to cognition and one another [b = 0.27, p = 0.01]. Pupil-linked arousal correlated with synchrony and global coherence state maintenance.

DISCUSSION: In health, cortical activity shows widespread but dynamic synchrony across regions to meet changing demands. In AD, arousal dysfunction appears to disrupt these dynamics, impacting cognition.},
}

@article {pmid42273887,
year = {2026},
author = {Cottez, RJ and Peyrot, C and Denis, HL and Tremblay, C and Loiselle, A and Dallaire-Théroux, C and Filali-Mouhim, A and Hébert, SS and Leclerc, N and Blennow, K and Zetterberg, H and , and Kergoat, MJ and Calon, F and Pichet Binette, A},
title = {Plasma p-tau markers, vascular factors, and cognitive decline in the CIMA-Q cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71588},
doi = {10.1002/alz.71588},
pmid = {42273887},
issn = {1552-5279},
support = {361227//FRQ/ ; 00356//the Swedish Research Council/ ; 01018//the Swedish Research Council/ ; 02397//the Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation program/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; //European Union's Horizon Europe research and innovation programme under grant agreement/ ; //Fond d'enseignement et de recherche du cercle du congrès de la Faculté de pharmacie, Université Laval/ ; //Fondation de l'Institut de gériatrie de Montréal/ ; //Fonds de Recherche du Québec (FRQ)/ ; //Fondation Famille Lemaire/ ; //Consortium for the Neurodegeneration associated with Aging (CCNA)/ ; //Courtois Foundation/ ; //Quebec Network for Research on aging (RQRV)/ ; //(FRQS) - Pfizer Innovation Program/ ; 279261//FRQ cohort funds/ ; },
abstract = {INTRODUCTION: We evaluated associations between phosphorylated au 217 (p-tau217), p-tau181, p-tau231, and vascular risk factors with cognitive outcomes across the Alzheimer's disease (AD) continuum.

METHODS: Baseline plasma p-tau concentrations and vascular risk factors were assessed in 277 Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q) participants. Associations between these markers, cognition, and clinical progression over on average 3.10 years were examined.

RESULTS: Higher plasma p-tau levels were associated with worse cognition at baseline and over time, with the strongest effect observed with p-tau217 in cognitively impaired individuals (β = -0.49, p < 0.001). Hypertension was further linked to steeper memory and executive function decline (β = -0.10, both p = 0.04) in this group, and it amplified the effect of p-tau217 on cognitive decline across the whole group. Higher p-tau217 levels were associated with cognitive decline in cognitively unimpaired individuals, and it also predicted progression from mild cognitive impairment (MCI) to AD dementia (hazard ratio [HR] = 1.22, p = 0.016).

DISCUSSION: Plasma p-tau217 was the most sensitive marker of cognitive decline, with hypertension contributing to longitudinal cognitive changes.},
}

@article {pmid42274018,
year = {2026},
author = {Johnson, KE},
title = {The Educational Exposome: A life-course socioenvironmental framework for advancing Alzheimer's disease and ADRD research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71413},
doi = {10.1002/alz.71413},
pmid = {42274018},
issn = {1552-5279},
support = {R01AG051142/AG/NIA NIH HHS/United States ; U01AG009740/AG/NIA NIH HHS/United States ; //University of Michigan Institute for Social Research/ ; //Regula Herzog Young Investigators Fund/ ; },
abstract = {INTRODUCTION: The exposome encompasses all environmental exposures across the life course, yet educational environments, a critical socioenvironmental exposure, remain underexplored despite their role in cognitive aging and Alzheimer's disease and related dementias (AD/ADRD). Traditional measures, such as years of schooling, underestimate exposure heterogeneity and mechanisms influencing cognitive reserve.

METHODS: The Educational Exposome Framework integrates psychosocial, resource-based, environmental, and structural domains of education: academic self-efficacy, home and community learning resources, and institutional learning contexts drawing on life-course, exposomic, and cognitive health research.

RESULTS: The framework conceptualizes education as a multidimensional, interacting system shaping cognitive development, stress biology, and neurodegeneration. Legacy and emerging datasets, including High School & Beyond, Health and Retirement Study, and Add Health, enable life-course reconstruction of educational exposures linked to midlife and later-life cognition.

DISCUSSION: By capturing mechanistic pathways and leveraging linked data, the framework supports equity-focused dementia prevention and clarifies education's role in AD/ADRD risk.},
}

@article {pmid42274194,
year = {2026},
author = {Wladkowski, SP and Washington, KT and Coccia, KW and Wallace, CL},
title = {Understanding the "circle of support" for caregivers of adults with Alzheimer's disease and related dementias following a hospice live discharge.},
journal = {Death studies},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/07481187.2026.2683688},
pmid = {42274194},
issn = {1091-7683},
abstract = {Hospice patients with Alzheimer's disease and related dementias (ADRD) are more likely to experience a live discharge. This places increased burden on primary caregivers who may be unprepared for this transition and are more likely to be socially isolated. This study explored primary caregivers' "Circle of Support" (CoS) and how social context influences service utilization patterns, perceived support, and experiences of care transitions following a hospice live discharge. Semi-structured interviews were conducted with 32 caregivers and analyzed using thematic analysis. Caregivers described their CoS, how their CoS functioned (or failed to function) post-hospice, and key caregiver and network attributes affecting support use. Findings show that caregivers reporting no changes in their tasks after discharge described more absent CoS functions. Experiences were also influenced by patient location of care and resources availability, suggesting opportunities for targeted interventions to improve caregivers' experiences and outcomes.},
}

@article {pmid42274471,
year = {2026},
author = {Yang, Y and Ma, Y and Wang, P and Guan, PP},
title = {Triptolide Reduces Cholesterol Synthesis and Alleviates Neuroinflammation by Inhibiting CD33 in Alzheimer's Disease Development and Progression.},
journal = {Biology},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biology15110818},
pmid = {42274471},
issn = {2079-7737},
support = {D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; 2025ZDZX2061//Special projects in key areas of ordinary universities in Guangdong Province/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau[P301S] transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner.},
}

@article {pmid42274555,
year = {2026},
author = {Khan, MS and Zafar, I and Noman, M and Yang, G and Kang, KS and Bopassa, JC},
title = {Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks.},
journal = {Cells},
volume = {15},
number = {11},
pages = {},
pmid = {42274555},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Signal Transduction/drug effects ; *Polypharmacology ; Animals ; Oxidative Stress ; Mitochondria/metabolism ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial-ROS-inflammatory signaling, aggregation-proteostasis failure, synaptic-neuroimmune dysfunction, and gut-brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways-play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood-brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Signal Transduction/drug effects
*Polypharmacology
Animals
Oxidative Stress
Mitochondria/metabolism

@article {pmid42274577,
year = {2026},
author = {Schuldt, ON and Leitch, SR and Jones, LK and Buckley, PR and Morrison, BE},
title = {Neuroinflammatory Remodeling by Type 2 Immune Pathways Links Allergic Signaling to Neurodegenerative Disease.},
journal = {Cells},
volume = {15},
number = {11},
pages = {},
pmid = {42274577},
issn = {2073-4409},
support = {R15HL165397//National Heart Lung and Blood Institute/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/immunology/pathology ; Animals ; *Signal Transduction/immunology ; *Hypersensitivity/immunology ; *Neuroinflammatory Diseases/immunology ; },
abstract = {The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington's disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson's disease, where epidemiology suggests an important role in dementia/Alzheimer's disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/immunology/pathology
Animals
*Signal Transduction/immunology
*Hypersensitivity/immunology
*Neuroinflammatory Diseases/immunology

@article {pmid42274583,
year = {2026},
author = {Bisht, J and Rawat, P and Shin, AC and Hegde, V},
title = {Mitochondrial Dysfunction in Alzheimer's Disease and Mitochondria-Targeted Therapeutics.},
journal = {Cells},
volume = {15},
number = {11},
pages = {},
pmid = {42274583},
issn = {2073-4409},
support = {R01 AG071560/NH/NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive cognitive decline due to the loss of neurons. The accumulation of extracellular senile plaques (Aβ) and intracellular tau neurofibrillary tangles (NFTs) is a key pathological feature of AD. Mitochondrial dysfunction is implicated in all key AD pathologies, whether as a cause or a consequence of disease progression. Growing evidence indicates that mitochondrial impairment plays a central role in AD pathogenesis by disrupting cellular homeostasis, promoting oxidative stress, and contributing to progressive neuronal death. Therefore, targeting mitochondria may offer promising insights into the development of disease-modifying therapies. In this review, we summarize current evidence on the role of mitochondrial dysfunction in the pathophysiology of AD and on its therapeutic potential.},
}

@article {pmid42274592,
year = {2026},
author = {Sgalletta, B and Agostini, F and Bisaglia, M},
title = {The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword.},
journal = {Cells},
volume = {15},
number = {11},
pages = {},
pmid = {42274592},
issn = {2073-4409},
abstract = {Iron is an essential micronutrient that plays a central role in numerous biological processes. Despite its relatively low abundance in the human body, iron is particularly critical for brain function. Systemic and cerebral iron homeostasis is tightly regulated through coordinated mechanisms involving absorption, transport, storage, and recycling. Within the brain, iron metabolism is further controlled by the blood-brain barrier and specialized neural cell populations, including neurons, astrocytes, oligodendrocytes, and microglia. Iron is indispensable for neurodevelopment, supporting neurogenesis, myelination, and neurotransmitter synthesis. However, both iron deficiency and iron overload have detrimental consequences. Early-life iron deficiency disrupts neural development and leads to long-lasting cognitive, motor, and behavioral impairments, whereas excessive iron accumulation promotes oxidative stress, ferroptosis, and neuroinflammation. These mechanisms have been described to contribute to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation, and amyotrophic lateral sclerosis. This review first outlines systemic and brain iron metabolism, highlighting how neural cells regulate homeostasis. Next, it examines iron's physiological roles, particularly in neurogenesis and neurodevelopment. Finally, it explores iron's involvement in neurodegenerative diseases, emphasizing neuroinflammation as a primary mechanism of iron toxicity.},
}

@article {pmid42274595,
year = {2026},
author = {Del Seppia, C and Sabatino, L},
title = {Beyond Hormone Levels: Thyroid Hormone Signaling from Neurogenesis to Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {11},
pages = {},
pmid = {42274595},
issn = {2073-4409},
abstract = {Thyroid hormones (THs) critically regulate metabolism and the central nervous system (CNS) functions, acting as key factors in neuronal differentiation, synaptogenesis and myelination. Furthermore, they play a central role in regulation of cognitive process and behavior. Therefore, compromised TH signaling can interfere with normal brain function and promote neurodegenerative progression and dementia. This review explores the role of THs from embryonic development through adulthood, with particular emphasis on their crucial role in neurogenesis. We discuss key components of TH metabolism and signaling, highlighting their neuroprotective functions in maintaining cellular homeostasis. Furthermore, we address how disruptions in TH signaling contribute to cognitive decline observed in dementia with effects that are even more pronounced in Alzheimer's Disease (AD).},
}

@article {pmid42274621,
year = {2026},
author = {Chmiel, J and Gawełczyk, W and Soczyńska, J and Leszek, J},
title = {Emerging Function of Prolactin-Inducible Protein-Is This Important Tear Protein Found in Alzheimer's Disease?.},
journal = {Cells},
volume = {15},
number = {11},
pages = {},
pmid = {42274621},
issn = {2073-4409},
abstract = {Alzheimer's disease is characterized by a chronic, long-term neurodegenerative process and an increasing need for easily accessible biomarkers that enable early diagnosis and disease monitoring. For this reason, tears have attracted growing interest as a potential source of such biomarkers, and prolactin-inducible protein is a candidate tear protein of mechanistic interest whose clinical value remains to be established as a biomarker of Alzheimer's disease. The literature indicates that prolactin-inducible protein is physiologically present in the lacrimal apparatus. Proteomic studies in patients with Alzheimer's disease have repeatedly demonstrated decreased levels of prolactin-inducible protein in tears, typically accompanied by reduced concentrations of other proteins associated with normal lacrimal gland function. Although the evidence remains inconclusive, these findings suggest that alterations in prolactin-inducible protein levels may reflect lacrimal gland dysfunction related to neurodegenerative processes, autonomic dysregulation, and inflammation. Nevertheless, the lack of specificity of prolactin-inducible protein for Alzheimer's disease, as well as the influence of various factors on its concentration, limit its value as a standalone biomarker. The most plausible approach is the incorporation of prolactin-inducible protein into multimarker panels, which could enable improved patient stratification and assessment of lacrimal gland dysfunction in Alzheimer's disease.},
}

@article {pmid42274769,
year = {2026},
author = {Taha, MME and Abdelwahab, SI and Alshahrani, S and Jali, AM and Qadri, M and Alarifi, A and Al-Shamsi, HO},
title = {Alzheimer's disease-cancer research (inception to 2025): trends, themes, translational pathways, and insights from highly cited studies.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42274769},
issn = {1432-1912},
abstract = {Alzheimer's disease-cancer research (ADCR) has gained increasing attention due to paradoxical epidemiological associations and shared yet oppositely regulated biological mechanisms; however, the field lacks an integrated synthesis of its intellectual and thematic structure. This study comprehensively mapped the longitudinal evolution, collaboration patterns, and conceptual architecture of ADCR. Scopus-indexed articles published between 1968 and 2025 were retrieved using a structured TITLE-ABS-KEY search strategy. Bibliometric indicators were analyzed using the Bibliometrix R package (Biblioshiny), and network, density, overlay, and thematic visualizations were generated using VOSviewer. Analyses included productivity trends, citation impact, collaboration networks, institutional and author performance, Bradford's and Lotka's laws, keyword co-occurrence, thematic evolution, and strategic mapping. The dataset comprised 7460 publications, with an annual growth rate of 11.98% and 24.79% international collaboration. Scientific output and citation impact were dominated by North America, Europe, and East Asia, led by the USA (2418 documents; 121,747 citations) and China (1406 documents; 40,410 citations). Thematically, Alzheimer's disease-centered neuroinflammatory mechanisms emerged as the principal motor theme, while cancer persisted as a foundational but less cohesive domain. Temporal analyses indicated a transition from early mechanistic fragmentation to consolidated interdisciplinary research, accompanied by the recent rise of molecular docking, machine learning, and network pharmacology. Collectively, ADCR is evolving into a mature, integrative field characterized by methodological innovation and growing translational convergence between neurodegeneration and oncology.},
}

@article {pmid42274838,
year = {2026},
author = {Lior, N and Anna, P and Roni, H and Daniel, MM and Dan, F and Ronit, PK},
title = {APOE4-Expressing Astrocytes Exhibit Parkinson's Disease-Related Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42274838},
issn = {1559-1182},
abstract = {Parkinson's disease (PD) is characterized by motor symptoms that are mainly attributed to the progressive loss of dopaminergic neurons of the substantia nigra (SN). It is also characterized by abnormal inclusion vesicles, termed Lewy bodies (LBs), enriched with α-synuclein aggregates that may induce inflammation and neurotoxicity. The possibility that factors involved in other neurodegenerative diseases also affect PD-related pathologies, such as α-synuclein uptake, was examined. The apoe4 allele is a major genetic risk factor for Alzheimer's disease (AD) and has also been suggested to be involved in PD. Here, we examined the effects of APOE isoform expression on α-synuclein uptake and autophagy in astrocytes expressing the apoe3 or apoe4 alleles. Using multiple autophagy manipulations (EBSS, chloroquine, and rapamycin treatments), we found that α-synuclein uptake and autophagy readouts differ between APOE3 and APOE4 astrocytes, supporting a functional link between autophagy status and α-synuclein levels. Astrocytes expressing APOE4 exhibit reduced uptake of α-synuclein and reduced autophagy. Moreover, α-synuclein treatment inhibits autophagy mainly in APOE3-expressing cells. Additional experiments showed that the autophagy inhibitor chloroquine reduced α-synuclein uptake in APOE3 astrocytes but not in APOE4 astrocytes, while the autophagy enhancer rapamycin increased α-synuclein uptake in APOE4-expressing astrocytes. In addition, we found that Toll-like receptor 2 (TLR2) levels are elevated at both the mRNA and protein levels in APOE4-expressing astrocytes, whereas α-synuclein increased only TLR2 mRNA levels in APOE3-expressing astrocytes. Using the neurotoxin 1-methyl-4-phenylpyridinium (MPP[+]), we found that it affects cell growth in both APOE3 and APOE4-expressing astrocytes. MPP[+] treatment also reduced autophagy which was partially corrected by rapamycin. Taken together, these findings show that in astrocytes, APOE4 impairs α-synuclein uptake, which was emended by rapamycin and α-synuclein inhibits autophagy mainly in APOE3. These findings suggest that autophagy-targeting strategies can modulate astrocyte α-synuclein uptake; however, given the observed reductions in astrocyte cell number following rapamycin treatment, further optimization or examination of alternative autophagy modulators is needed.},
}

@article {pmid42274849,
year = {2026},
author = {Bindal, P and Kuwar, OK and Singh, VK and Attri, M and Pallavi, and Tejpal, S},
title = {α-Klotho as a central integrative signalling hub in cognitive function and neuroprotection in neurodegenerative diseases.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42274849},
issn = {1573-7365},
abstract = {α-Klotho, a transmembrane protein predominantly expressed in the kidney and brain, has garnered significant attention for its anti-ageing and neuroprotective properties. Beyond its systemic role in mineral metabolism and oxidative stress regulation, emerging evidence highlights its critical involvement in maintaining cognitive function and protecting against neurodegenerative processes. This review explores the multifaceted role of α-Klotho in the central nervous system, emphasizing its physiological functions, underlying molecular mechanisms, and therapeutic potential. α-Klotho exerts neuroprotective effects by modulating calcium and phosphate homeostasis, attenuating oxidative stress, and suppressing neuroinflammation. Additionally, it regulates signalling pathways such as IGF-1, Wnt/β-catenin, and Nrf2, which are essential for neuronal survival and synaptic plasticity. Reduced α-Klotho expression has been linked to cognitive impairment, Alzheimer's disease, Parkinson's disease, and other age-related neurodegenerative disorders. Preclinical studies demonstrate that enhancing α-Klotho expression or administering a recombinant protein improves learning, memory, and neuronal resilience, positioning α-Klotho as a promising therapeutic target. However, challenges such as limited blood-brain barrier penetration, stability of recombinant forms, and incomplete mechanistic understanding hinder clinical translation. Overall, α-Klotho stands as a novel biomarker and a promising intervention strategy for mitigating neurodegeneration and promoting healthy brain ageing.},
}

@article {pmid42274866,
year = {2026},
author = {Lefcourt, S and Kim, A and Huang, P and Weiss, C and , and Jones, C},
title = {Multi-scale Radiomic Fingerprint: Quantifying Spatial Changes in Biology.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02041-8},
pmid = {42274866},
issn = {2948-2933},
support = {HT9425-23-1-0032//U.S. Department of Defense/ ; },
abstract = {Traditional radiomic studies build texture matrices using single-voxel increments. However, useful information may emerge when radiomic features are instead evaluated across multiple spatial scales. Moreover, basing these scales on physical units may produce results that are more interpretable to clinicians. We propose a multi-scale radiomic approach that defines texture distances in millimeter-based units to capture a more inclusive range of texture information, promote reproducibility, and improve clinician interpretability. We examine the variance in quantified radiomics across multiple spatial scales and diseases, including venous malformations, gliomas, Alzheimer's disease, brain metastases, and multiple sclerosis. We subsequently generated anisotropic counterparts to originally isotropic datasets to compare their performance in clinical predictive modeling. Finally, we evaluate differences between radiomic features captured at millimeter and voxel units. We discovered that the radiomic features captured at different millimeter scales were almost always statistically different (p < 0.05) across five diseases. Predictive modeling revealed that models trained on radiomics extracted from multiple millimeter scales consistently had a higher mean F1 across folds compared to those built from voxel scales. Roughly 93%, 90%, and 88% of texture metrics were statistically different between millimeter and voxel scales for venous malformations, Alzheimer's, and gliomas, respectively, suggesting that variations in spatial scale may capture differences in biology. We demonstrate that a multi-scale, millimeter-based alternative to fixed-distance voxel-based radiomics captures previously unacquired textural information while remaining clinically interpretable. This approach may have broad implications in all applications of clinical radiomic analysis, including disease diagnosis, monitoring, and treatment evaluation.},
}

@article {pmid42274906,
year = {2026},
author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X},
title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42274906},
issn = {1995-8218},
abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.},
}

@article {pmid42274938,
year = {2026},
author = {Sanjay, and Jaiswal, V and Park, M and Lee, HJ},
title = {Nobiletin Modulates Transcriptomic and Metabolomic Alterations in Aβ42-Induced Primary Rat Astrocytes: Implications for Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42274938},
issn = {1559-1182},
abstract = {Beta-amyloid (Aβ) aggregates interact with glial cells, particularly astrocytes, leading to altered morphology, disrupted homeostasis, and ultimately contributing to neurodegeneration in Alzheimer's disease (AD). Astrocytes, once considered passive support cells, are now recognized as active participants in neuroinflammatory and neurodegenerative cascades. Recent research has highlighted profound transcriptomic and metabolomic disturbances in astrocytes under AD pathology, implicating them as key players in disease progression. Nobiletin (NOB), a polymethoxylated flavonoid abundantly found in citrus peels, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. However, its effects on the integrated transcriptomic and metabolomic landscape of Aβ42-induced primary rat astrocytes (PRAs) have not been fully elucidated. In this study, PRAs were treated with Aβ42 (4 µM) in the presence or absence of NOB (20 and 40 µM), for 50 min and 24 h, followed by high-throughput RNA sequencing and comprehensive metabolomic profiling. NOB significantly modulated several AD-associated molecular pathways, including acetate utilization, chemokine- and cytokine-mediated inflammatory signaling, and cholesterol biosynthesis. Additionally, metabolomic analysis revealed notable alterations in cytidine, guanosine, S-lactoylglutathione, and 2'-deoxycytidine. Integrated analysis of transcriptomic and metabolomic data showed that NOB influenced crucial pathways such as ABC transporters, steroid biosynthesis, and amino acid metabolism, including glycine, serine, and threonine metabolism and alanine, aspartate, and glutamate metabolism. These findings demonstrate that NOB might modulate transcriptional and metabolomic alterations induced by Aβ42 exposure in astrocytes, offering new insights into its multitargeted neuroprotective actions. This study supports the potential of NOB as a promising therapeutic candidate for mitigating astrocyte-mediated neuroinflammation and metabolic dysfunction in AD.},
}

@article {pmid42274941,
year = {2026},
author = {Kamal, F and Dadar, M},
title = {Amyloid and tau pathologies are drivers of white matter damage in aging and Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42274941},
issn = {2509-2723},
abstract = {White matter hyperintensities (WMHs) are increasingly recognized as neuroimaging biomarkers of cerebrovascular pathology in Alzheimer's disease (AD), yet their temporal relationship with amyloid and tau accumulation remains unclear. While previous studies suggest bidirectional associations between WMHs and AD pathology, regional associations between WMHs and AD pathology have yet to be examined. This study investigated the temporal and regional associations between PET measures of amyloid (Aβ) and tau pathology and WMH burden in older adults. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) included 1,241 older adults with Aβ and 636 with tau for cross-sectional analyses. Longitudinal analyses included 613 participants for Aβ change and 980 for WMH change (Aβ group), and 92 for tau change and 342 for WMH change (tau group). Linear models were used to i) assess associations between baseline regional WMH and Aβ and tau pathology, and ii) examine whether baseline pathology in one measure was associated with change in the other measure over two years. Baseline analyses revealed significant bidirectional associations between WMH burden and both Aβ (t = 2.29-3.70, p < .05) and tau pathology (t = 2.01-2.56, p < .05). Longitudinal analyses showed that baseline Aβ levels were associated with future WMH progression in frontal and parietal regions and in anterior and posterior composite regions (t = 2.07-3.09, p < .04), while baseline tau was linked to WMH increases in parietal regions (t = 2.98, p < .03). However, baseline WMH burden was not associated with accumulation of Aβ or tau pathology in any region. These findings suggest that Aβ and tau pathology drive future WMH progression rather than the reverse, with distinct regional patterns for each pathology type.},
}

@article {pmid42275022,
year = {2026},
author = {Cruickshank Campbell, H and Bowden, SC and Saw, G and Cheung, MW},
title = {Differential utility of immediate versus delayed memory measures for the identification of episodic memory impairment: Systematic review and meta-analysis.},
journal = {Psychological assessment},
volume = {},
number = {},
pages = {},
doi = {10.1037/pas0001478},
pmid = {42275022},
issn = {1939-134X},
abstract = {Delayed recall measures are considered sensitive to episodic long-term memory impairment, and longer delays are argued to aid diagnostic accuracy. This meta-analysis examined whether delayed recall provides an advantage in identifying memory impairment relative to very short-delay or "immediate" recall. Eligible studies included a patient sample with suspected or known episodic memory impairment and a healthy control sample, both administered immediate and delayed recall trials. The standardized mean difference (Hedges' g) between patients and controls on immediate and delayed recall was calculated using multivariate random-effects meta-analysis. The meta-analysis included 290 studies, comprising 71,381 controls and 45,054 patients. Delayed recall ranged from 40 s filled delay to 6 weeks. Controls outperformed patients on immediate (g = 1.074, 95% CI [0.973, 1.176]) and delayed recall (g = 1.148, 95% CI [1.034, 1.261]). Patient-control differentiation was greater on delayed compared to immediate recall (g = -0.083, 95% CI [-0.126, -0.041]), though the difference was not clinically meaningful. Delay length (minutes) did not predict the delayed recall effect (β^ < 0.001) or moderate the difference between immediate and delayed recall (β^ = 0.020). Analyzed separately, word list, story, and shape recall measures showed no effect for increasing delay, and word list measures showed no delayed recall advantage. In mild cognitive impairment and Alzheimer's disease, delayed recall offered a small to medium advantage, but this was not present across all measures. All clinical subgroups analyzed showed no effect for increasing delay length. Further research is needed to clarify the utility of delayed recall. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42275077,
year = {2026},
author = {Zhang, Y and Jiang, Y and Edalati, K and Duong, C and Henry, S and Gong, Z and Jayadev, S and Wu, Y and Lee, AY and Lee, CS and Wang, RK},
title = {Quantitative Swept-Source Optical Coherence Tomography Angiography Indicators of Neurovascular Dysfunction in Alzheimer Disease.},
journal = {JAMA ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaophthalmol.2026.1986},
pmid = {42275077},
issn = {2168-6173},
abstract = {IMPORTANCE: Alzheimer disease (AD) affects millions globally, but current diagnostic approaches typically can be costly and invasive. Accessible, noninvasive screening tools for early detection of cognitive impairment are needed.

OBJECTIVE: To determine whether optical coherence tomography angiography (OCTA)-based biomarkers of the retina, choroid, and choriocapillaris differ across cognitive states and whether these biomarkers might discriminate among normal cognition, mild cognitive impairment (MCI), and AD dementia.

This cross-sectional study enrolled 103 individuals referred from the University of Washington Alzheimer's Disease Research Center (ADRC) between April 2022 and September 2024. Participants included 49 cognitively normal controls, 29 with MCI, and 25 with AD dementia per ADRC research-criteria evaluations. All participants underwent swept-source OCTA (SS-OCTA). These data were analyzed from February 2025 to March 2026.

MAIN OUTCOMES AND MEASURES: Cognitive status, retinal vessel skeleton density (VSD), choriocapillaris flow deficit (CCFD), and ganglion cell complex (GCC) thickness.

RESULTS: Among 103 participants (mean [SD] age, 74.8 [6.72] years; 50 [48.5%] female and 53 male [51.5%]), the adjusted mean GCC was thinner in AD dementia (63.31 μm) vs controls (67.93 μm) (difference, -4.62 μm; 95% CI, -8.92 to -0.31 μm; P = .03). Adjusted mean CCFD was lower in MCI (8.12%) than AD dementia (9.07%) (difference, -0.95%; 95% CI, -1.71 to -0.19; P = .01) but higher in AD dementia than controls (8.33%) (difference, 0.74%; 95% CI, 0.02-1.46; P = .04). In multivariable models, VSD (MCI: odds ratio [OR], 0.79; 95% CI, 0.77-0.81; AD dementia: OR, 0.66; 95% CI, 0.65-0.68; P < .001) and CCFD (MCI: OR, 0.66; 95% CI, 0.65-0.67; AD dementia: OR, 1.50; 95% CI, 1.49-1.52; P < .001) were significantly associated with cognitive status, with an area under the curve of 0.72 to 0.87 in a 21-participant test set (10 controls, 6 MCI, 5 AD dementia).

CONCLUSIONS AND RELEVANCE: In a relatively small cohort study, OCTA revealed distinct microvascular signatures across cognitive stages. VSD decreased, and CCFD showed a biphasic pattern across cognitive stages in multivariable models, which may suggest early compensatory choriocapillaris hyperperfusion followed by perfusion failure in AD dementia. These findings suggest OCTA biomarkers may serve as accessible, noninvasive indicators of cognitive neurodegeneration, warranting larger longitudinal validation.},
}

@article {pmid42275263,
year = {2026},
author = {He, A and Wang, Y and Yao, X and Sun, W and Zhao, B and Lai, H and Ma, K and Mao, W and Wang, Y and Song, H},
title = {The shifting burden of Alzheimer's disease and other dementias in China: a systematic analysis and forecasting to 2035 based on the Global Burden of Disease Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-20},
doi = {10.1159/000552995},
pmid = {42275263},
issn = {1423-0208},
abstract = {Introduction Alzheimer's disease and other dementias (ADOD) represent an escalating challenge for global health systems. This study evaluates spatiotemporal trends in ADOD burden from 1990 to 2023 and forecasts incidence trajectories in China through 2035. Methods Using the Global Burden of Disease Study 2023, we analyzed ADOD metrics globally, by Socio-demographic Index (SDI) quintile, and across China. Temporal trends were assessed via estimated annual percentage changes (EAPCs) and compound annual growth rates (CAGRs). Absolute burden shifts were partitioned into population growth, population aging, and epidemiological change using the Dash-Gupta decomposition. Future China-specific incidence was projected using a Bayesian age-period-cohort (BAPC) model. Results Global age-standardized incidence rates (ASIR) exhibited a marginal increase (EAPC 0.06), with progressively higher rates across increasing SDI levels. Decomposition analysis identified population growth as the dominant contributor to rising incidence, peaking in low SDI regions (94.72%), whereas population aging contributed more substantially in high SDI (21.34%). China recorded the fastest ASIR growth (EAPC 0.42), with estimated contributions from both population aging (20.03%) and the epidemiological change (15.71%), particularly within the 60-79 age cohorts. While global mortality and disability-adjusted life-years shifted toward the oldest-old (≥ 80 years), China experienced a disproportionate incidence increase among the younger-old (70-74 years; CAGR 1.10% vs global 0.27%). However, BAPC projections suggest a plateau or decline in incidence among the younger-old in China, contrasted by persistent increases among the oldest-old, with the most pronounced growth observed in the ≥ 95-year cohort. Conclusion China is undergoing a distinct dementia transition characterized by rising younger-old incidence and prolonged disease duration. This pattern suggests a need to combine earlier risk reduction with strengthened integrated long-term care for the oldest-old. The trajectory serves as a reference for rapidly aging middle-to-high SDI nations.},
}

@article {pmid42275473,
year = {2026},
author = {Dougnon, G and Otsuka, T and Nakamura, Y and Sakai, A and Yamanaka, T and Matsui, N and Nakahara, A and Ito, A and Hatano, A and Matsumoto, M and Igarashi, H and Kakita, A and Ueno, M and Matsui, H},
title = {A protective role for APP in nuclear waste clearance via lysosomal exocytosis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {24},
pages = {e2524190123},
doi = {10.1073/pnas.2524190123},
pmid = {42275473},
issn = {1091-6490},
support = {N/A//Takeda Science Foundation (TSF)/ ; JP 23790744; JP 22484842; JP 18955907//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP23gm1710010; JP22gm6110028; JP20dm0107154; JP24wm0625506//Japan Agency for Medical Research and Development (AMED)/ ; N/A//Tokyo Biochemical Research Foundation (TBRF)/ ; N/A//Chugai Foundation for Innovative Drug Discovery Science/ ; N/A//Uehara Memorial Foundation (UMF)/ ; JPMJMS2024//MEXT | JST | Moonshot Research and Development Program (Moonshot)/ ; },
abstract = {Amyloid precursor protein (APP) is widely known for its role in Alzheimer's disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear waste material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.},
}

@article {pmid42275797,
year = {2026},
author = {Lahiri, D and Kathir, S and Punjwani, Z and Liu, A and Pasvanis, S and Seixas-Lima, B and Roncero, CT and Chertkow, H and , },
title = {Application of a clinical scale for predicting Aβ-positivity in a multicentre Canadian dementia cohort: A necessity in the era of amyloid targeting treatment.},
journal = {Journal of the neurological sciences},
volume = {488},
number = {},
pages = {126047},
doi = {10.1016/j.jns.2026.126047},
pmid = {42275797},
issn = {1878-5883},
abstract = {BACKGROUND: Clinical Amyloid positivity Prediction Score (CAPS) is a clinical tool developed on a small Canadian cohort with clinical Alzheimer's Disease (AD) to help predict amyloid-beta (Aβ) positivity. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study is a national Canadian observational study of participants clinically diagnosed with various neurodegenerative disorders, including Alzheimer's syndrome, making it an ideal platform to validate CAPS on an independent but similar cohort of participants.

METHODS: Participants from the COMPASS-ND cohort with Subjective Cognitive Impairment (SCI), Mild Cognitive Impairment (MCI) or dementia due to AD, and a known Aβ status were included. CAPS was assigned to the individuals as follows: cognitive decline of >2 points/year on the Mini-Mental State Examination (MMSE) = 1-point, Neuropsychiatric Inventory Questionnaire (NPI-Q) ≥2 = 2 points, and low Fazekas score (0 or 1) = 1 points. A total CAP score ≥ 2 was considered indicative of Aβ positivity.

RESULTS: Total 86 participants fulfilled the inclusion criteria. Aβ + individuals had higher NPI-Q scores (2 vs 0.5, p = 0.005) and a lower baseline MMSE score (26.5 vs 28.0, p = 0.009). High WMH on brain MRI was reported more frequently in the Aβ- subgroup (50.0% vs 33.8%, p < 0.001). The frequency of people with a CAPS score of ≥2 is significantly higher in the Aβ + subgroup (75% vs 50%, p < 0.001). CAPS demonstrated a reasonable predictive value in this cohort, with 67% accuracy, and 73% sensitivity.

CONCLUSION: This validation study in a larger Canadian cohort showed that CAPS demonstrated reasonable accuracy in distinguishing between Aβ + and Aβ- subgroups.},
}

@article {pmid42276010,
year = {2026},
author = {Mook-Jung, I},
title = {Gut-brain axis in Alzheimer's disease: neural and immune circuits linking peripheral dysbiosis to neurodegeneration.},
journal = {Current opinion in neurobiology},
volume = {99},
number = {},
pages = {103234},
doi = {10.1016/j.conb.2026.103234},
pmid = {42276010},
issn = {1873-6882},
abstract = {Alzheimer's disease (AD) is increasingly conceptualized as a system-level disorder shaped by bidirectional communication between the gut and the brain. The gut-brain axis (GBA) integrates neural, immune, and metabolic signaling pathways that influence central neuroinflammation and proteopathy. Recent mechanistic studies demonstrate that gut dysbiosis alters microbial metabolite profiles, promotes microglial immunometabolic reprogramming, and facilitates amyloid and tau pathology. The vagus nerve functions as a bidirectional conduit enabling neural transmission of inflammatory signals and tau propagation directly. Emerging evidence implicates microbiota-derived extracellular vesicles as mediators of peripheral-to-central immune modulation. Human gut-brain organoid platforms now allow causal interrogation of these interactions in physiologically relevant systems. Together, these advances reframe AD as a disorder of dysregulated neural-immune communication and identify the GBA as a tractable therapeutic target.},
}

@article {pmid42276063,
year = {2026},
author = {Ishikawa, KI and Shiga, T and Hirose, T and Kuzumaki, N and Miyoshi, S and Yamaguchi, A and Tamune, H and Sarkar, AK and Nakai, K and Baba, K and Okabe, S and Hattori, N and Okano, H and Akamatsu, W},
title = {Suppression of ATM kinase signaling accelerates cellular senescence.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102956},
doi = {10.1016/j.stemcr.2026.102956},
pmid = {42276063},
issn = {2213-6711},
abstract = {Cells derived from rejuvenated human induced pluripotent stem cells (hiPSCs) require extended culture periods to achieve functional maturation, and it remains difficult to recapitulate cellular senescence in these cells in vitro. This limitation hinders the accurate and efficient modeling of age-related neurodegenerative diseases. Here, we aimed to establish a simple approach to promote neuronal maturation and improve the efficiency of hiPSC-based disease modeling. Using a small-molecule inhibitor library, we identified an ATM kinase inhibitor, KU60019, that promotes both maturation-associated features and senescence-associated phenotypes in hiPSC-derived neurons and fibroblasts. KU60019 treatment promoted the manifestation of disease-relevant phenotypes in hiPSC models of age-related neurodegenerative diseases. Furthermore, senolytic analyses suggested that KU60019-induced senescent cells depend on pro-survival pathways, including HSP90-associated signaling. These findings suggest that KU60019 provides a simple and useful tool for accelerating phenotypic recapitulation in hiPSC models of age-related neurodegenerative diseases.},
}

@article {pmid42276104,
year = {2026},
author = {Kumar, H and Agarwal, R},
title = {PAM-MoE-AD: A plane-aware multi-stage mixture-of-experts framework for Alzheimer's disease classification from sMRI.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae7c0a},
pmid = {42276104},
issn = {2057-1976},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder for which accurate and early diagnosis remains difficult. Structural magnetic resonance imaging is widely used to assess disease-related brain changes, but automated classification methods are frequently affected by class imbalance, inter-subject anatomical variability, and orientation-dependent structural patterns. This study addresses three recognised limitations of existing automated systems, namely orientation-blind fusion, fixed expert weighting, and the absence of subject-adaptive plane relevance estimation, by proposing a plane-aware multi-stage mixture-of-experts framework, designated PAM-MoE-AD, for T1-weighted structural MRI. Axial, coronal, and sagittal 2.5D slice stacks were constructed through a content-aware slice-selection procedure, and each plane was modelled with an independent Swin Transformer V2 encoder. Training proceeded through three sequential stages comprising plane-specific representation learning, supervised refinement of plane-specific experts, and mixture-of-experts fusion governed by a learned gating network. Experiments were conducted on subject-level data splits derived from the Alzheimer's Disease Neuroimaging Initiative. Under five-fold subject-level cross-validation the framework achieved a mean accuracy of 97.21% and a mean balanced accuracy of 93.14%, with 95% confidence intervals from 96.71% to 97.71% and from 92.47% to 93.81% respectively. External evaluation on a 124-scan AIBL subset, performed without fine-tuning, retained an accuracy of 93.52% and a balanced accuracy of 91.31%. The framework outperformed three same-split baselines comprising a 3D ResNet-18, a 3D Swin Transformer, and a multi-plane CNN. Quantitative Grad-CAM analysis grounded model decisions in established atrophic regions including the hippocampus and entorhinal cortex.},
}

@article {pmid42276197,
year = {2026},
author = {Nadeem, RI and Sayed, RH and Elbaz, EM and Abdel Rahman, AAS and Saeed, MM},
title = {Canagliflozin attenuates cognitive deficits in the streptozotocin-induced mouse model of sporadic Alzheimer's disease via modulating PINK1/Parkin signaling pathway and miR-34a expression.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111781},
doi = {10.1016/j.pnpbp.2026.111781},
pmid = {42276197},
issn = {1878-4216},
abstract = {Mitochondrial deficits and impairments in mitophagy, a specialized form of mitochondrial degradation by autophagy, contribute to Alzheimer's disease (AD). Furthermore, dysregulated miR-34a was reported to contribute to AD progression. Sodium-glucose cotransporter-2 inhibitors are evolving as potential therapeutic agents in AD. To date, no data are available to elucidate the role of gliflozins in the mitophagy cascade in AD. Accordingly, this work was designed to investigate the central impact of canagliflozin (Cana) on PINK1/Parkin signaling in mice with streptozotocin (STZ)-induced cognitive impairment. Animals were arbitrarily allocated into 4 groups; the first received saline, while the other groups were injected intracerebroventricularly with STZ (3 mg/kg) once and then a daily oral administration of saline in the second group, Cana (30 mg/kg) in the third group and Cana together with the commonly used mitophagy/autophagy blocker 3-methyladenine (3-MA, 30 mg/kg/day, i.p.) in the fourth group, for 21 days. Cana alleviated cognitive impairments in the novel object recognition and Morris water maze tests, while also restoring the histological architecture. Cana induced a marked reduction in the amyloid beta deposition and phosphorylated tau protein. The neuroprotective role of Cana was manifested by modulation of mitophagy signaling through amplifying PINK1/Parkin protein expression, modifying the autophagic markers Beclin1 and LC3 II expression, and down-regulating miR-34a. Interestingly, co-administration of 3-MA hindered Cana's actions. Therefore, this study presents Cana as a potential therapeutic candidate for AD, possibly via modulation of mitophagy signaling.},
}

@article {pmid42276200,
year = {2026},
author = {Alruwaili, NS and Al-Kuraishy, HM and Al-Gareeb, AI and Shokr, MM and Bogari, NM and Alhelfawi, S and Alruwaili, M and Batiha, GE},
title = {Beyond categorical boundaries: Common molecular and cellular pathways in autism spectrum disorder and schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111774},
doi = {10.1016/j.pnpbp.2026.111774},
pmid = {42276200},
issn = {1878-4216},
abstract = {Historically, ASD and schizophrenia have been classified as two distinct disorders, one being a neurodevelopmental disorder and the other a psychotic disorder. Recent studies, however, suggest that there may be substantial overlap between these disorders. Here, we will discuss some of the biological mechanisms involved in the development of these diseases that show similarities. These include dysregulation of the dopaminergic, serotonergic, glutamatergic, GABAergic, and acetylcholinergic systems; changes in BDNF signaling; histamine dysregulation; microglial activation; neuroinflammation; complement-mediated synapse elimination; gut-brain axis signaling; and endocannabinoid system dysfunction. It is important to note that the aforementioned biological mechanisms are present in several CNS disorders, such as major depressive disorder, Alzheimer's disease, and multiple sclerosis. While it is true that other CNS disorders share the same biological mechanisms as ASD and schizophrenia, the similarity between these disorders stands out for a particular reason. First, the biological mechanisms present in ASD and schizophrenia are significantly similar; second, their heritability is highly consistent; third, they have similar developmental trajectories; fourth, they exhibit similar circuit-level pathology; fifth, they share bidirectional epidemiological risks; and sixth, they follow a neurodevelopmental continuum. Recognizing this overlap has potential implications for early detection, biomarker development, and transdiagnostic treatment strategies, including repurposing medications such as memantine, α7-nicotinic agonists, and anti-inflammatory agents. However, longitudinal studies are needed to determine whether early targeting of shared pathways modifies long-term psychosis risk in ASD.},
}

@article {pmid42276260,
year = {2026},
author = {Cho, S and Gabr, MT},
title = {Identification of a novel aβ-overlapping binding site on the TREM2 Ectodomain engaged by the small-molecule agonist VG-3927.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130712},
doi = {10.1016/j.bmcl.2026.130712},
pmid = {42276260},
issn = {1464-3405},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first small-molecule TREM2 agonist to enter clinical development, has been proposed to act as a transmembrane molecular glue and positive allosteric modulator (PAM), but whether it also engages the TREM2 ectodomain has not been systematically explored. Here, we used DiffDock-L, a deep learning-based blind docking algorithm, to map potential VG-3927 binding sites across the TREM2 structure and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed VG-3927 interaction with TREM2 under optimized polyethylene glycol 400 (PEG-400) buffer conditions and showed that Aβ1-42 binds directly to TREM2. In the presence of Aβ, the VG-3927 MST signal was reduced, supporting interference at an overlapping ectodomain binding surface. Consistently, Aβ induced a rightward shift in the VG-3927 dose-response curve in a Jurkat TREM2-DAP12 Nuclear Factor of Activated T Cells (NFAT) reporter assay and attenuated VG-3927-induced phospho-spleen tyrosine kinase (p-SYK) signaling. Together, these findings support the presence of a previously unrecognized ectodomain interaction mode for VG-3927 and suggest that amyloid-associated ligand occupancy may modulate TREM2 agonist activity in the AD microenvironment.},
}

@article {pmid42276279,
year = {2026},
author = {Gurung, N and Choi, DY and Park, PH},
title = {Naringenin as a Multi-Target Neuroprotective Agent in Neurodegenerative Diseases.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106203},
doi = {10.1016/j.neuint.2026.106203},
pmid = {42276279},
issn = {1872-9754},
abstract = {Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) are characterized by progressive neuronal loss driven by complex and multifactorial pathogenic mechanisms. Naringenin (NAR), a citrus-derived flavanone, has attracted considerable interest as a neuroprotective molecule due to its pleiotropic pharmacological activities such as antioxidant, anti-inflammatory and ability to modulate multiple cellular targets. This review provides a comprehensive overview of NAR pharmacokinetic profile, mechanistic actions, and therapeutic potential across major ND. We highlight how NAR's multi-target effects-including redox homeostasis maintenance, suppression of neuroinflammation, protein aggregation inhibition, and modulation of signaling pathways-contribute to neuroprotection in various experimental models of AD, PD, HD, ALS, and MS. Preclinical studies demonstrate that NAR can ameliorate cognitive and motor deficits in toxin and transgenic models of neurodegeneration, attenuate pathological hallmarks such as amyloid-beta toxicity, dopaminergic neuronal loss, and neuroinflammation, and induce cytoprotective pathways including Nrf2-mediated antioxidant response and autophagy. However, NAR's clinical translation is challenged by poor bioavailability; thus, novel delivery systems are being explored to enhance brain uptake. NAR emerges as a promising multi-functional neuroprotective agent that can simultaneously target diverse pathogenic processes in ND. Further research including advanced formulation development and well-designed clinical trials is warranted to fully establish NAR's therapeutic efficacy and safety in humans.},
}