@article {pmid41580393,
year = {2026},
author = {Feiten, AF and Dahm, K and Schlepckow, K and van Lengerich, B and Suh, JH and Reifschneider, A and Wefers, B and Bartos, LM and Wind-Mark, K and de Weerd, L and Ulas, T and De-Domenico, E and Grundschöttel, P and Paulusch, S and Tast, B and Honda, T and Müller, SA and Becker, M and Khalin, I and Ricci, A and Liesz, A and Brunner, B and Krenner, C and Buschmann, K and Nuscher, B and Spieth, L and Junker, N and Berghoff, SA and Davis, SS and Neher, JJ and Wurst, W and Plesnila, N and Lewcock, JW and Simons, M and Lichtenthaler, SF and Di Paolo, G and Brendel, M and Capell, A and Monroe, KM and Schultze, JL and Haass, C},
title = {TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-68706-8},
pmid = {41580393},
issn = {2041-1723},
support = {HA1737/16-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.},
}

@article {pmid41579987,
year = {2026},
author = {Jeon, YN and Baek, JS},
title = {TPGS-coated zein nanoparticles encapsulating Haematococcus pluvialis extract for Alzheimer's disease: An in vitro evaluation towards brain-targeted delivery.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150378},
doi = {10.1016/j.ijbiomac.2026.150378},
pmid = {41579987},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) aggregation and limited treatment efficacy due to the restrictive nature of the blood-brain barrier (BBB). To address this, we developed d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-coated Zein nanoparticles (Hp-Zein-TPGS NPs) encapsulating Haematococcus pluvialis (Hp) extract as a brain-targeted drug delivery system. Hp-Zein-TPGS NPs exhibited high physical stability over 14 days, sustained astaxanthin release, and potent antioxidant activity. The NPs also demonstrated excellent biocompatibility, showing minimal cytotoxicity in both bEnd.3 and SH-SY5Y cells, along with enhanced cellular uptake in vitro. Based on the reported effects of TPGS on P-glycoprotein (P-gp) inhibition and membrane fluidity, a delivery strategy was designed to facilitate BBB transport. In an in vitro BBB model, Hp-Zein-TPGS NPs exhibited increased transport, and Rhodamine 123 (Rh123) accumulation analysis indicated properties associated with the regulation of P-gp mediated efflux. In addition, Thioflavin T (ThT) fluorescence and morphological analyses confirmed that Hp-Zein-TPGS NPs effectively inhibited Aβ1-42 aggregation and fibril formation, while WST and Annexin V-FITC/PI assays demonstrated that Hp-Zein-TPGS NPs significantly attenuated Aβ1-42-induced neuronal toxicity, indicating their neuroprotective effects. Taken together, these findings suggest that Hp-Zein-TPGS NPs possess favorable stability, biocompatibility, BBB transport potential, and neuroprotective effects, highlighting their promise as a nanocarrier system for brain-targeted therapeutic delivery in AD.},
}

@article {pmid41579901,
year = {2026},
author = {Tariot, PN and Lopera, FS and Ríos-Romenets, S and Sink, KM and Giraldo-Chica, M and Acosta-Baena, N and Villegas, G and Espinosa, A and Castaño, ML and Muñoz, C and Ospina, P and Bocanegra, Y and Tirado, V and Henao, E and Cardona, E and Luna, E and Lopez, H and Sánchez, G and Collazos, MM and Alvarez, S and Aguillón, D and Hu, N and Clayton, D and Bittner, T and Schneider, A and Dolton, M and Poon, V and Nguyen, J and Thomas, RG and Schneider, LS and Chen, K and Su, Y and Alexander, RC and Quiroz, YT and Cai, Y and Xu, YR and Ostaszewski, B and Selkoe, DJ and Ashton, NJ and Denkinger, MN and Jakimovich, LJ and Doody, RS and Langbaum, JB and Reiman, EM},
title = {Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1[Glu280Ala] mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial.},
journal = {The Lancet. Neurology},
volume = {25},
number = {2},
pages = {147-159},
doi = {10.1016/S1474-4422(25)00426-0},
pmid = {41579901},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy ; Double-Blind Method ; Male ; *Presenilin-1/genetics ; Female ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Colombia ; Adult ; Mutation/genetics ; Heterozygote ; Treatment Outcome ; },
abstract = {BACKGROUND: To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1[Glu280Ala] mutation at high imminent risk of developing symptoms due to Alzheimer's disease.

METHODS: This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1[Glu280Ala] autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed.

FINDINGS: 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred.

INTERPRETATION: Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials.

FUNDING: US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.},
}

Humans
*Alzheimer Disease/genetics/drug therapy
Double-Blind Method
Male
*Presenilin-1/genetics
Female
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
Colombia
Adult
Mutation/genetics
Heterozygote
Treatment Outcome

@article {pmid41576501,
year = {2026},
author = {Jayaswamy, PK and Ambrish, T and Sangamesh, VC and Kabekkodu, SP and Kellarai, A and Shetty, J and Shetty, P},
title = {EGFR-Annexin A2 signaling-mediated tauopathy in amyloid-β and aluminum chloride-induced Alzheimer's disease and its modulation by the HDAC inhibitor butyrate.},
journal = {Ecotoxicology and environmental safety},
volume = {310},
number = {},
pages = {119775},
doi = {10.1016/j.ecoenv.2026.119775},
pmid = {41576501},
issn = {1090-2414},
abstract = {Alzheimer's disease (AD) is typified by amyloid-β (Aβ) accumulation and tauopathy, culminating in synaptic destabilization, dendritic atrophy, and widespread neurodegeneration. Epidermal growth factor receptor (EGFR), prominently expressed during neurodevelopment, is largely quiescent in adulthood but undergoes pathological reactivation in AD, with its mechanistic contribution remaining elusive. Here, we delineate the EGFR-Annexin A2 (AnxA2) signaling nexus as a pivotal mediator of tau hyperphosphorylation in Aβ1-42-challenged SH-SY5Y and PC12 neuronal cultures and in aluminum chloride (AlCl3)/D-galactose (D-gal)-induced AD rat models. In vitro, Aβ1-42 orchestrated synergistic EGFR-AnxA2 activation, triggering site-specific tau phosphorylation (Thr231/Ser396), synaptic protein depletion, apoptotic cascades, neuroinflammatory signaling, and plasminogen activator inhibitor-1 (PAI-1)-driven fibrinolytic deficits. In vivo, AlCl3/D-gal rats displayed hippocampal EGFR-AnxA2 upregulation, region-specific tauopathy, cognitive impairments in Open Field and Novel Object Recognition paradigms, oxidative perturbations, and elevated TNF-α. Butyrate intervention abrogated EGFR-AnxA2 hyperactivity, attenuated tau pathology, restored PAI-1/tissue plasminogen activator homeostasis, and mitigated oxidative stress and neuroinflammation. Moreover, butyrate preserved synaptic and dendritic architecture, modulated apoptotic effectors by upregulating Bcl-2 and suppressing Bad, and enhanced neuronal viability. In vivo pre-and post-treatment paradigms improved behavioral and molecular outcomes, with prophylactic administration exhibiting superior efficacy. Collectively, these findings establish EGFR-AnxA2 as a central driver of tauopathy and identify prophylactic butyrate as a mechanistically grounded, diet-derived neuroprotective strategy capable of attenuating tau hyperphosphorylation, synaptic loss, and neuroinflammation in AD.},
}

@article {pmid41575675,
year = {2026},
author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M},
title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {42},
pmid = {41575675},
issn = {1573-6768},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/therapy/microbiology ; *Aging/physiology ; Animals ; Probiotics/therapeutic use ; },
abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Dysbiosis/therapy/microbiology
*Aging/physiology
Animals
Probiotics/therapeutic use

@article {pmid41575410,
year = {2026},
author = {Neth, BJ and Graff-Radford, J and Cogswell, PM and Johnson, DR and Botha, H and McCarter, SJ and Jones, DT and Conkins, MM and Hardin, DB and Spence, JJ and Rhegness, CL and Allen, LA and Coburn, RP and Pounders, JD and Burkett, BJ and Pillai, JJ and Day, GS and Graff-Radford, NR and Lachner, C and Messina, SA and Jain, MK and Stricker, NH and Machulda, MM and Fields, JA and Boots, EA and Aduen, PA and Barnard, LR and Remold, MA and Anderlik, AM and Asleson, KM and Martin, LL and Klaassen, JA and Larsen, JJ and Algeciras-Schimnich, A and Bornhorst, JA and Rumilla, AM and Jack, CR and Boeve, BF and Knopman, DS and Petersen, RC and Ramanan, VK},
title = {Establishing an Alzheimer Disease Therapeutics Clinic: Experience From a Year of Evaluations.},
journal = {Mayo Clinic proceedings},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.mayocp.2025.09.019},
pmid = {41575410},
issn = {1942-5546},
abstract = {OBJECTIVE: To describe the establishment and initial experience of a multidisciplinary Alzheimer disease treatment clinic (ADTC), focusing on the evaluation of eligibility for novel disease-modifying therapies, as well as the treatment and monitoring of qualifying patients.

PATIENTS AND METHODS: We completed a retrospective review of cases seen through the Mayo Clinic ADTC between October 2, 2023, and December 31, 2024. Typical evaluations occurred over 4 to 5 days and included multimodal testing, office visits, and a weekly case conference modeled on tumor board meetings.

RESULTS: Patients evaluated in the ADTC (N=232) ranged from 52 to 85 years of age (mean age, 71.2 years). Most patients had mild cognitive impairment (128 of 232 [55%]) or mild dementia (72 of 232 [31%]) syndromes. Overall, 121 patients (52%) were judged eligible for antiamyloid therapy. Eligibility rates were higher among internal (from our institution) referrals compared with external referrals (63% [146 of 232] vs 37% [86 of 232). Reasons for treatment ineligibility were typically multiple but commonly included magnetic resonance imaging features, too severe cognitive/functional impairment, and general health conditions believed likely to increase therapeutic risks. In some cases, the ADTC evaluation uniquely identified treatment risk factors, such as cerebral amyloid angiopathy, that had not been previously discussed with patients. Through shared decision making, approximately 30% of eligible patients (25 of 81) ultimately deferred antiamyloid therapy. In addition, approximately 10% of patients evaluated in the ADTC were amyloid-negative by positron emission tomography, suggesting non-Alzheimer disease diagnoses for their presentations.

CONCLUSION: The ADTC facilitated systematic implementation of antiamyloid therapies for early Alzheimer disease and provided a scalable foundation for integrating future approved treatment options.},
}

@article {pmid41574617,
year = {2026},
author = {Sharma, P and Goyal, R},
title = {Mitigation of Circadian Disruption-Induced Amyloid Pathology, Neuroinflammation, and Cognitive Disability in C57BL/6J Mice Using Estradiol.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00650},
pmid = {41574617},
issn = {1948-7193},
abstract = {Circadian rhythms (CRs) are intrinsic 24 h cycles that regulate critical physiological processes, including sleep-wake behavior, hormonal signaling, and cognition. Disruption of CRs, often caused by chronic aberrant light exposure, has been linked to neurodegenerative diseases such as Alzheimer's disease (AD), through altered expression of core clock genes and neurotransmitter imbalances. Estrogen is a known neuromodulator that influences both circadian timing and cognitive function, yet the mechanistic interplay between estrogen and circadian dysregulation in neurodegeneration remains underexplored. In this study, we investigated whether estradiol could mitigate neuropathological and circadian disturbances induced by chronic, constant light (LL) exposure in female C57BL/6J mice. Mice were exposed to LL for 6 or 10 weeks (LL6, LL10) to model progressive CR disruption. LL10 significantly delayed locomotor rhythms (p < 0.0001), elevated hippocampal amyloid-β (Aβ) levels (p = 0.0018), and reduced SCN GABA and glutamate levels (p < 0.01), compared to LL6 and light-dark (LD) controls. Both LL6 and LL10 also showed decreased hippocampal nitric oxide and glutathione levels (p < 0.05), indicating oxidative stress. Estradiol treatment (1.5 or 3 μg/kg) restored activity rhythms, reduced Aβ accumulation (p = 0.0019), and normalized SCN neurotransmitter levels (GABA; p = 0.0046; glutamate: p = 0.0003). These effects were abrogated by tamoxifen, suggesting estrogen receptor-mediated signaling. Histological analysis further showed that estradiol attenuated hippocampal inflammation and neuronal damage in LL10-exposed animals. These results demonstrate that estrogen protects against circadian disruption-induced neuropathology and supports its potential as a therapeutic agent in mitigating cognitive decline via ER-dependent pathways.},
}

@article {pmid41573517,
year = {2025},
author = {Ham, HJ and Park, SS and Lee, YS and Kim, TH and Son, DJ and Kim, JH and Lim, KH and Park, H and Lee, HJ and Yun, J and Han, SB and Choi, MK and Hong, JT},
title = {CHI3L1 monoclonal antibody therapy mitigates cognitive impairment by inhibiting neuroinflammation through ERK and NF-κB pathway in Tg2576 mice.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1728279},
pmid = {41573517},
issn = {1662-5099},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is neurodegenerative disorder characterized by chronic inflammation in the brain. Chitinase-3-like 1 (CHI3L1), a secreted glycoprotein that is upregulated in a variety of diseases with chronic inflammation, represents a promising target for AD. Here, we studied the inhibitory effect of a novel CHI3L1 monoclonal antibody (H1) on memory impairment and neuroinflammation in Tg2576 transgenic mice.

METHODS AND RESULTS: H1 was shown to cross the blood-brain barrier selectively, as confirmed by fluorescence imaging. Tg2576 mice were administered H1 (2 mg/kg, i.v., weekly for 1 month), and cognitive functions were assessed through behavioral tests. H1 treatment alleviated memory impairment and reduced amyloid deposition and neuroinflammation both in Tg2576 mice and Aβ-induced BV-2 microglial cells. Mechanistically, H1 inhibited the ERK and NF-κB signaling pathways and suppressed M1 microglial marker expression. Global proteomic analysis and gene expression profiling in BV-2 cells and Tg2576 mouse brains revealed a strong association between CHI3L1 and HAX1 expression. H1 therapy significantly reduced HAX1 levels in both in vivo and in vitro models. Moreover, HAX1 induction by Aβ or CHI3L1 was blocked by an NF-κB inhibitor.

DISCUSSION: These findings suggest that CHI3L1 monoclonal antibody therapy may attenuate cognitive decline in AD by modulating neuroinflamma.},
}

@article {pmid41573383,
year = {2025},
author = {Liu, B and Chen, C and Cai, P and Zhang, J and Yang, L and Chen, X and Ma, X and Jiang, X and Zhang, A and Song, L and Jiang, L},
title = {The alterations in brain network functional gradients and dynamic functional connectivity in Alzheimer's disease: a resting-state fMRI study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1716076},
pmid = {41573383},
issn = {1663-4365},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by progressive cognitive decline. Extensive evidence from dynamic functional connectivity (dFC) studies has demonstrated unstable functional states, reduced network flexibility, and impaired transitions between large-scale neurocognitive networks across the AD continuum. However, how these temporal abnormalities are embedded within the hierarchical spatial organization of brain networks, as captured by functional gradients (FG), and whether combined FG-dFC metrics can provide mechanistically interpretable and potentially sensitive imaging biomarkers, remain to be elucidated.

METHODS: This study enrolled 46 AD patients who were diagnosed according to the Amyloid/Tau/Neurodegeneration (ATN) biological diagnostic framework and 37 age- and sex-matched healthy controls (HC). All participants underwent resting-state fMRI. Functional gradients were derived using connectivity similarity matrices and diffusion embedding (aligned and standardized), while dFC was estimated with a sliding window approach and clustered into four recurrent states. Group differences were assessed with two-sample t-tests with Gaussian Random Field (GRF) correction. Correlation analyses included ATN biomarkers and cognitive scores. A linear support vector machine (SVM) with leave-one-out cross-validation evaluated classification performance based on significant FG features.

RESULTS: Compared to the healthy controls, AD patients exhibited widespread FG alterations between regions of the Default Mode Network (DMN) and the Sensorimotor Network (SMN). In the first gradient DMN, the left precuneus showed reduced gradient scores, whereas the right medial superior frontal gyrus and bilateral angular gyri were increased. In the first gradient of the SMN, the right supplementary motor area increased while bilateral superior temporal gyri decreased. Second-gradient reductions were confined to two regions: the left postcentral gyrus (SMN) and left middle occipital gyrus (visual network, VIS). The right medial superior frontal gyrus first-gradient score correlated negatively with T-Tau (r = -0.50, P = 0.006) and age (r = -0.36, P = 0.02); the right angular gyrus correlated negatively with age (r = -0.29, P = 0.04); the left precuneus correlated positively with age (r = 0.38, P = 0.009). dFC revealed four recurrent states (27.59, 17.67, 28.27, 26.47% of total occurrences). Relative to HC, AD showed higher FT and MDT in states 1-2 and lower scores in state 3, with NT unchanged, alongside state-dependent bidirectional connectivity changes (fronto-insular-sensorimotor increases; DMN-temporal and visuo-auditory decreases). The SVM achieved an AUC of 0.776, sensitivity 78.26%, specificity 67.57%, and accuracy 73.49%, with the right superior temporal gyrus within SMN first-gradient contributing most.

CONCLUSION: AD is characterized by macro-scale hierarchical disorganization centered on the principal functional gradient, accompanied by reduced cross-state flexibility and state-dependent connectivity abnormalities. The combined functional gradient-dynamic functional connectivity (FG-dFC) analysis provides complementary spatiotemporal insights and reveals imaging features associated with T-Tau levels and age, offering new perspectives on the neuropathological mechanisms of AD and potential imaging biomarkers. Moreover, these network topology and dynamic connectivity metrics may prove useful for monitoring disease progression, evaluating treatment effects, and stratifying patients in future clinical and interventional studies.},
}

@article {pmid41573059,
year = {2025},
author = {Ayla, S and Saygi, HI and Sahin, M and Ciftkaya, E and Kilic, A and Pence, S and Bahadori, F and Dolanbay, EG and Elibol, B},
title = {Urtica dioica can regulate autophagy pathway in the rat hippocampal tissue after STZ-induced neurodegeneration.},
journal = {Northern clinics of Istanbul},
volume = {12},
number = {5},
pages = {531-539},
pmid = {41573059},
issn = {2536-4553},
abstract = {OBJECTIVE: Autophagy plays a crucial role in neuroprotection by helping to clear toxic substances, like misfolded proteins. In neurodegeneration, autophagy is impaired leading to the accumulation of harmful proteins that disrupt neuronal function, promote inflammation, and contribute to the degeneration of brain cells. Therefore, because of its anti-inflammatory and anti-oxidative actions, the effects of Urtica dioica (UD) on the proteins of autophagy signaling pathways was studied in the hippocampus of rats with streptozotocin-(STZ) induced neurodegeneration.

METHODS: Neurodegeneration model of rats was induced by intracerebroventricular injection of STZ (3 mg/kg) to observe both cognitive deficits and autophagic dysfunction. Then, the rats in the treatment group were consumed UD at the dose of 50 mg/kg/day for 4 weeks. At the end of 4 weeks, passive avoidance test was applied for cognitive functions and hippocampal tissue of rats were investigated to determine the changes in the proteins related to autophagy by western blotting and immunofluoresecence.

RESULTS: UD treatment slightly attenuated the STZ-induced memory deficiencies in the rats. In addition, an increase in the autophagy was noted by increasing the expression of Beclin, ATG5, and LC3β proteins in the STZ-UD group compared to the STZ group.

CONCLUSION: In summary, UD may be a candidate molecule as a therapeutic strategy to protect neurons in neurodegeneration through increasing autophagy to reduce toxic protein accumulation.},
}

@article {pmid41572310,
year = {2026},
author = {Kashem, M and Haldenby, O and Ahmad, JF and Muhammad, AA and Mostert, CM and Ali, S},
title = {Are diagnostic technologies for alzheimer's disease and dementia cost-effective? A systematic review of economic evaluations.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01933-1},
pmid = {41572310},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia pose a significant clinical and economic burden globally. Early diagnosis and intervention can potentially delay disease progression. Current diagnostic guidelines recommend considering imaging and biomarker analysis in conjunction with clinical evaluation. Given limited healthcare resources, evidence on the cost-effectiveness of diagnostic technologies is critical to guide allocation of resources.

OBJECTIVE: To systematically review the economic evaluation studies of neuroimaging, biomarkers, and other diagnostic or screening strategies for diagnosing and/or tracking the progression of AD or dementia.

METHODS: A comprehensive search was conducted across Medline, Embase, PsycINFO, CINAHL and EconLit, and to identify relevant studies, with no restrictions on country, language, or publication period. Quality of the studies was evaluated using the Consensus on Health Economic Criteria-Extended (CHEC-Extended) checklist.

RESULTS: Out of 6,804 records, 21 studies met the eligibility criteria. These included evaluations of neuroimaging technologies such as Positron Emission Tomography, Single Photon Emission Computed Tomography, Computed Tomography, and Magnetic Resonance Imaging (n = 10), cerebrospinal fluid and blood biomarkers (n = 7), and alternative diagnostic strategies including screening programs, machine learning-based models, and multidisciplinary care approaches (n = 4). Among the studies evaluating imaging technologies, most (n = 6) did not find them to be cost-effective. In contrast, CSF and blood biomarker studies found these technologies to be cost-effective, with some variability in results. Methodological quality score ranged between 15% and 95%, indicating a mix of low- to high-quality studies. Due to heterogeneity in study designs and reported outcomes, direct comparisons were not feasible.

CONCLUSIONS: While many studies were of high quality, heterogeneity in study objectives, design, and outcomes restricted evidence synthesis. Future research should ensure methodological consistency, transparent cost reporting, and integration of new treatment frameworks to improve the policy relevance and reliability of economic evidence for AD diagnostics.},
}

@article {pmid41571954,
year = {2026},
author = {Ahn, NH and Hong, SC and Hong, CR and Lee, EH and Lee, JH and Choi, SB and Jung, J and Kim, Y and Kim, JS and Park, K and Kim, YK and Kim, Y and Yang, SH},
title = {Fucoxanthin Extracted from the Microalgae Phaeodactylum tricornutum Ameliorates Alzheimer's Pathologies with the Reduction of Aβ-Induced NLRP3 Inflammasome Activation in APP/PS1 Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {385},
pmid = {41571954},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Xanthophylls/pharmacology/therapeutic use/isolation & purification ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Inflammasomes/metabolism ; Mice ; *Microalgae/chemistry ; Microglia/drug effects/metabolism ; Mice, Inbred C57BL ; Astrocytes/drug effects/metabolism/pathology ; tau Proteins/metabolism ; *Presenilin-1/metabolism ; Male ; *Amyloid beta-Protein Precursor/metabolism ; Brain/pathology/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, one of the most common types of dementia, accompanying severe learning and memory dysfunctions. In AD brains, the misfolded aggregation and deposits of amyloid-β (Aβ) and tau are frequently observed before the cognitive symptom onset; thus, trials for alleviation of these lesions are considered commensurate strategies with AD treatment. Additionally, increasing evidence suggests that misfolded and aggregated proteins induce the activation of microglia and astrocytes by the release of the inflammatory mediators via the activation of the inflammatory signaling cascade, which consequently contributes to AD pathogenesis. Here, we investigated the therapeutic potential of fucoxanthin, a compound derived from the microalgae Phaeodactylum tricornutum, in mitigating AD pathologies. Fucoxanthin was shown to inhibit the aggregation of Aβ and tau, converting their aggregates to monomeric forms. In the brain of APP/PS1 transgenic mice, fucoxanthin administration significantly reduced the levels of Aβ plaques and hyperphosphorylated tau and further ameliorated cognitive impairments by inhibiting the activation of microglia and astrocytes. Notably, fucoxanthin effectively regulated Aβ-induced NLRP3 inflammasome activation in astrocytes, reducing neuroinflammation associated with AD. Thus, our findings showing the multifaceted therapeutic mode of action of fucoxanthin against AD provide that fucoxanthin would have promising roles in the strategies of AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Xanthophylls/pharmacology/therapeutic use/isolation & purification
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Inflammasomes/metabolism
Mice
*Microalgae/chemistry
Microglia/drug effects/metabolism
Mice, Inbred C57BL
Astrocytes/drug effects/metabolism/pathology
tau Proteins/metabolism
*Presenilin-1/metabolism
Male
*Amyloid beta-Protein Precursor/metabolism
Brain/pathology/drug effects/metabolism

@article {pmid41571775,
year = {2026},
author = {Sathish, R and Muthukumar, R and Kumaran, KM and Murugan, SP},
title = {Intelligent decision-making systems for early detection of alzheimer's disease using wearable technologies and deep learning.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-36895-3},
pmid = {41571775},
issn = {2045-2322},
abstract = {Intelligent decision-making systems using wearable electronics and deep learning (DL) might identify Alzheimer's disease (AD) early for treatment. These technologies can continually monitor vital signs and behavioral characteristics to identify early cognitive deterioration in patients. Clinical examinations, neuroimaging, and cognitive testing are the main ways to identify Alzheimer's, but they are difficult, expensive, and frequently miss the illness early on. Such approaches lack the sensitivity and real-time monitoring essential for early intervention. Through wearable technology and sophisticated DL approaches, Early Detection using Deep Learning Algorithm (ED-DLA) tackles these constraints. In real time, wearable sensors capture data on heart rate, sleep habits, and physical activity. DL algorithms evaluate this data to identify early Alzheimer's. Continuous and non-invasive monitoring improves detection sensitivity and accuracy. To evaluate sequential wearable device data, the suggested technique uses an RNN-based image classification model. Temporal patterns are essential for understanding AD development, and the RNN does so well. The slight changes in cognitive and physical activities may indicate early-stage dementia. The suggested AD diagnosis and management system improves early detection accuracy and real-time monitoring, making it more dependable and scalable.},
}

@article {pmid41571077,
year = {2026},
author = {Abdel-Aal, RA and Meligy, FY and Kamel, G and Ashry, IEM},
title = {Cognitive Enhancing Effect of Canagliflozin in Aluminum-Induced Rat Model of Alzheimer's-Like Disease: Cross Talk Between Amyloid-Β and BDNF/GSK-3β Signaling.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178581},
doi = {10.1016/j.ejphar.2026.178581},
pmid = {41571077},
issn = {1879-0712},
abstract = {The strong relationship between Alzheimer's Disease (AD) and diabetes mellitus (DM) is described by the term "type 3 diabetes". Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is an antidiabetic agent under investigation as a potential new treatment for AD due to its acetylcholinesterase (AChE) inhibitory properties. We aimed to examine the effect of CAN on the efficacy of the anti-acetylcholinesterase, rivastigmine (RIV), against aluminum chloride (AlCl3)-induced AD rat model. The efficacy of CAN, RIV, and CAN plus RIV against abnormal behavioral, biochemical, and histological changes in AlCl3-induced AD in rats was examined. Three weeks of treatment with CAN partially reversed the AlCl3-induced behavioral dysfunction, along with significantly elevated levels of brain-derived neurotrophic factor (BDNF) and decreased levels of AChE, glycogen synthase kinase-3β (GSK3β), amyloid beta (Aβ) deposits, and inducible nitric oxide synthase (iNOS) expression. Histological examination revealed that CAN administration significantly increased RIV's efficacy by protecting neurons in rats' hippocampal tissues from AlCl3-induced damage. Interestingly, the RIV+CAN combination exhibited a more pronounced inhibitory effect on Aβ plaque formation, iNOS activity, and neurodegeneration compared to either RIV or CAN alone. However, this combination did not show any additive benefits for behavior, AChE activity, BDNF, or GSK3β concentrations compared with RIV alone. Our research indicates that CAN has potential benefits for AD, as evidenced by improvements in cognitive abilities, cholinergic activity, and neurogenesis in rats with AD. This is attributed to the upregulation of BDNF/GSK3β signaling, reduced neuroinflammation, and Aβ deposition.},
}

@article {pmid41570950,
year = {2026},
author = {Guo, J and Shi, C and Yu, C and Wang, Y and He, M},
title = {Protein S-Sulfhydration: Mechanisms and Therapeutic Implications in Alzheimer's Disease and Parkinson's Disease.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.01.033},
pmid = {41570950},
issn = {1873-4596},
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases have complex pathogenic mechanisms. Traditional theories (e.g., free radical damage/oxidative stress, inflammatory responses) have laid a foundation for understanding these pathological processes. However, single mechanisms cannot fully explain their complexity. In recent years, post-translational modifications (PTMs)-especially redox-related types such as S-sulfhydration-have emerged as key complementary regulators of nervous system homeostasis and disease progression. It is mediated by the endogenous gas signaling molecule hydrogen sulfide (H2S) and has unique regulatory effects.

AIM OF REVIEW: This review systematically summarizes the molecular mechanisms and therapeutic targets of S-sulfhydration in AD and PD. It discusses the potential of S-sulfhydration in disease intervention and treatment. It also looks into H2S-based therapeutic strategies and their clinical application prospects. This review aims to provide a theoretical basis for understanding the role of PTMs in neurological diseases.

This review summarizes clearly: in AD and PD, S-sulfhydration interacts with protein modifications like phosphorylation, S-nitrosylation and succinylation. It regulates key pathogenic proteins such as Tau, Aβ and Parkin. It also takes part in regulating energy metabolism, resisting oxidative stress and inhibiting inflammatory responses. These effects influence neuronal survival and functional homeostasis. This indicates that S-sulfhydration plays an important regulatory role in AD and PD progression. It is part of the complex network of pathological mechanisms. Its modification mechanisms and interaction pathways offer promising complementary molecular targets and intervention strategies for treating AD, PD, and other potential neurodegenerative diseases.},
}

@article {pmid41570699,
year = {2026},
author = {Razzaq, R and Ahmed, T and Butt, AM and Jabeen, Z and Khalid, A and Shahid, I and Alzahrani, AR and Rehman, S},
title = {Betanin-encapsulated nanoparticles mitigate neurotoxicity against AlCl3-induced Alzheimer's disease via modulation of AChE/TNF-α/IL-1β expression.},
journal = {Biochemical and biophysical research communications},
volume = {801},
number = {},
pages = {153293},
doi = {10.1016/j.bbrc.2026.153293},
pmid = {41570699},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD), the most common health problem, is significantly characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction, provoking growing interest in natural antioxidants with improved bioavailability. This study is intended to evaluate the neuroprotective impact and the probable mechanism of betanin and formulated betanin-encapsulated nanoparticles (ChBetNPs) in an AlCl3 and D-galactose-induced rat model Alzheimer's-like neurotoxicity. The rats were treated daily with AlCl3 and D-galactose for 21 days to induce neurotoxicity, followed by two weeks of treatment with low and high doses of betanin and ChBetNPs. After treatment, cognitive performance, oxidative stress markers, acetylcholinesterase (AChE) activity, and hippocampal inflammatory gene expression were assessed. Both low and high doses of ChBetNPs (40 mg/kg/day and 80 mg/kg/day respectively) significantly improved learning and memory performance in AlCl3 + D-galactose-treated rats. Treatment with ChBetNPs also markedly restored antioxidant defenses, as evidenced by increased activities of CAT (∗∗P < 0.01), elevated reduced GSH, and reduced levels of the lipid peroxidation marker MDA. The higher dose of ChBetNPs produced a pronounced protective effect on cholinergic function, reflected by a robust reduction in brain AChE activity (∗∗∗∗P < 0.0001). In addition, both free betanin and ChBetNPs at low and high doses significantly (∗∗P < 0.01) downregulated the hippocampal mRNA expression of AChE, α-synuclein, TNF-α, and IL-1β in hippocampal region of brain as compared with untreated group, indicating attenuation of neuroinflammatory and protein-aggregation-related pathways. In summary, our findings demonstrate that ChBetNPs enhanced learning, memory, and cholinergic neurotransmission, likely by mitigating oxidative stress and the associated NF-κB-mediated inflammatory responses.},
}

@article {pmid41570392,
year = {2026},
author = {Wischik, CM and Stefanacci, R and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Penny, LK and Arastoo, M and Staff, R and Sandu, AL and Shiells, H and Lo, S and Nazlee, N and Evans, E and Hull, C and Schelter, BO},
title = {Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100480},
doi = {10.1016/j.tjpad.2026.100480},
pmid = {41570392},
issn = {2426-0266},
abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.

OBJECTIVES: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

SETTING: 82 centres in Canada, European Union, United Kingdom and United States of America.

PARTICIPANTS: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.

INTERVENTION: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.

MEASUREMENTS: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.

RESULTS: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.

CONCLUSIONS: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.},
}

@article {pmid41569280,
year = {2026},
author = {Huynh, ALH and Wang, S and Lee, K and Amadoru, S and Wrigley, S and Zisis, G and Ernstrom, K and Raman, R and Aisen, P and Sperling, RA and Masters, CL and Ward, D and Yates, PA},
title = {Prevalence of frailty and its association with cognition in preclinical Alzheimer's disease: a cross-sectional analysis of baseline data from the A4 study.},
journal = {Age and ageing},
volume = {55},
number = {1},
pages = {},
doi = {10.1093/ageing/afaf378},
pmid = {41569280},
issn = {1468-2834},
mesh = {Humans ; Aged ; Female ; Cross-Sectional Studies ; Male ; *Alzheimer Disease/epidemiology/diagnosis/psychology ; *Frailty/epidemiology/diagnosis/psychology ; Prevalence ; *Cognition ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; *Frail Elderly ; Geriatric Assessment ; Risk Factors ; Prodromal Symptoms ; },
abstract = {BACKGROUND: The prevalence and role of frailty in preclinical Alzheimer's disease (AD) is unclear.

METHODS: Cross-sectional analyses of pre-randomization data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) study were analysed to derive two models of a frailty index (FI)-full [FI-Full] and cognitive variables removed [FI-CVR]. The prevalence of frailty (FI > 0.25) according to amyloid status (Aβ+/-), and the association of frailty and cognition (determined by the Preclinical Alzheimer Cognitive Composite (PACC) score) and whether frailty moderates the relationship between amyloid status and cognition was assessed, adjusting for age, sex and education.

RESULTS: Four thousand four hundred eighty-six participants were included (mean age 71.3 ± 4.7 years, 30% participants Aβ+, 59% female). The prevalence of frailty in preclinical AD was 22% (or 44% when cognitive variables were removed from the FI). Using either FI model, in adjusted analyses, Aβ+ participants were more likely to be frail compared to Aβ- [FI-Full-Odds ratio (OR) 1.43 95% confidence interval (CI) 1.20-1.71, P < .001; FI-CVR-OR 1.21 95% CI 1.05-1.40, P < .008]. Frail participants had lower PACC scores compared to non-frail participants, on average (FI-Full-PACC score -0.58 95% CI -0.76 to -0.40, P < .001; FI-CVR-PACC score -0.26 95% CI -0.40 to -0.12, P < .001). Frailty did not influence the relationship between Aβ status and cognition.

CONCLUSIONS: In a cohort screened for a preclinical AD trial, elevated Aβ levels were associated with frailty and frailty was associated with reduced cognitive performance independent of elevated Aβ levels. These associations, and whether or not frailty is associated with longitudinal cognitive decline independent of Aβ status, warrant further study.},
}

Humans
Aged
Female
Cross-Sectional Studies
Male
*Alzheimer Disease/epidemiology/diagnosis/psychology
*Frailty/epidemiology/diagnosis/psychology
Prevalence
*Cognition
Amyloid beta-Peptides/metabolism
Aged, 80 and over
*Frail Elderly
Geriatric Assessment
Risk Factors
Prodromal Symptoms

@article {pmid41569242,
year = {2026},
author = {Zuliani, G and Boscolo Bragadin, F and Romagnoli, T and Polastri, M and Cervellati, C and Dario, FDP and Brombo, G and Zuin, M},
title = {Long-Term Effect of Acetylcholinesterase Inhibitors on Behavioral and Psychological Symptoms of Dementia.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {1},
pages = {e70195},
doi = {10.1002/gps.70195},
pmid = {41569242},
issn = {1099-1166},
mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use ; Aged ; Male ; Female ; *Dementia/drug therapy/psychology ; Aged, 80 and over ; Severity of Illness Index ; Behavioral Symptoms/drug therapy ; },
abstract = {OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) are critical aspects of the clinical presentation of dementia. There is no universally accepted approach for the managment of BPSD, currently based first on a non-pharmacological and subsequently on a pharmacological approach. We explored the potential effect of long-term treatment with acetylcholinesterase inhibitors (AChEI) on BPSD severity over time.

METHODS: The initial sample included 4032 older patients with mild-moderate dementia (Alzhemier's disease - AD, Lewy body dementia - LBD, or vascular dementias - VaD) from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). After propensity score matching, a cohort of 1408 patients (704 treated with AChEI = AChEI+ and 704 not treated = AChEI-) was generated. The mean age was 73.2 years (females: 50.4%). The mean follow-up duration was 4.3 ± 1.6 years (range: 2.2-8.3 years). Patients were evaluated at baseline, T1 (2 years), T2 (4 years), T3 (6.2 years), and T4 (8.1 years). BPSD severity was assessed by Neuropsychiatric Inventory (NPI-Q).

RESULTS: The baseline mean NPI-Q severity score was 1.33. At T4, the score increased to 1.41 in AChEI- patients (+6% from baseline), while it decreased to 1.26 in AChEI+ (-6%) (all p < 0.01 from T1 to T4). As regards the NPI-Q sub-items, six of them (hallucinations, agitation/aggression, depression/dysphoria, anxiety, disinhibition and irritability/lability) exhibited significant differences over time (all p < 0.01) in favor of the AChEI + group (stabilization or improvement). Similar trends were observed when LOAD, LBD and VaD were considered separately. In contrast, for five domains (delusions, elation/euphoria, motor disturbances, night-time behaviors, and appetite/eating changes) no differences were observed.

CONCLUSIONS: Our study supports the potential role for AChEI in BPSD management, demonstrating a trend toward symptoms stabilization or improvement in patients with mild-moderate dementia. Although the effects were not uniform across all NPI-Q domains, and the limitations of the study, our results reinforces the relevance of AChEI in the comprehensive treatment of dementia.},
}

Humans
*Cholinesterase Inhibitors/therapeutic use
Aged
Male
Female
*Dementia/drug therapy/psychology
Aged, 80 and over
Severity of Illness Index
Behavioral Symptoms/drug therapy

@article {pmid41568736,
year = {2025},
author = {Liu, W and Li, Y and Qin, W and Wang, X and Li, W and Li, Y and , and Jia, J},
title = {The impact of cholinesterase inhibitors on cognitive trajectories in mild cognitive impairment patients based on amyloid beta status.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70193},
doi = {10.1002/alz.70193},
pmid = {41568736},
issn = {1552-5279},
support = {CX23YZ15//Chinese Institutes for Medical Research/ ; U20A20354//Key Project of the National Natural Science Foundation of China/ ; 81530036//Key Project of the National Natural Science Foundation of China/ ; 7244355//Beijing Municipal Natural Science Foundation/ ; 31627803//National Key Scientific Instrument and Equipment Development Project/ ; No.2021ZD0201802//STI2030-Major Projects/ ; Z201100005520016//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; 82401404//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Female ; Disease Progression ; *Cholinesterase Inhibitors/therapeutic use/adverse effects ; *Amyloid beta-Peptides/metabolism ; Aged ; *Alzheimer Disease ; Aged, 80 and over ; *Cognition/drug effects ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: This study examines whether cholinesterase inhibitors (ChEIs) influence the progression to Alzheimer's disease (AD) dementia and cognitive trajectories in amnestic mild cognitive impairment (MCI) patients, considering their amyloid beta (Aβ) status.

METHODS: Kaplan-Meier and time-varying Cox models evaluated ChEI use and different Aβ status on MCI-to-AD progression. Linear mixed-effects models assessed cognitive trajectories. Locally estimated scatterplot smoothing regression analyzed cognitive changes before and after ChEI initiation.

RESULTS: Among 558 amnestic MCI participants (168 ChEI users), ChEI users exhibited higher risk of progression to AD dementia (hazard ratio = 1.77, 95% confidence interval: 1.15 to 2.73, p = 0.001). Both ChEI use and Aβ burden independently accelerated MCI progression and cognitive decline. Cognitive trajectories demonstrated decline before ChEI initiation and continued to decline after treatment began.

DISCUSSION: The association between ChEI treatment and accelerated progression to AD dementia and cognitive decline, independent of Aβ status, emphasized the need to reconsider optimal timing for ChEI initiation in MCI.

HIGHLIGHTS: ChEI use in MCI was associated with increased risk of progression to AD dementia. ChEI use in MCI was associated with accelerated longitudinal cognitive decline. Cognitive decline persisted after ChEI initiation rather than reversing. ChEI effects on MCI progression to AD dementia were independent of Aβ status.},
}

Humans
*Cognitive Dysfunction/drug therapy/metabolism
Male
Female
Disease Progression
*Cholinesterase Inhibitors/therapeutic use/adverse effects
*Amyloid beta-Peptides/metabolism
Aged
*Alzheimer Disease
Aged, 80 and over
*Cognition/drug effects
Neuropsychological Tests

@article {pmid41568664,
year = {2026},
author = {Jootar, T and Hongeng, S and Chiangjong, W},
title = {Engineering nanobodies for drug delivery systems in Alzheimer's disease.},
journal = {Artificial cells, nanomedicine, and biotechnology},
volume = {54},
number = {1},
pages = {104-118},
doi = {10.1080/21691401.2026.2617707},
pmid = {41568664},
issn = {2169-141X},
mesh = {*Alzheimer Disease/drug therapy/metabolism/immunology/pathology ; *Single-Domain Antibodies/therapeutic use/chemistry/immunology ; Humans ; Animals ; *Drug Delivery Systems ; *Protein Engineering ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with current therapies offering only symptomatic relief. A significant constraint in the development of effective treatments is the blood-brain barrier (BBB), as it greatly limits the access of therapeutic drugs targeting amyloid-β (Aβ) aggregation, tau hyperphosphorylation and neuroinflammation. Nanobodies, single-domain antibody fragments derived from camelids, have emerged as versatile tools with unique properties such as small size, high stability and the ability to penetrate the BBB. Engineered formats allow for specific targeting of Aβ and tau, receptor-mediated transcytosis, and conjugation with therapeutic or diagnostic substances. Preclinical studies show that nanobody-based strategies can reduce pathological burden, attenuate neuroinflammation and improve cognitive outcomes in AD models. Manufacturing scale-up, long-term safety and regulatory validation are among the remaining challenges, yet nanobody engineering represents a viable path to disease-modifying medicines. Innovative approaches, including artificial intelligence-driven design, i.e. 4-1BB agonist nanobodies, and clustered regularly interspaced short palindromic repeat-facilitated diversification of nanobody libraries - such as targeted complementarity-determining region 3 mutagenesis followed by functional screening against disease-relevant tau or Aβ conformers - alongside half-life extension strategies, are commencing to surmount these obstacles and enhance the potential of nanobody platforms to develop into clinically viable disease-modifying therapies.},
}

*Alzheimer Disease/drug therapy/metabolism/immunology/pathology
*Single-Domain Antibodies/therapeutic use/chemistry/immunology
Humans
Animals
*Drug Delivery Systems
*Protein Engineering
Blood-Brain Barrier/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41567052,
year = {2026},
author = {Tziakouri, A and Loser, V and Vicino, A and Baumgartner, T and Di Liberto, G and Pantazou, V and Bernard-Valnet, R and Theaudin, M and Pot, C and Castro-Jimenez, M and Hübsch, CA and Bally, J and Strambo, D and Hirt, L and Caranzano, L and Rouaud, O and Allali, G and Salvioni, P and Sokolov, AA and Pignat, JM and Ryvlin, P and Perrenoud, MP and Rossetti, AO and Novy, J and Beuchat, I and Du Pasquier, R and Michel, P},
title = {[Neurology : what's new in 2025].},
journal = {Revue medicale suisse},
volume = {22},
number = {946},
pages = {161-164},
doi = {10.53738/REVMED.2026.22.946.48114},
pmid = {41567052},
issn = {1660-9379},
mesh = {Humans ; *Neurology/trends ; Female ; Pregnancy ; *Nervous System Diseases/therapy/diagnosis ; Multiple Sclerosis/therapy/drug therapy ; },
abstract = {In 2025, several major advances have marked the field of neurology. Anti-FcRN and anti-C5 antibodies have confirmed their long-term efficacy in the treatment of myasthenia gravis. Bruton tyrosine kinase inhibitors have expanded the therapeutic arsenal for multiple sclerosis. An antibody targeting α-synuclein appears to slow motor decline in early-stage Parkinson's disease. The efficacy of late thrombolysis in strokes with radiological mismatch has been confirmed. A blood biomarker facilitates early detection of Alzheimer's disease, and Swiss guidelines specify the modality for the use of anti-amyloid therapies in this disease. Finally, in pregnant women with epilepsy, the recommended dose of folic acid has been reduced.},
}

Humans
*Neurology/trends
Female
Pregnancy
*Nervous System Diseases/therapy/diagnosis
Multiple Sclerosis/therapy/drug therapy

@article {pmid41566034,
year = {2026},
author = {Peng, Y and Wang, SS and Lai, KD and Ye, JR and He, WB and Yan, X and Zhang, Z and Chu, SF and Chen, NH},
title = {Protopanaxatriol restores cognitive function in okadaic acid-treated mice via direct inhibition of pathological CDK5 activity.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41566034},
issn = {1745-7254},
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative dementia, presents therapeutic challenges due to safety concerns about amyloid-targeting strategies. Traditional Chinese medicine (TCM) may offer alternative avenues for exploration. Ginsenoside Rg1, a key bioactive component of ginseng, has shown neuroprotective potential in okadaic acid (OKA)-induced rat model, its limited brain bioavailability suggests that its metabolite protopanaxatriol (Ppt) may exert these effects. In this study, we investigated the therapeutic effects of Ppt on OKA-induced mice model and the underlying mechanisms. Cultured hippocampal neurons were treated with OKA (0.5 nM) with or without Ppt co-treatment for 24 h. We showed that Ppt (1.25-40 nM) exerted dose-dependent neuroprotection against OKA-induced cytotoxicity, with the maximal protection observed at 10 nM. The suppressed tau aggregation by Ppt was confirmed using a Venus-tau bimolecular fluorescence complementation (BiFC) system. Molecular dynamics simulations and microscale thermophoresis (MST) revealed that Ppt bound to the catalytic domain of CDK5 at Cys83, destabilizing the CDK5/p25 complex. Co-immunoprecipitation (Co-IP) assays with CDK5 mutants (S159T, C83A, F80A and D86A) validated this interaction. In vivo mice were treated with Ppt (10 mg/kg, i.g.) for 25 days. On D8 and D9, the mice were bilaterally microinjected with OKA into the cerebral ventricles. We showed that Ppt administration improved spatial memory deficits in Novel Object Recognition and Barnes Maze tests; these effects were abolished in mice expressing a lentivirus-mediated CDK5[C83A] mutant. Hippocampal transcriptomic profiling in OKA-challenged mice following Ppt intervention revealed that Ppt modulated Drp1-mediated mitochondrial fission/fusion dynamics, mitigating OKA-induced mitochondrial homeostasis disruption. Collectively, these results demonstrate that Ppt attenuates tau pathology by selectively targeting CDK5 at Cys83, thereby reducing pathological kinase activity, rebalancing mitochondrial function, and improving cognitive outcomes in an OKA-induced mice neurodegeneration model. The study underscores the therapeutic potential of Ppt in AD treatment and supports CDK5 modulation as a strategic approach for addressing tau-related neurodegeneration.},
}

@article {pmid41565079,
year = {2026},
author = {Doshi, PP and Desale, SH and Khutale, AA and Sabarathinam, S and Suresh, S},
title = {Evaluating Senescence-Targeted Approaches in Alzheimer's Disease: What We Know and What Lies Ahead.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103029},
doi = {10.1016/j.arr.2026.103029},
pmid = {41565079},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer's brain and adopt a senescence-associated secretory phenotype characterized by sustained release of pro-inflammatory and neurotoxic factors. This chronic inflammatory milieu promotes neurodegeneration, disrupts the synaptic activity and is involved in cognitive deficit. Senolytics, which selectively eliminate senescent cells, have demonstrated benefit in multiple preclinical models of AD, including decreased neuroinflammation, improvement in neuronal function and cognitive performance. Several senolytic agents, such as dasatinib, quercetin, fisetin and navitoclax, hit anti-apoptotic modalities that support the survival of senescent cells. Early-phase human studies suggest the feasibility of senescence-targeted interventions and indicate that senescence-associated molecular changes may compromise blood-brain barrier integrity. Consistently, preclinical studies demonstrate partial restoration of barrier function following senolytic therapy; however, clinical translation remains limited and at an early stage. Major challenges include the identification of senolytic agents with effective central nervous system penetration, the determination of optimal dosing regimens and treatment schedules, generation of robust long-term safety profile in human population, and the development of predictive biomarkers to guide patient selection and clinical study design. As senolytics and senomorphic strategies continue to evolve, they hold promise as complementary approaches to existing anti-amyloid and anti-tau therapies by offering a multi-mechanistic approach toward AD modification. This review synthesizes current evidence on cellular senescence in AD, outlines the mechanistic rationale for senescence-targeted therapies, summarizes available clinical data, while providing future directions for integrating senolytics into AD management.},
}

@article {pmid41565030,
year = {2026},
author = {Zhang, X and Ding, W and Guo, C and Chen, X and Chen, B},
title = {Choline serves as the primary active compound of anti-aging tablets and targets PTGS2 to alleviate neuronal damage in Alzheimer's disease by modulating ferroptosis and apoptosis in nerve cells.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116040},
doi = {10.1016/j.bbr.2026.116040},
pmid = {41565030},
issn = {1872-7549},
abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive impairment, involves pathological mechanisms including β-amyloid protein deposition, hyperphosphorylation of Tau proteins, and neuronal damage mediated by ferroptosis. As a traditional Chinese medicine, anti-aging tablets have potential neuroprotective effects, but their active ingredients and mechanisms have not been fully elucidated.

METHODS: We screened active ingredients and AD-related targets in anti-aging tablets using liquid chromatography-mass spectrometry combined with network pharmacology analysis. A protein-protein interaction network was established, and GO/KEGG enrichment analyses were performed. The binding of choline to PTGS2 was verified through molecular thermal shift assay. qPCR was utilized to detect PTGS2 expression. An AD model was constructed, with cellular injury levels evaluated through CCK-8, LDH assays, and WB detection by examining the expression of apoptosis-related biomarkers. The expression of ferroptosis-related proteins (FSP1, SLC7A11, GPX4) was examined through Western blot analysis. MDA and GSH/GSSG analyses determined lipid peroxidation and antioxidant capacity. DCFH-DA detected ROS levels.

RESULTS: The combined use of UPLC-MS/MS with network pharmacology led to the identification and characterization of choline as the key active ingredient in anti-aging tablets. PTGS2 was determined as its primary target. The direct binding of choline to PTGS2 was verified through molecular thermal shift assay. In vitro experiments revealed that choline significantly repressed cell damage in the AD model, as indicated by enhanced cell viability, reduced release of LDH, lowered levels of reactive oxygen species (ROS), and downregulated expression of caspase-3 and Bax. Additional studies uncovered that overexpression of PTGS2 exacerbated ferroptosis-related parameters (upregulation of MDA, decrease in GSH/GSSG ratio, downregulation of FSP1, SLC7A11, and GPX4 expression), whereas Fer-1 treatment reversed these changes.

CONCLUSION: This study revealed that choline targets PTGS2 to depress ferroptosis, thus alleviating AD-related neuronal injury. This study provides a theoretical basis for the pharmacodynamic effects of anti-aging tablets as well as new therapeutic strategies for AD.},
}

@article {pmid41564814,
year = {2026},
author = {Harris, K and Shyer, M and Wang, D and He, E and Cattani, M and Zhang, C and Farrell, CM and Jiang, X and Kim, Y and Schulz, PE},
title = {The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100483},
doi = {10.1016/j.tjpad.2026.100483},
pmid = {41564814},
issn = {2426-0266},
abstract = {BACKGROUND: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.

OBJECTIVES: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.

DESIGN: Retrospective cohort study.

SETTING: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).

PARTICIPANTS: 4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.

INTERVENTION: Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).

MEASUREMENTS: Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.

RESULTS: Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.

CONCLUSIONS: This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer's disease.},
}

@article {pmid41564595,
year = {2026},
author = {Muzurović, E and Katsiki, N and Volčanšek, Š and Plescia, F and Rizzo, M and Mantzoros, CS},
title = {Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond.},
journal = {Metabolism: clinical and experimental},
volume = {177},
number = {},
pages = {156494},
doi = {10.1016/j.metabol.2026.156494},
pmid = {41564595},
issn = {1532-8600},
abstract = {While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.},
}

@article {pmid41564288,
year = {2026},
author = {Chen, ZH and Li, R and Jiang, YH and He, JK and Yan, SS and Zong, GH and Yi, ZX and Ren, XY and Jia, BH},
title = {Predictive Model of Acupuncture Adherence in Alzheimer Disease: Secondary Analysis of Randomized Controlled Trials.},
journal = {JMIR aging},
volume = {9},
number = {},
pages = {e82787},
doi = {10.2196/82787},
pmid = {41564288},
issn = {2561-7605},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Male ; Aged ; Female ; *Acupuncture Therapy/statistics & numerical data ; Middle Aged ; Aged, 80 and over ; Randomized Controlled Trials as Topic ; China ; },
abstract = {BACKGROUND: The therapeutic efficacy of acupuncture in treating Alzheimer disease (AD) largely depends on consistent treatment adherence. Therefore, identifying key factors influencing adherence and developing targeted interventions are crucial for enhancing clinical outcomes.

OBJECTIVE: This study aims to develop and validate a predictive model for identifying patients with AD who are likely to maintain good adherence to acupuncture treatment.

METHODS: This secondary analysis included 108 patients with probable AD, aged 50 to 85 years, from 2 independent randomized controlled trials conducted at Guang'anmen Hospital, China Academy of Chinese Medical Sciences. Of all, 66 patients were assigned to the development cohort and 42 to the external validation cohort. Acupuncture adherence was defined as the proportion of completed sessions relative to scheduled sessions, with good adherence defined as ≥80% completion. Baseline data included demographic, clinical, cognitive, functional, psychological, and caregiving variables. Multivariable logistic regression with backward stepwise selection was used to identify significant predictors, and a nomogram was constructed based on the final model. Model performance was assessed using receiver operating characteristic curves, calibration plots, and decision curve analysis, with external validation performed by receiver operating characteristic analysis. Sensitivity analysis was performed using alternative adherence thresholds of 70% and 90%.

RESULTS: A higher number of treatments during the first month was associated with a significant increase in the odds of good adherence (odds ratio [OR] 3.06, 95% CI 1.68-7.01; P=.002), while longer disease duration (OR 0.97, 95% CI 0.94-1.00; P=.049) and receiving care from a part-time caregiver (OR 0.19, 95% CI 0.04-0.72; P=.022) were associated with lower odds of adherence. Sensitivity analyses further supported the stability and reliability of the model.

CONCLUSIONS: This study is the first to develop and validate a predictive model for acupuncture adherence in patients with AD. In clinical research, it can facilitate participant stratification and help identify individuals who may need additional adherence support, thereby reducing bias and enhancing trial quality. In clinical practice, the nomogram enables proactive adherence management by prospectively identifying high-risk patients and guiding targeted strategies to improve adherence and optimize therapeutic outcomes.},
}

Humans
*Alzheimer Disease/therapy/psychology
Male
Aged
Female
*Acupuncture Therapy/statistics & numerical data
Middle Aged
Aged, 80 and over
Randomized Controlled Trials as Topic
China

@article {pmid41563682,
year = {2026},
author = {Paul, R and Firdous, SM},
title = {Unraveling the molecular mechanisms of aluminium chloride-induced Alzheimer's disease.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {41563682},
issn = {1572-8773},
abstract = {The most prevalent neurodegenerative illness is Alzheimer's disease (AD). Aluminium chloride (AlCl3) is a heavy metals that produces several neurodegenerative diseases, commonly AD. AlCl3 easily goes through the blood-brain barrier and reaches to brain. In this study, we reviewed literature, highlighting the various molecular mechanisms targeting AlCl3-induced neurodegenerative disorders like AD in numerous in vivo and in vitro models. AlCl3 can cause conformational changes in the beta-sheet of amyloid beta (Aβ) peptide that lead to the aggregation of Aβ in the brain's neuronal cells. AlCl3 can also decrease the expression of protein phosphatase 2A (PP2A), which is essential for evading tau aggregation and neurofibrillary tangles (NFTs) formation. It can increase acetylcholinesterase (AChE) levels in the brain, which can produce cognitive impairment. AlCl3 also produces calcium (Ca[2+]) and iron dyshomeostasis in neuronal cells. It activates various inflammatory mediators such as interleukin-6 (IL-6), interleukin-1β (IL-1β), plasminogen activator inhibitor-1 (PAI-1), and tumour necrosis factor-α (TNF-α). In addition, AlCl3 can increase the production of reactive oxygen species (ROS), which induce telomere degradation, may initiate telomere dysfunction that can initiate neuroinflammation, and induce cellular senescence. AlCl3 may increase the expression of glycogen synthase kinase-3 beta (GSK3β), which produces various cognitive impairments, leading to AD. Various therapeutic techniques like chelation, antioxidant, and drug therapy are used to treat AD, but a better-targeted approach and a deeper understanding of the molecular basis of Alzheimer's due to AlCl3 intoxication are crucial. AlCl3-induced neurotoxicity involves mitochondrial disruption, oxidative stress, neuroinflammation, and DNA impairment, necessitating further research for treatment against aluminium (Al)-induced AD. AlCl3 can cause neurodegenerative diseases like AD, but understanding its molecular mechanisms is challenging due to its interaction with biological systems.},
}

@article {pmid41563466,
year = {2026},
author = {Ueffing, M and Lange, C and Schlunck, G and Wolf, J},
title = {[Liquid biopsy proteomics in ophthalmology : A clinical and scientific perspective].},
journal = {Die Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {41563466},
issn = {2731-7218},
abstract = {BACKGROUND: For many patients with age-related macular degeneration, diabetic retinopathy and other partially monogenetic retinal diseases as well as for tumors of the eye that are relatively rare but are usually associated with profound consequences for affected patients, there is still no effective treatment available. Metastatic melanoma, for example, remains poorly predictable with respect to disease progression, response to treatment and outcome. This illustrates the urgent need for a deeper molecular understanding of the disease with the goal to develop novel therapeutic strategies. Liquid biopsies of the aqueous humor represent a promising possibility for molecular analyses in the eyes of patients.

OBJECTIVE: A clinical and scientific perspective with respect to potential fields of applications of liquid biopsy proteomics in ophthalmology is presented.

MATERIAL AND METHODS: A systematic literature search was carried out in PubMed and the personal experiences of the authors are presented.

RESULTS AND CONCLUSION: Aqueous humor proteomics offer a plethora of potential applications in ophthalmology and could become a key factor in personalized ophthalmology. Potential areas of application include the selection of treatment based on the activated biological signalling pathways, the selection of patients for clinical trials as well as the diagnostics, prognosis estimation and monitoring of the response to treatment. In addition, it can be a valuable component of multimodal diagnostics and enable insights into neurodegenerative diseases, such as Alzheimer's or Parkinson's disease.},
}

@article {pmid41562905,
year = {2025},
author = {Fedotcheva, TA and Shimanovsky, NL},
title = {Current State of the Neurotrophin-Based Pharmaceutics in the Treatment of Neurodegenerative Diseases and Neuroinflammation.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {1},
pages = {},
doi = {10.3390/medsci14010015},
pmid = {41562905},
issn = {2076-3271},
support = {124020900031-0//Ministry of Health of the Russian Federation/ ; },
mesh = {Humans ; *Nerve Growth Factors/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; *Neuroinflammatory Diseases/drug therapy ; Animals ; },
abstract = {BACKGROUND: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development.

METHODS: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications.

RESULTS: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF-cenegermin and recombinant CNTF-Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance.

CONCLUSIONS: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance.},
}

Humans
*Nerve Growth Factors/therapeutic use
*Neurodegenerative Diseases/drug therapy
*Neuroinflammatory Diseases/drug therapy
Animals

@article {pmid41562838,
year = {2026},
author = {Wozniczka, CM and Weaver, DF},
title = {β-Alanine Is an Unexploited Neurotransmitter in the Pathogenesis and Treatment of Alzheimer's Disease.},
journal = {NeuroSci},
volume = {7},
number = {1},
pages = {},
doi = {10.3390/neurosci7010013},
pmid = {41562838},
issn = {2673-4087},
support = {KF-2023-1//Krembli Foundation/ ; ASC-2024//Alzheimer's Society Canada/ ; },
abstract = {Alzheimer's disease (AD) remains an unmet medical challenge, as there are no effective therapies that alter the disease's progression. While approaches have targeted molecules like acetylcholine (ACh) and glutamate, these strategies have provided only limited benefits and do not address the complex molecular mechanisms underlying AD development. This review suggests that β-alanine (3-aminopropanoic acid) is an underexplored neurotransmitter that could serve as a potential AD drug target. Existing evidence indicates that β-alanine modulates GABAergic and glutamatergic neurotransmission, thereby affecting neuronal hyperexcitability. Additionally, studies suggest that β-alanine has antioxidant effects, reducing oxidative stress caused by reactive oxygen species (ROS). We propose that β-alanine might bind to Aβ/tau proteins, possibly targeting the six-amino acid sequences EVHHQK/DDKKAK, which are involved in protein aggregation. β-Alanine may also influence the release of pro-inflammatory cytokines from microglia, potentially reducing neuroinflammation. We also hypothesize that β-alanine may help regulate metal dyshomeostasis, which leads to ROS production. Taurine, structurally like β-alanine, appears to influence comparable mechanisms. Although structural similarity doesn't ensure therapeutic effectiveness, this evidence supports considering β-alanine as a treatment for AD. Furthermore, β-alanine and its analogues face challenges, including crossing the blood-brain barrier (BBB) and optimizing structure-activity relationships (SAR). This review includes articles through September 2025, sourced from four databases.},
}

@article {pmid41561733,
year = {2026},
author = {Curd, BC and Zubrick, C and Brown, CJC and Sorweid, MK and Dehoney, SB and Anzai, Y and Minoshima, S and Parks, AL and Frost, NA},
title = {Real-world experience with lecanemab therapy for Alzheimer's disease in the Intermountain West.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70251},
pmid = {41561733},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid plaques that has been approved for the treatment of early symptomatic Alzheimer's disease. Here, we report on the clinical history and outcomes of the first 70 patients at the University of Utah to receive amyloid-removal therapy.

METHODS: This is a retrospective analysis of patients treated with lecanemab over a 26-month period. We extracted patient data from charts and analyzed demographics, health history, and clinical details with outcomes on lecanemab treatment.

RESULTS: In total, we observed 14 cases (20%) of amyloid-related imaging abnormalities (ARIAs), which was significantly associated with apolipoprotein E ε4 homozygosity. Zero cases of ARIAs were symptomatic, and there was no association between distance from clinic and adverse effects.

DISCUSSION: Our study examined the safety and tolerability of centrally managed lecanemab administration across a widely distributed region and suggests that use of distributed infusion sites increases access to disease-modifying treatment without significant increase in risk.

HIGHLIGHTS: Lecanemab therapy can be safely administered to patients across a broadly distributed area through a single clinical center.In our first 70 treated patients, 14 developed amyloid-related imaging abnormalities (ARIAs)-a rate of 20%, which is consistent with clinical trials of lecanemab.No patients experienced symptomatic ARIAs.ARIA incidence was significantly associated with apolipoprotein E genotype, but not other demographic factors, comorbid conditions, or baseline clinical details.},
}

@article {pmid41560836,
year = {2026},
author = {Zhang, Y and Yin, C and Tian, Y and Li, X and Wang, H and Han, S and Chen, H and Hou, H},
title = {Intranasal delivery of Odorranalectin-modified lipid nanoparticles for multi-targeted therapy of Alzheimer's disease.},
journal = {Materials today. Bio},
volume = {36},
number = {},
pages = {102764},
pmid = {41560836},
issn = {2590-0064},
abstract = {Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. In vitro, siB silenced BACE1 expression and inhibited Aβ generation, while QU alleviated Aβ-induced oxidative stress and neuroinflammation, thereby suppressing neuronal apoptosis. In APP/PS1 mice, siB/QU@L-OL restored Aβ homeostasis and redox balance, attenuated neuroinflammation and neuronal loss, and consequently improved cognitive performance. Collectively, this brain-targeted nanoplatform demonstrates strong potential for synergistic intervention in AD.},
}

@article {pmid41560713,
year = {2026},
author = {Barnwal, M and Baksh, S and Ismail, Z and Shade, DM and Moghekar, A and Ho, SG and Rosenberg, PB and Porsteinsson, AP and Lyketsos, CG and , },
title = {Blood biomarkers for Alzheimer's disease are correlated with measures of agitation and cognition in a randomized trial assessing the effects of escitalopram on agitation.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70203},
pmid = {41560713},
issn = {2352-8737},
abstract = {INTRODUCTION: Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) is a National Institutes of Health-funded randomized controlled trial that randomized 173 participants with clinically diagnosed Alzheimer's disease (AD) and agitation to escitalopram or placebo for 12 weeks, assessing efficacy and safety. There was no advantage for escitalopram in treating agitation, potentially attributed to including participants at various stages of AD brain pathology, reflected in levels of blood biomarkers. Here, we (1) estimated the fraction of participants meeting blood biomarker criteria for AD pathology, (2) examined associations between baseline blood biomarkers and agitation severity or cognitive functioning, and (3) evaluated whether baseline blood biomarkers predicted treatment response.

METHODS: Eighty-two randomized participants provided blood for biomarker measurement prior to randomization. Plasma amyloid beta (Aβ)42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (p-tau)217 were measured using standard methods. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow-up with (1) agitation severity (Neuropsychiatric Inventory Clinical Rating of the agitation and aggression domains [NPI-C-A+A]), (2) cognitive status (Mini-Mental State Examination [MMSE]), and (3) escitalopram treatment.

RESULTS: Seventy-seven out of 82 (94%) scored above threshold for p-tau217, supporting the clinical diagnosis of AD. Baseline higher p-tau217 predicted higher NPI-C-A+A scores at weeks 6 (beta = 3.26, p < 0.001) and 12 (beta = 2.86, p = 0.01) after randomization. Baseline higher levels of GFAP (beta = -0.02, p = 0.0002) and p-tau217 (beta = -2.68, p = 0.003) were associated with lower baseline MMSE scores. After adjusting for treatment, higher baseline p-tau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (odds ratio [OR] = 2.79, p = 0.02) and 12 (OR = 2.55, p = 0.02).

DISCUSSION: In this clinical trial cohort, elevated plasma p-tau217 confirmed AD pathology in 94% of participants and forecast greater agitation severity and worse cognitive functioning, underscoring its practical value for stratifying and monitoring patients in neuropsychiatric intervention studies.

HIGHLIGHTS: We examined whether Alzheimer's disease (AD) blood biomarkers predicted severity of agitation and cognitive impairment and/or treatment response in the 12-week Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) randomized controlled trial.Blood phosphorylated tau (p-tau)217 confirmed the presence of significant AD brain amyloid pathology in 94% of these clinically diagnosed participants.Independent of treatment assignment, higher baseline p-tau217 predicted lower baseline and future Mini-Mental State Examination (MMSE) scores and worse agitation overtime.Independent of treatment assignment, higher baseline levels of glial fibrillary acidic protein were associated with lower baseline and follow-up MMSE scores.},
}

@article {pmid41560694,
year = {2026},
author = {Wan, Z and Feng, X and Chou, J and Zhou, X and Ma, T and Zhang, T},
title = {Sex- and brain region-specific gene expression in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251413797},
doi = {10.1177/13872877251413797},
pmid = {41560694},
issn = {1875-8908},
abstract = {BackgroundWomen with Alzheimer's disease (AD) have higher prevalence and more severe dementia syndrome than men with AD, and the brain regions are also affected differently. However, the underlying mechanisms are poorly understood.ObjectiveTo characterize the sex-dependent and region-specific gene expression in AD brain.MethodsA previously published large scale bulk tissue gene expression dataset from postmortem brain samples across 19 cortical regions of normal control and individuals diagnosed with dementia and neuropathology of AD was used for differential gene expression analysis. Functional enrichment analysis was used to identify enriched biological functions or pathways related to selected genes. Protein expression level of a selected gene was validated by western blot.ResultsWe identified 113 dysregulated genes in 11 AD brain regions (9 in men, 7 in women, and 5 shared between men and women). Notably, more dysregulated genes were found in women AD brain (77 genes) than in men (49 genes), and 13 dysregulated genes across these 11 brain regions were shared between women and men. Functional analysis further revealed the distinctive enrichment in categories of cellular component, biological process, and/or molecular function in these dysregulated genes. GPR34 gene expression was upregulated in the men AD brain across three different regions and a significant elevation of GPR34 protein level was confirmed in men AD brain.ConclusionsThese findings provide insight into sex- and brain region-specific gene expression dysregulation, which may indicate novel mechanisms underlying AD pathogenesis and will facilitate the development of personalized diagnosis and treatment strategies for AD.},
}

@article {pmid41560693,
year = {2026},
author = {Custodio, B and Montesinos, R and Bayona, W and Rojas Benites, MJ and Camargo, I and Ibañez, M and Huilca, J and Noriega de la Colina, A and Matias-Guiu, JA and Custodio, N},
title = {Perceptions of Peruvian neurologists toward the implementation of anti-amyloid drugs for early Alzheimer's disease in the departments of neurology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410959},
doi = {10.1177/13872877251410959},
pmid = {41560693},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disease affecting millions globally, with particular severity in low- and middle-income countries due to barriers in timely diagnosis and treatment. To date, two monoclonal anti-amyloids have shown positive results in phase III clinical trials. However, their administration is complex, requiring specialized infrastructure, highly trained professionals, and regular follow-ups, posing major challenges for healthcare systems.ObjectiveThis study explores Peruvian neurologists' perceptions of changes needed to implement monoclonal antibodies in line with clinical guidelines.MethodsA cross-sectional study was conducted in Peru using the key informant (KI) methodology. KI were neurologists from multiple regions across the country. A comprehensive list of tertiary-level hospitals (public healthcare system, social security, and police and armed forces) was compiled, and at least one neurologist from each institution was contacted. The instrument used was adapted from a study conducted in Spain, which included questions focusing on changes in diagnosis, patient care, diagnostic and therapeutic techniques, public and family impact, neurology resources, and dementia research. Data analysis was employed using Stata18, using descriptive statistics and frequency distributions.ResultsTwenty-eight neurologists completed the survey. There was consensus on the significant impact monoclonal antibodies would have on neurology services. Over 85% agreed that more neurologists and nurses would be needed. Additionally, 93% supported using brief diagnostic scales in primary care and increasing follow-up visit frequency.ConclusionsThe introduction of monoclonal antibodies for AD in Peru requires modifications to healthcare institutions, highlighting the urgent need for strategic healthcare planning.},
}

@article {pmid41559471,
year = {2026},
author = {Liu, T and Chen, D and Liu, F and Sun, Y},
title = {ZFP36-mediated ZBP1 degradation inhibits microglia pro-inflammatory and NLRP3 inflammasome activation in Alzheimer's disease.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10139-6},
pmid = {41559471},
issn = {1573-6822},
abstract = {Alzheimer's disease (AD) is a heterogeneous disease with limited treatment efficacy. Identifying novel molecular targets and mechanisms is therefore crucial for developing therapeutic strategies. Zinc finger protein 36 (ZFP36) has not been reported in AD. This study found that the hippocampus of APP/PS1 mice showed ZFP36 upregulation. Using recombinant adeno-associated virus to overexpress ZFP36 improved the cognitive function of APP/PS1 mice, as assessed by Morris maze and Y maze tests. Furthermore, ZFP36 overexpression reduced Aβ deposition, expression of pro-inflammatory markers, and inhibited NLRP3 inflammasome activation in the hippocampus. These inhibitory effects of ZFP36 overexpression on the aforementioned proteins were also observed in Aβ1-42-treated BV-2 cells. mRNA sequencing identified Z-DNA Binding Protein 1 (ZBP1) as a target of ZFP36. After ZFP36 overexpression, ZBP1 was downregulated in the hippocampus and Aβ1-42-treated BV-2 cells. The interaction between ZFP36 and ZBP1 RNA was verified by RIP-PCR, and ZFP36 was shown to promote the degradation of ZBP1 mRNA. The inhibitory effects of ZFP36 on the NLRP3 inflammasome activation and microglial pro-inflammatory activation was reversed by ZBP1 overexpression. In summary, ZFP36 inhibits microglia pro-inflammatory and NLRP3 inflammasome activation through promoting the degradation of ZBP1 mRNA, thereby ameliorating cognitive deficits of APP/PS1 mice.},
}

@article {pmid41558720,
year = {2026},
author = {Zhou, R and Li, J and Liu, W and Zheng, R and Han, J and Liao, Z and Ning, W and Tang, C},
title = {[Systematic review and mechanistic exploration of "intelligence three-needling" in treatment of Alzheimer's disease].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {1},
pages = {153-160},
doi = {10.13703/j.0255-2930.20250723-k0001},
pmid = {41558720},
issn = {0255-2930},
mesh = {*Alzheimer Disease/therapy/metabolism/genetics ; Humans ; Animals ; *Acupuncture Therapy ; Acupuncture Points ; Brain/metabolism ; },
abstract = {The "intelligence three-needling" therapy, developed by Professor JIN Rui, the eminent acupuncture- moxibustion master in the south of Five Ridges, is effective on cognitive dysfunction in practice. The paper reviews the animal experiment researches of Alzheimer's disease (AD) treated with this therapy, aiming to explain its core mechanism and effect characteristics for AD. The results showed that the "intelligence three-needling" therapy exerts its effect through multiple targets and diverse pathways. It improves cholinergic system function, enhances glucose metabolism in brain regions, reduces oxidative stress damage, suppresses neuroinflammation, regulates the Wnt/β-catenin signaling pathway, promotes autophagy-lysosomal clearance of pathological proteins, activates the transmembrane receptor protein (Notch) pathway to strengthen synaptic plasticity, demonstrates neuroprotective and anti-apoptotic effects, and modulates gut microbiota. In experiments, this therapy demonstrated specific effect in brain regions of 5xFAD mouse models. Compared with the single application at "Benshen" (GB13) or "Shenting" (GV24), the acupoint combination in this therapy displayed the synergistic advantages, regulating more comprehensively adenosine monophosphate activated protein kinase (AMPK)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) kinase network. This review provides the theoretical basis for optimizing the protocol of acupuncture and moxibustion for AD, and is conducive to promoting the deep integration of traditional acupuncture-moxibustion therapy with modern neuroscience.},
}

*Alzheimer Disease/therapy/metabolism/genetics
Humans
Animals
*Acupuncture Therapy
Acupuncture Points
Brain/metabolism

@article {pmid41557600,
year = {2026},
author = {Fisher, DW and Borisovskaya, A and Lindley, E and Domoto-Reilly, K},
title = {Somatic Symptom Disorder as a Prodrome of Alzheimer Disease and Successful Treatment of Pain and Agitation With Electroconvulsive Therapy: A Case Report.},
journal = {The journal of ECT},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCT.0000000000001229},
pmid = {41557600},
issn = {1533-4112},
support = {T32AG052354//National Institute of Aging/ ; },
abstract = {Neuropsychiatric symptoms in dementia can be heterogeneous and hard to treat, though electroconvulsive therapy (ECT) is becoming more widely accepted as a viable treatment option. Here, we describe a patient with Alzheimer disease (AD) who developed Somatic Symptom Disorder as a prodrome to cognitive and functional decline, though atypical, primary affective disorder in AD was also on the differential. This patient further developed debilitating anxiety and agitation that was refractory to multiple behavioral and pharmacological interventions. ECT was able to treat the patient's neuropsychiatric symptoms, resulting in sustained, full remission with minimal transient, cognitive side effects. This case depicts a rare presentation of AD and further adds to the growing body of literature that suggests ECT is safe and effective for treating neuropsychiatric symptoms in dementia.},
}

@article {pmid41555828,
year = {2026},
author = {Merten, N and Dawes, P and Munro, KJ and Brenowitz, WD},
title = {Hearing impairment and cognitive decline: Alternative explanations to causality.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410502},
doi = {10.1177/13872877251410502},
pmid = {41555828},
issn = {1875-8908},
abstract = {Despite growing interest in hearing impairment as a potentially modifiable risk factor for dementia, the association is poorly understood. This has implications for whether treating hearing impairment can prevent or delay onset of dementia, as causation is not the only explanation for the association. In this editorial, we highlight how biases in research studies might account for the reported associations. We suggest future research using different study designs and novel biomarkers to help us overcome methodological limitations. This may allow us to determine the strength of the causal pathways linking hearing impairment to dementia, ultimately informing prevention and treatment strategies.},
}

@article {pmid41555825,
year = {2026},
author = {Wang, EJ and Oğuztüzün, Ç and Xu, R and Gao, Z},
title = {Comparative evaluation of large language models in retrieving known and predicting novel drug combinations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415635},
doi = {10.1177/13872877261415635},
pmid = {41555825},
issn = {1875-8908},
abstract = {BackgroundLarge language models (LLMs) are increasingly used in the biomedical field for information retrieval, information extraction and knowledge discovery. However, their potential in retrieving and discovering drug combinations for diseases remains underexplored.ObjectiveThis study aims to evaluate the effectiveness of LLMs in retrieving known drug combinations and to identify novel drug combinations for treating Alzheimer's disease (AD).MethodsWe developed a series of prompts to guide LLMs in retrieving drug combinations. Their performance was evaluated using both FDA-approved combinations and combinations identified through PubMed literature mining. We then assessed the feasibility of identifying novel drug combination candidates for AD. In collaboration with domain experts, we performed pathway enrichment analyses to evaluate their potential mechanisms of action within the context of AD.ResultsIn a comparative evaluation of multiple LLMs, GPT-5 demonstrated the strongest overall performance, achieving an accuracy of 0.95 and a balanced F1 score of 0.95 in identifying FDA-approved drug combinations. Among the top 10 drug-combination candidates for AD treatment suggested by GPT-5, the combination of donepezil and memantine is already FDA-approved. Three other combinations have been tested in AD clinical trials, and three have supporting evidence in the literature. We also identified 10 off-label drug combinations, with pathway enrichment analyses indicating that several target key AD-related biological pathways.ConclusionsLLMs is effective in retrieving drug combinations for a given disease and the performance varies among different language models with best performance for GPT-5. However, the suggestions from LLM models require further validation to be considered reliable.},
}

@article {pmid41555820,
year = {2026},
author = {Smith, PJ and Blumenthal, JA and Ingle, K and Watkins, LL and Avorgbedor, F and Mabe, SK and Kraus, W and Tyson, C and Hinderliter, A and Sherwood, A},
title = {Lifestyle, sleep quality, and cognitive function in resistant hypertension: One-year follow-up from the TRIUMPH trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409716},
doi = {10.1177/13872877251409716},
pmid = {41555820},
issn = {1875-8908},
abstract = {BackgroundTreatment resistant hypertension (TRH) is associated with increased risk of cognitive decline, which may be reduced by healthy lifestyle changes.ObjectiveTo examine the effects of a comprehensive, rehabilitation-based lifestyle hprogram on cognitive function during a one-year follow-up of participants from the TRIUMPH clinical trial.MethodsAmong the 140 TRIUMPH participants originally randomized, 91 (65%) were available for one-year assessments prior to the COVID-19 lockdown. Participants were originally randomized to a Cardiac rehabilitation-based LIFEstyle program (C-LIFE) or to a Standardized Education and Physician Advice (SEPA) condition for 4-months. During their one-year follow-up, participants underwent assessments of sleep quality, body mass index, actigraphy-assessed physical activity levels, and cerebrovascular reactivity using functional near infrared spectroscopy (fNIRS). Cognitive function was assessed using a 45-min test battery incorporating tests of Executive Function/Learning, Memory, and Processing Speed. Regression-based models incorporating reliable change indices were used to assess cognitive change.ResultsParticipants included 91 individuals (mean age = 63.6 [SD = 8.6]), evenly distributed in biological sex and race/ethnicity, and tended to be college-educated. The C-LIFE group had more preserved cognitive functioning compared to SEPA (C-LIFE: z = -0.26 [-0.40, -0.12] versus SEPA: -0.60 [-0.81, -0.39]; d = 0.44, p = 0.008), with reduced PSQI sleep symptoms associating with more preserved cognitive function (B = -0.18, p = 0.050 per 3-points). Treatment did not improve fNIRS markers, although changes in weight and physical activity associated with fNIRS outcomes.ConclusionsLifestyle modification may help preserve cognitive functioning among individuals with resistant hypertension.},
}

@article {pmid41408289,
year = {2025},
author = {Kantor, AB and Rickert, M and Cheng, H and Flanagan, K and Salgotra, V and Suppahia, A and Ryu, JK and Widboom, PF and Warfield, JR and Akassoglou, K and Stavenhagen, JB},
title = {Development of a humanized anti-fibrin monoclonal antibody for the treatment of neuroinflammatory and retinal diseases.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {19},
pmid = {41408289},
issn = {1742-2094},
abstract = {UNLABELLED: Vascular dysfunction and subsequent innate immune activation are key players of neurodegenerative, retinal, and inflammatory diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), diabetic retinopathy (DR), and age-related macular degeneration (AMD). At sites of vascular damage, conversion of the blood coagulation protein fibrinogen to fibrin exposes a cryptic inflammatory epitope, γ377–395, which can bind CD11b/CD18 and CD11c/CD18 complement receptors on microglia, macrophages, and dendritic cells. Genetic targeting of the fibrin γ377–395 epitope or its pharmacologic inhibition with the mouse monoclonal antibody 5B8 protects from inflammation and neurodegeneration in AD and MS mouse models. Here, we present the development of THN391, a first-in-class humanized antibody, to neutralize fibrin toxicity without adverse anticoagulant effects for the treatment of neurodegenerative, retinal, and inflammatory diseases. THN391 was affinity matured with 100-fold greater affinity than 5B8, engineered to lack Fc effector function, and have improved developability properties for clinical use. THN391 blocks the interaction of fibrin with CD11b/c and does not bind fibrinogen nor interfere with coagulation, consistent with the crystal structure of its binding interface to the γ377–395 epitope. THN391 and its Fc wild-type counterpart THN313 showed preclinical efficacy in experimental autoimmune encephalomyelitis (EAE) mouse models of MS and in a rodent model of retinal disease. Both THN391 and THN313 reduced demyelination, inflammatory foci, and clinical scores in EAE, demonstrating that anti-fibrin γ377-395 antibodies function as pure antagonists, blocking fibrin from activating CD11b/c complement receptors. THN391 was as effective as the standard of care vascular endothelial growth factor (VEGF) antagonists in reducing laser-induced neovascular lesions in a rat model of neovascular macular degeneration. Taken together, these results support the clinical development of THN391 for neurological diseases and ophthalmic indications.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03650-w.},
}

@article {pmid41554303,
year = {2026},
author = {Çelik, H and Çelik, O and Aydın, Ş and Küçükler, S and Çomaklı, S and Topal, A and Akay, R and Gönüllü, S and Yıldız, MO and Alım, B and Özdemir, S},
title = {Small extracellular vesicles carrying miRNA34 in Alzheimer's disease: effects on oxidative stress, neuroinflammation, cognitive function, and mitochondrial/ferroptosis-related protein regulation.},
journal = {Gene},
volume = {},
number = {},
pages = {150014},
doi = {10.1016/j.gene.2026.150014},
pmid = {41554303},
issn = {1879-0038},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and persistent neuroinflammation. Recent studies have increasingly focused on the regulatory role of microRNAs in AD pathogenesis. In this study, we investigated the therapeutic potential of small extracellular vesicles (sEV) enriched with microRNA34 (miRNA34) to target key pathogenic mechanisms of AD. We hypothesized that miRNA34-loaded sEV could alleviate oxidative damage, inhibit neuroinflammatory responses and ferroptosis, reduce mitochondrial impairment, and ultimately improve cognitive function. We evaluated the effects of miRNA34 administration on oxidative stress markers, pro-inflammatory cytokines, synaptic plasticity indicators, and behavioral outcomes in an in vivo Aβ-induced mouse model of AD. The experimental design included five groups, each consisting of seven mice. The findings demonstrated that miRNA34-loaded sEV treatment significantly reduced oxidative stress and neuroinflammation while enhancing memory and learning performance. Overall, our results indicate that miRNA34-enriched sEV represent a promising and minimally invasive therapeutic strategy capable of modulating AD pathogenesis. This research provides a novel perspective on the potential clinical application of miRNA34 and sEVin neurodegenerative disorders.},
}

@article {pmid41553693,
year = {2026},
author = {Brandt, PJ and Pototska, O and Stys, PK},
title = {Fluorescence from dual molecular rotors allows sensitive detection of widespread brain pathology in a mouse model of Alzheimer's disease.},
journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},
volume = {},
number = {},
pages = {},
pmid = {41553693},
issn = {1474-9092},
abstract = {Amyloid fibrils formed by the misfolding and aggregation of proteins are a pathological hallmark of many neurodegenerative conditions including Alzheimer's disease (AD). Although recent studies have shown that pre-fibrillar species including low molecular-weight oligomers are more toxic in vitro than mature fibrils, and correlate better with cognitive decline in AD patients, techniques to study this subtle pathology remain limited. Here, we describe the use of the dye pair 9-(dicyanovinyl)julolidine (DCVJ) and crystal violet (CV), two fluorescent molecular rotors, to detect widespread pathology in the 5xFAD mouse model of AD via fluorescence spectroscopy. DCVJ and CV individually displayed a limited ability to detect spectral differences between WT and non-plaque areas of 5xFAD brain samples. However, when used in combination, the two probes discerned subtle but significant differences in a much higher proportion of tissue compared to either dye alone. These spectral differences were eliminated after treatment to disaggregate macromolecular protein assemblies, providing evidence that the dye pair was able to detect subtle pathology present in the parenchyma of the 5xFAD mouse brain. These findings demonstrate that the combined use of DCVJ and CV could be a valuable addition to the tools currently available to study the early stages of protein misfolding, which is essential for advancing therapeutics and diagnostic technologies in many neurodegenerative diseases.},
}

@article {pmid41552820,
year = {2025},
author = {Fakhri, S and Gravandi, MM and Majnooni, MB and Farzaei, MH and Abbaszadeh, F and Rashidi, K and Echeverría, J},
title = {Ferula ammoniacum gum aqueous extract exerts anti-inflammatory and antioxidant mechanisms to combat aluminum chloride-induced Alzheimer's disease in rats: possible involvement of opioid pathways.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1708643},
pmid = {41552820},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, significantly affects memory and behavior due to dysregulated pathways involving oxidative stress, inflammation, and opioidergic systems. Currently, no effective treatments are available, underscoring the need for novel alternatives. Ferula ammoniacum (D.Don) Spalik, M. Panahi, Piwczyński, and Puchałka [Apiaceae] (FA), an Iranian medicinal plant, is known for its anti-seizure, anti-inflammatory, and analgesic properties, with its gum utilized as a nerve tonic.

PURPOSE: This study investigates the anti-AD effects of F. ammoniacum gum aqueous extract (FAGAE) using an aluminum chloride (AlCl3)-induced Wistar rat model of AD.

MATERIALS AND METHODS: The aqueous extract, prepared by macerating powdered gum in distilled water for 48 h at ambient temperature, was subjected to phytochemical analysis using ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. Thirty rats were assigned to five different groups: one receiving saline, one receiving AlCl3 (100 mg/kg, i.p.), two receiving AlCl3 followed by oral treatment with FAGAE at doses of 50 or 100 mg/kg, and one receiving naloxone (an opioid receptor antagonist) along with AlCl3 and the effective dose of FAGAE. Behavioral changes were evaluated using the open-field, passive avoidance, and elevated plus maze tests. Furthermore, biochemical analyses were conducted to measure the serum nitrite levels, changes in weight, matrix metalloproteinase (MMP) activity, and histopathological changes in brain tissue.

RESULTS AND DISCUSSION: The phytochemical analysis of FAGAE revealed the presence of polysaccharide compounds with tentative arabinogalactan structures. FAGAE decreased step-through latency in the passive avoidance test and modified AlCl3-induced weight changes. FAGAE also significantly increased mobility, grooming, and crossing in the open-field test. Naloxone reversed the anti-AD effects of FAGAE, suggesting a possible role for opioidergic pathways in its therapeutic effects. Zymography results showed that FAGAE reduced MMP-9 activity while increasing MMP-2 activity. Histopathological analysis revealed a preserved number of intact neurons in the hippocampus, whereas reduced serum nitrite levels were observed after FAGAE administration in rats with AD.

CONCLUSION: Behavioral, biochemical, and histopathological impairments induced by AlCl3 were significantly attenuated by FAGAE, possibly through the opioidergic pathway, which combats inflammation and oxidative stress and supports neuronal survival.},
}

@article {pmid41551731,
year = {2025},
author = {Lim, S and Lee, HW and Yoon, S and Han, JW and Chung, JY and Yoon, S},
title = {Sex differences in efficacy/safety of anti-amyloid-beta monoclonal antibodies for the treatment of Alzheimer's disease.},
journal = {Translational and clinical pharmacology},
volume = {33},
number = {4},
pages = {212-223},
pmid = {41551731},
issn = {2289-0882},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. AD exhibits notable sex-related disparities in prevalence, progression, and treatment response. With the recent approval of anti-amyloid-beta monoclonal antibodies-aducanumab, lecanemab, and donanemab-understanding sex differences in their clinical effects has become increasingly relevant. This review article investigates sex differences in the pharmacokinetics, efficacy, and safety of aducanumab, lecanemab, and donanemab and discusses the possible mechanism underlying the observed differences. Although sex-specific analyses were largely underreported in clinical trials, population pharmacokinetic models identified sex as a covariate affecting clearance and volume of distribution for aducanumab and lecanemab and higher exposure to lecanemab was predicted for females. Subgroup analyses of phase 3 trials revealed that males tended to experience greater benefit from aducanumab and lecanemab, whereas females showed better response to donanemab. The overall incidence of adverse events, including amyloid-related imaging abnormalities, did not show significant differences between sexes. Potential mechanisms underlying these differences include sex-related variations in blood-brain barrier permeability, apolipoprotein E4-associated neuroinflammatory responses, and baseline disease characteristics. These findings underscore the need for future AD clinical trials to incorporate sex-based analyses and to consider sex as a key factor in optimizing treatment strategies.},
}

@article {pmid41550978,
year = {2026},
author = {Moien, MAS and Saghravanian, SJ and Fereidoni, M},
title = {Evaluating the impact of intracerebroventricular norepinephrine on spatial memory in rats: Insights into sporadic Alzheimer's pathogenesis.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {84-93},
pmid = {41550978},
issn = {2667-2421},
abstract = {One consequence of stress is the increased release of norepinephrine (NE) in the central nervous system, primarily driven by activation of the sympathetic nervous system. Given the importance of chronic stress in the development and progression of Alzheimer's disease (AD), clarifying the specific contributions of stress-related pathways, including the sympathetic axis and the hypothalamic-pituitary-adrenal (HPA) axis, is critical. In this study, we examined the effects of repeated central NE administration, as a potential contributor to stress-related cognitive impairment, on spatial memory in rats, alone or in combination with a low-dose streptozotocin (STZ) model of sporadic AD. Forty-nine rats were assigned to seven groups: control (no treatment), sham (saline; i.c.v.), low-dose streptozotocin (0.5 mg/kg, i.c.v.), norepinephrine administration at either 1 (adolescent) or 3 (adult) months of age (30 or 50 μg, respectively; i.c.v.), and co-administration of norepinephrine with streptozotocin at 1 or 3 months of age. Spatial memory was assessed using the Morris Water Maze test. Norepinephrine administration during adolescence and adulthood impaired spatial memory similar to streptozotocin in different parameters of the MWM, with adult rats showing the most significant vulnerability (p < 0.001). However, co-administration of both substances did not exacerbate the impairment caused by each alone. The results suggest that norepinephrine may impair cognition through mechanisms distinct from those of STZ-induced deficits. Additionally, they raise questions about the contribution of the sympathetic axis of chronic stress to the progression of sporadic AD.},
}

@article {pmid41550956,
year = {2025},
author = {Piccolino, I and Iannuzzi, F and Lionetti, L and Mazzonello, B and Barreca, V and Banaj, N and Arezzini, V and Piras, F and Bossù, P},
title = {The immunomodulating effect of palmitoylethanolamide on human myeloid dendritic cells and its possible impact on Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1664164},
pmid = {41550956},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/drug therapy/metabolism ; *Palmitic Acids/pharmacology ; *Dendritic Cells/immunology/drug effects/metabolism ; *Ethanolamines/pharmacology ; *Amides/pharmacology ; *Myeloid Cells/immunology/drug effects/metabolism ; Cells, Cultured ; *Immunomodulation/drug effects ; *Immunologic Factors/pharmacology ; },
abstract = {Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has emerged as a promising therapeutic candidate for neurodegenerative disorders, particularly Alzheimer's disease (AD). Recognized for its inherent anti-inflammatory, analgesic, immunomodulatory, and neuroprotective properties, PEA possesses a good potential as a novel treatment addressing neuroinflammation associated with neurodegeneration, even though its precise mechanisms of action remain to be fully understood. Dendritic cells (DCs) are specialized migratory innate immune cells that play a crucial role in initiating and regulating immune responses and inflammation in both the body and the brain. In AD, DCs display a dysfunctional, pro-inflammatory profile, suggesting their involvement in disease pathology and progression. To explore the therapeutic potential of PEA, this study investigated its effects in vitro on human monocyte-derived DCs under both normal and AD-like conditions. The results show that PEA exerts significant immunomodulatory effects, promoting the maturation of DCs in both healthy and disease states. Notably, PEA treatment appears to correct the dysregulated state of DCs observed in AD conditions. This study reveals a novel mechanism by which PEA modulates immune activity through its action on DCs. By restoring normal DC function in neurodegenerative settings, PEA may help reduce inflammation, highlighting its potential as a therapeutic agent for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/immunology/drug therapy/metabolism
*Palmitic Acids/pharmacology
*Dendritic Cells/immunology/drug effects/metabolism
*Ethanolamines/pharmacology
*Amides/pharmacology
*Myeloid Cells/immunology/drug effects/metabolism
Cells, Cultured
*Immunomodulation/drug effects
*Immunologic Factors/pharmacology

@article {pmid41550591,
year = {2026},
author = {Madhi, I and Kim, JH and Shin, HS and So, YH and Jung, EM and Kim, Y},
title = {Ginsenoside Re mitigates Aβ1-42-induced neurotoxicity by promoting autophagy and suppressing NLRP3 inflammasome.},
journal = {Journal of ginseng research},
volume = {50},
number = {1},
pages = {100911},
pmid = {41550591},
issn = {1226-8453},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and neuroinflammation. Activation of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in microglia significantly contributes to AD-associated neuroinflammation and neuronal damage. Ginsenoside Re (G-Re), a major bioactive constituent of Panax ginseng, exhibits anti-inflammatory properties, but its role in modulating inflammasome activation in AD remains unclear.

METHODS: This study evaluated the therapeutic potential of G-Re in mice intracerebroventricularly injected with Aβ1-42 and delineated its molecular mechanisms in complementary cell-based models. We employed behavioral testing, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assays, Annexin V apoptosis assays, and mitochondrial functional assays.

RESULTS: Intraperitoneal administration of G-Re significantly improved cognitive performance, as evidenced by enhanced outcomes in the T-maze and novel object recognition tests. G-Re treatment reduced microglial activation and interleukin-1β (IL-1β) levels in the cortex and hippocampus. In vitro, G-Re protected neurons from conditioned medium derived from Aβ1-42-stimulated microglia, showing neuroprotection comparable to anti-IL-1β treatment. G-Re also inhibited Aβ1-42-induced activation of the NLRP3 inflammasome, as indicated by diminished levels of NLRP3, cleaved caspase-1, cleaved gasdermin D (GSDMD), IL-1β, and IL-18 in brain tissues and cultured microglia. Mechanistically, G-Re reduced mitochondrial reactive oxygen species (mtROS), preserved mitochondrial membrane potential, and activated autophagy via SIRT1/AMPK/mTOR signaling, thereby suppressing inflammasome activation.

CONCLUSION: G-Re ameliorates Aβ1-42-induced neuroinflammation and cognitive impairment by restoring mitochondrial homeostasis, enhancing autophagy, and suppressing NLRP3 inflammasome activation. These findings suggest G-Re as a potential therapeutic intervention for neurodegenerative disorders including AD.},
}

@article {pmid41550486,
year = {2026},
author = {Gao, H and Yang, S and Zhaorong, O and Wang, Y and Tang, J and Hou, Q and Fang, Z and Shao, N and Cai, B},
title = {Aloe-emodin attenuates Aβ25-35-induced HT22 cell pyroptosis via inhibiting NLRP3 inflammasome pathway.},
journal = {3 Biotech},
volume = {16},
number = {2},
pages = {71},
pmid = {41550486},
issn = {2190-572X},
abstract = {Neuronal death in Alzheimer's disease (AD) is closely associated with NLRP3 inflammasome-mediated pyroptosis. This study aimed to investigate the protective effects of Aloe-emodin (AE) in an AD cellular model and to explore the underlying mechanisms involving the NLRP3 inflammasome pathway. Molecular docking simulations predicted strong binding affinities between AE and key pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD), with the highest affinity observed for NLRP3. In an Aβ25-35-induced AD cellular model, AE (6 µM) significantly enhanced cell viability and alleviated pyroptotic morphological changes, including cellular swelling and rupture. EdU staining and immunofluorescence analysis further revealed that AE promoted HT22 cell proliferation and reduced Aβ deposition. Moreover, assessments of plasma and mitochondrial membrane integrity, via Hoechst 33,342/PI staining and mitochondrial permeability transition pore (MPTP) assay, respectively, revealed that AE treatment reduced the population of PI-positive cells and suppressed MPTP opening. Western blot, immunofluorescence, and ELISA analyses consistently demonstrated that AE downregulated the expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD, GSDMD-N) and suppressed the release of inflammatory cytokines (IL-1β, IL-18, IL-6, TNF-α). The inhibitory effect of AE on the pyroptosis pathway was comparable to that of the specific NLRP3 inhibitor MCC950. These results suggest that AE exerts neuroprotective effects in the AD cellular model by inhibiting NLRP3 inflammasome activation, thereby blocking Caspase-1 and GSDMD-N activation, attenuating neuronal pyroptosis, reducing inflammatory responses, and mitigating Aβ-induced pathological damage. Collectively, these findings identify AE as a promising therapeutic candidate for AD.},
}

@article {pmid41549413,
year = {2026},
author = {Burns, JM and Alford, S and Coppinger, J and Jiménez-Mausbach, M and Ray, S and Pandey, H and Laird, R},
title = {Early Alzheimer's diagnosis: U.S. primary care physicians and use of blood biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e70986},
doi = {10.1002/alz.70986},
pmid = {41549413},
issn = {1552-5279},
support = {//Novo Nordisk Inc./ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; *Physicians, Primary Care/psychology ; United States ; Male ; Female ; *Attitude of Health Personnel ; Early Diagnosis ; Middle Aged ; },
abstract = {INTRODUCTION: We aimed to explore primary care physicians' (PCP) attitudes, perceptions, and barriers toward Alzheimer's disease (AD) diagnosis and incorporating blood biomarker (BBM) tests into the diagnostic workflow.

METHODS: Remote 60-min interviews with 20 PCPs were conducted (May 2023). Participants included generalists and geriatricians representing urban, suburban, and rural U.S. practices. Interviews encompassed early AD diagnosis, PCP role, and BBM test implementation.

RESULTS: Most PCPs view investigating cognitive decline as an important part of their role and are somewhat confident in diagnosing AD. Barriers include the complexity and inefficiency of current diagnostic workflows, lack of effective treatments, and stigma. PCPs consider BBM tests accurate and cost-effective but have concerns about reimbursement and diagnostic pathway placement.

DISCUSSION: PCPs are interested in AD diagnosis and receptive toward BBM testing. Education on BBM test use and AD diagnosis may benefit PCPs in the care of individuals with cognitive decline.

HIGHLIGHTS: Early Alzheimer's disease (AD) diagnosis is crucial for initiating treatment Primary care physicians (PCPs) find investigation of cognitive decline important PCPs consider blood biomarker (BBM) tests accurate and cost-effective PCPs seek clarity on reimbursement of BBM tests and their context of use Education on BBM test interpretation and AD diagnosis may benefit primary care.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
*Physicians, Primary Care/psychology
United States
Male
Female
*Attitude of Health Personnel
Early Diagnosis
Middle Aged

@article {pmid41549381,
year = {2026},
author = {Lee, S and Lee, J and Jeon, J and Lee, H and Choi, B and Hong, J and Lee, SJ},
title = {PLGA Nanoparticle-based Anti-TLR2 scFv Gene Delivery for the Treatment of Alzheimer's Disease.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25047},
pmid = {41549381},
issn = {1226-2560},
abstract = {In Alzheimer's disease (AD), persistent microglial neuroinflammation and the poor brain exposure and durability of current therapies underscore the need for new, long-acting treatments. We developed a non-viral gene therapy that suppresses microglial Toll-like receptor 2 (TLR2) signaling using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with a plasmid encoding the anti-TLR2 single-chain variable fragment (scFv33). Following intra-cisterna magna delivery, PLGA NPs exhibited microglia-biased uptake and enabled brain-wide transgene expression in mice. In 5xFAD mice, a single administration of scFv33 NPs improved recognition memory in the novel object recognition (NOR) assay, outperforming 8 weeks of weekly recombinant scFv33-Fc dosing. Histology showed selective reduction of small hippocampal Aβ plaques and a shift toward a ramified microglial morphology, indicative of reduced activation. In primary neuron-microglia co-culture, scFv33 reduced microglial hypertrophy, restored process complexity, and enhanced Aβ phagocytosis. Together, these data indicate that sustained, local expression of an anti-TLR2 scFv via a clinically translatable PLGA platform recalibrates microglial state and preferentially limits early-stage plaque accumulation, yielding cognitive benefit after a single dose.},
}

@article {pmid41550171,
year = {2024},
author = {Kamaljeet, and Singh, S and Gupta, GD and Aran, KR},
title = {Emerging role of antioxidants in Alzheimer's disease: Insight into physiological, pathological mechanisms and management.},
journal = {Pharmaceutical science advances},
volume = {2},
number = {},
pages = {100021},
pmid = {41550171},
issn = {2773-2169},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, cognitive decline, impairment in activities of daily living, and loss of independent function. Cognitive decline and brain shrinkage, particularly hippocampal atrophy, are associated with the accumulation of tau proteins. They cause inflammation, amyloid plaque deposition, neuronal loss, temporofrontal cortex atrophy, aberrant protein fragment clusters, and twisted fiber bundles. Given the significant role of oxidative processes in neurodegeneration, it is logical to consider the potential of antioxidants in the treatment of AD. Several antioxidants, including glutathione, astaxanthin, ascorbyl palmitate, catalase, and molecular hydrogen, play important roles in AD. Antioxidants interact with free radicals to neutralize them. Several studies have suggested that oxidative stress or damage is involved in the development of AD via different mechanisms and pathways. Thus, new approaches are needed to reduce the extent of oxidative damage that may be therapeutically effective against AD. Although certain antioxidants have exhibited notable benefits in animal models, their efficacy in human clinical trials has been limited, casting doubt regarding the efficacy of antioxidant treatments for AD. Therefore, a more focused and precise strategy that incorporates antioxidants is essential for slowing or stopping AD progression. The integrated role of antioxidants in reducing inflammation must be considered, because the link between inflammation and AD is undeniable. Therefore, the present study aimed to elucidate the role of antioxidants in AD, with the goal of aiding researchers in developing effective and potentially enhanced antioxidant-based therapeutic strategies.},
}

@article {pmid41552781,
year = {2022},
author = {Iddi, S and Donohue, MC},
title = {Power and Sample Size for Longitudinal Models in R - The longpower Package and Shiny App.},
journal = {The R journal},
volume = {14},
number = {1},
pages = {264-281},
pmid = {41552781},
issn = {2073-4859},
abstract = {Longitudinal studies are ubiquitous in medical and clinical research. Sample size computations are critical to ensure that these studies are sufficiently powered to provide reliable and valid inferences. There are several methodologies for calculating sample sizes for longitudinal studies that depend on many considerations including the study design features, outcome type and distribution, and proposed analytical methods. We briefly review the literature and describe sample size formulas for continuous longitudinal data. We then apply the methods using example studies comparing treatment versus control groups in randomized trials assessing treatment effect on clinical outcomes. We also introduce a Shiny app that we developed to assist researchers with obtaining required sample sizes for longitudinal studies by allowing users to enter required pilot estimates. For Alzheimer's studies, the app can estimate required pilot parameters using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Illustrative examples are used to demonstrate how the package and app can be used to generate sample size and power curves. The package and app are designed to help researchers easily assess the operating characteristics of study designs for Alzheimer's clinical trials and other research studies with longitudinal continuous outcomes. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).},
}

@article {pmid41548934,
year = {2026},
author = {Neghabi, M and Nategh, P and Stauffer, AM and Hahn, MK and Blakely, RD and Ranji, M},
title = {Elesclomol Diminishes Redox Imbalance in Peripheral Tissues of Mblac1 Knockout Mice.},
journal = {Journal of biophotonics},
volume = {19},
number = {1},
pages = {e70224},
doi = {10.1002/jbio.70224},
pmid = {41548934},
issn = {1864-0648},
support = {EY031533/NH/NIH HHS/United States ; 2154267//National Science Foundation/ ; //Florida Atlantic University I-SENSE Seed Funding to MR/ ; //Florida Department of Health award to RDB/ ; },
mesh = {Animals ; Oxidation-Reduction/drug effects ; Mice ; Mice, Knockout ; Male ; Female ; Liver/metabolism/drug effects ; Kidney/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Copper/metabolism ; *Hydrazines/pharmacology ; Organ Specificity/drug effects ; },
abstract = {OBJECTIVE: To determine whether loss of Mblac1, a gene implicated in copper metabolism and Alzheimer's disease, causes systemic mitochondrial redox imbalance and whether treatment with the copper chaperone elesclomol (ES) can restore this balance.

METHODS: We employed 3D cryoimaging to quantify redox ratio (RR) in kidneys and livers of Mblac1 knockout (KO) mice and their wildtype (WT) littermates. Mice of both sexes were administered either vehicle control (C) or ES (10 mg/kg, i.p.).

RESULTS: KO tissues exhibited reduced RR, indicating an oxidized metabolic state. ES treatment recovered 77% of the RR deficit in kidneys and 48% in livers, restoring RR to WT levels.

CONCLUSION: Mblac1 deletion disrupts mitochondrial redox homeostasis in peripheral tissues, while ES partially reverses this imbalance by restoring Cu(I)-dependent metabolism.

SIGNIFICANCE: Optical metabolic imaging reveals Mblac1 as a key regulator of systemic redox balance and supports ES as a potential therapy for Cu-linked metabolic dysfunctions.},
}

Animals
Oxidation-Reduction/drug effects
Mice
Mice, Knockout
Male
Female
Liver/metabolism/drug effects
Kidney/metabolism/drug effects
Mitochondria/metabolism/drug effects
Copper/metabolism
*Hydrazines/pharmacology
Organ Specificity/drug effects

@article {pmid41548855,
year = {2026},
author = {Jiang, A and Ma, Y and Bao, S and Shahbazi, MA and Reis, RL and Kundu, SC and Xiao, B and Shi, X},
title = {Metal-directed nanomedicines for imaging-guided disease treatment.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.01.032},
pmid = {41548855},
issn = {1878-7568},
abstract = {Metal-directed self-assembly, driven by metal-ligand coordination, represents a highly versatile and efficient strategy for constructing drug delivery systems with precisely tunable properties, inherent imaging capabilities, and broad biomedical applications. Stimuli-responsive metal-directed drug delivery systems (MDDSs), guided by advanced imaging techniques, enable precise control over their size and spatial architecture while facilitating site-specific drug release. Moreover, certain metal ions play a dual role, not only orchestrating the self-assembly process but also serving as therapeutic agents and regulatory components for the treatment of various diseases, including cancer, microbial infections, and Alzheimer's disease. This review provides a comprehensive overview of the self-assembly mechanisms underlying diverse MDDSs and their applications in image-guided therapy. Furthermore, we critically examine existing challenges in the field and propose strategic directions to propel the advancement of metal-directed self-assembly in drug delivery. Given the profound implications of this research, further exploration of the critical roles of metal coordination in self-assembly is imperative for the development of next-generation drug delivery platforms. STATEMENT OF SIGNIFICANCE: This review systematically summarize the self-assembly mechanisms of metal-directed drug delivery systems, outlines their applications in image-guided therapy and discusses the current challenges that remain. Furthermore, it elucidates the unique regulatory roles of metal ions in precise drug release and multimodal therapy, providing valuable insights and broad appeal for the development and clinical translation of next-generation smart nanomedicine platforms.},
}

@article {pmid41548697,
year = {2026},
author = {Takeda, A and Takeuchi, T and Minakawa, EN and Tanaka, N and Mochizuki, H and Nagai, Y},
title = {Blood extracellular vesicles contribute to the exercise-mediated suppression of brain Aβ pathology in the App[NL-G-F] knockin mouse model of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106120},
doi = {10.1016/j.neuint.2026.106120},
pmid = {41548697},
issn = {1872-9754},
abstract = {Epidemiological, clinical, and experimental evidence suggest that physical exercise suppresses the deposition of amyloid β (Aβ) plaques in the brain and reduces the risk of Alzheimer's disease (AD). However, how exercise provides such beneficial effects on AD remains largely unclear. In this study, we show that the exercise-mediated suppression of Aβ deposition requires blood extracellular vesicles (EVs) that are upregulated by exercise. We demonstrated that treadmill exercise induces a transient increase in the secretion of blood EVs in both wild-type mice and the App[NL-G-F] knockin mouse model of AD. Comprehensive analysis of protein contents of the exercise-induced blood EVs demonstrated that molecular chaperones, such as heat shock proteins and cochaperones, are substantially increased, together with substantial changes in proteomic profiles after exercise. Importantly, long-term exercise led to the suppression of Aβ plaque deposition in App[NL-G-F] knockin mice, but this suppressive effect was almost completely diminished by the pharmacological inhibition of EV secretion. These results indicate that the secretion of blood EVs is increased by exercise, which contributes to the suppression of Aβ pathology in the brain. Our study identifies blood EVs as a key mediator of the benefits of exercise throughout the body including the brain, highlighting the therapeutic potential of exercise-induced EVs for the treatment of AD pathology.},
}

@article {pmid41548619,
year = {2026},
author = {Shao, S and Zu, R and Lu, H and Yuan, Y and Chen, Y and Wu, C and Yang, Y and Shao, S and Ma, H and Zhang, Z and Sun, Y},
title = {Kai-Xin-San alleviates Alzheimer's disease by targeting the DHFR-mediated folate-mitochondrial axis.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121230},
doi = {10.1016/j.jep.2026.121230},
pmid = {41548619},
issn = {1872-7573},
abstract = {Kai-Xin-San (KXS) is a classical herbal formula first recorded in the Tang Dynasty and has been used for more than 1,000 years for cognitive impairment and dementia.

AIM OF THE STUDY: To investigate whether KXS granules (KXSG) alleviate mitochondrial dysfunction in AD by engaging dihydrofolate reductase (DHFR) -linked folate metabolism.

MATERIALS AND METHODS: The pharmacodynamic effects of KXSG were evaluated in APP/PS1 transgenic mice using behavioral testing, neuropathological assessment, and ultrastructural examination of mitochondria. Pathways and candidate targets were first prioritized by brain-tissue DIA proteomics, and were further supported by a network pharmacology analysis based on putative brain-penetrant constituents. Mechanistic validation was performed both in vivo using APP/PS1 transgenic mice and in vitro using an APP-overexpressing HT22 cell model. Mitochondrial function, folate-cycle-related indices, and target protein expression were assessed in both systems, and pharmacological inhibition of DHFR with methotrexate was employed to probe causality.

RESULTS: KXSG treatment improved learning and memory performance, preserved hippocampal neuronal integrity, and reduced Aβ burden in APP/PS1 mice. Proteomic profiling showed that proteins reversed by KXSG were enriched for mitochondrial localization and were closely linked to folate metabolism. DHFR emerged as a key candidate within this network. In cellular assays, KXSG mitigated AD-related mitochondrial impairment while partially normalizing folate-cycle-associated markers and DHFR expression. Notably, methotrexate, a DHFR inhibitor, attenuated the mitochondrial benefits conferred by KXSG.

CONCLUSION: These data support DHFR-associated folate metabolism as an important mechanistic axis through which KXSG promotes mitochondrial function in AD, providing experimental evidence for a folate-mitochondria link underlying its neuroprotective effects.},
}

@article {pmid41548526,
year = {2026},
author = {Moon, SY and Chen, TF and Lee, BC and Moon, WJ and Kandiah, N and Kumar, S and Park, YH and Inaba, K and Dash, A},
title = {A regional framework for the detection and management of ARIA with anti-amyloid therapies in early Alzheimer's disease in Asia.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100477},
doi = {10.1016/j.tjpad.2026.100477},
pmid = {41548526},
issn = {2426-0266},
abstract = {Alzheimer's disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.},
}

@article {pmid41548335,
year = {2026},
author = {Dong, W and Yuan, Q and Wu, B and Gao, S and Zhang, Y and Pan, Y and Zhou, K and Jiang, H},
title = {Age at type 2 diabetes onset and risk of dementia: The modifying role of genetic susceptibility and mitochondrial function.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {3},
pages = {100780},
doi = {10.1016/j.jnha.2026.100780},
pmid = {41548335},
issn = {1760-4788},
abstract = {OBJECTIVES: To assess dementia risk after incident type 2 diabetes (T2D) by age at diagnosis and evaluate modification by treatment, genetic susceptibility, and mitochondrial function.

DESIGN: Prospective 1:1 age- and sex-matched cohort study using inverse-probability-weighted Cox models.

SETTING: Kunshan Aging Research with E-health (KARE) cohort in China (2018-2024).

PARTICIPANTS: 42,514 adults without diabetes or dementia at baseline, including 21,257 incident T2D cases and 21,257 non-diabetic controls.

MEASUREMENTS: Outcomes were all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) from linked medical records and annual examinations. T2D onset age was grouped as 45-54 years, 55-64 years, and persons 65 years and older. In genotyped participants (n = 14,455), a T2D polygenic risk score (PRS) and blood mitochondrial DNA copy number (mtDNA-CN) were examined.

RESULTS: Over a median 3.67 years, incident T2D was associated with higher risks of all-cause dementia (adjusted hazard ratio [AHR] 1.95, 95% CI 1.71-2.21), AD (2.21, 1.88-2.59), and VaD (1.57, 1.20-2.07). Glucose-lowering treatment was associated with lower dementia risk versus no treatment. Among patients aged 55-64 years, the low-PRS/low-mtDNA-CN subgroup had the highest AD risk (AHR 2.41, 95% CI 1.12-5.19).

CONCLUSION: Age at T2D onset was associated with variation in dementia risk. Earlier diagnosis and treatment were associated with lower observed cognitive risk, while genetic susceptibility and mitochondrial function may inform individualised risk stratification.},
}

@article {pmid41547241,
year = {2025},
author = {Reichau, K and Crouzier, L and Gehrig, T and Flake, A and Schaller, E and Meunier, J and Bertrand-Gaday, C and Chatonnet, A and Zvejniece, L and Sotriffer, C and Maurice, T and Decker, M},
title = {Targeting neuroinflammation by activation of the sigma-1 receptor (S1R) and inhibition of butyrylcholinesterase (hBChE) leads to highly potent anti-amnesic compounds in an Alzheimer's disease mouse model.},
journal = {European journal of medicinal chemistry},
volume = {305},
number = {},
pages = {118486},
doi = {10.1016/j.ejmech.2025.118486},
pmid = {41547241},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective preventative or curative treatment has yet been identified. Due to the multifactorial nature and complex pathophysiology of the disease, we developed a multi-target ligand that both inhibits human butyrylcholinesterase (hBChE), a key enzyme linked to β-amyloid plaque formation, and activates the sigma-1 receptor (S1R), which modulates neuroinflammatory and protective pathways. To this end, a series of isoindolines were designed and synthesized, and their biological activities were evaluated. The most promising compound, 7c, exhibited significant dual activity, achieving nanomolar IC50 values against hBChE and potent S1R activation. Subsequent in vivo studies in an Aβ25-35 mouse model revealed a remarkable improvement in cognitive deficits in both short- and long-term memory at an effective dose of 0.01 mg/kg in WT Swiss-OF1 mice. This dose is 10-fold lower compared to single-target compounds 7a and 7b of this isoindoline series. The lack of neuroprotective effects in BChE knock-out (KO) mice confirmed the involvement of BChE inhibition in the pharmacological effects of compound 7c in WT mice. Further combinatorial studies employing a two-drug combination demonstrated synergy in the neuroprotective effect of addressing the two targets.},
}

@article {pmid41546910,
year = {2026},
author = {Elyasi, L and Wężyk, M},
title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119001},
doi = {10.1016/j.biopha.2026.119001},
pmid = {41546910},
issn = {1950-6007},
abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.},
}

@article {pmid41546373,
year = {2026},
author = {Massoumzadeh, P and Tiemann-Powles, S and Naghashzadeh, M and Rizzo, J and Hu, J and Yaeger, LH and Alkelani, H and Wang, Q and Chen, G and Dolatshahi, M and Joseph-Mathurin, N and Benzinger, TLS},
title = {Sex Differences in Alzheimer's Disease: A Systematic Review of Two Decades of Neuroimaging Research.},
journal = {The British journal of radiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/bjr/tqag011},
pmid = {41546373},
issn = {1748-880X},
abstract = {OBJECTIVES: Given the heterogeneous nature of Alzheimer's Disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain.

METHODS: : This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging.

RESULTS: : After a three-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as Magnetic Resonance Imaging (MRI), amyloid-beta Positron Emission Tomography (PET), tau-PET, and Fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression.

CONCLUSIONS: Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes.

ADVANCES IN KNOWLEDGE: This systematic review identifies sex-specific patterns in neuroimaging biomarkers of Alzheimer's Disease, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy.},
}

@article {pmid41544372,
year = {2026},
author = {Rosenberg, A and Solomon, A and Bonnard, A and Daniilidou, M and Hagman, G and Hall, A and Matton, A and Öhlund-Wistbacka, U and Westman, E and Kivipelto, M},
title = {Preparing for the implementation of anti-amyloid therapies in Europe: Assessing real-world eligibility for lecanemab and donanemab in a Swedish memory clinic.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100476},
doi = {10.1016/j.tjpad.2025.100476},
pmid = {41544372},
issn = {2426-0266},
abstract = {Lecanemab and donanemab are the first anti-Aβ treatments to receive approval in Europe. Eligibility criteria are strict, eg., APOE ε4/4 carriers are excluded. Successful implementation in public healthcare hinges on accurate estimates of eligibility rates in settings which will be the first to roll out the treatments (specialized memory clinics with early disease stages). We applied the appropriate use recommendations (AUR) to assess treatment eligibility in a Swedish tertiary memory clinic where Aβ and APOE assessments are routinely performed. Of the full cohort (N = 410), 26 and 25 patients met the AUR criteria for lecanemab and donanemab, respectively (6 %; partial overlap between the groups). After excluding APOE ε4/4 carriers in line with the European guidelines, only 14 and 13 patients remained eligible (3 %). In clinics with younger populations, a significant percentage of potentially eligible patients are likely to have the APOE ε4/4 genotype. These findings are important to inform the implementation of anti-Aβ treatments.},
}

@article {pmid41543510,
year = {2026},
author = {Dumoulin, D and Ghrayeb, M and Côté, S and Garneau, D and Chai, L and Frost, EH and Fülöp, T and Beauregard, PB},
title = {Bidirectional relationship between the biofilm of Porphyromonas gingivalis and the amyloid-beta peptide.},
journal = {Microbiology spectrum},
volume = {},
number = {},
pages = {e0198125},
doi = {10.1128/spectrum.01981-25},
pmid = {41543510},
issn = {2165-0497},
abstract = {UNLABELLED: Periodontitis and Porphyromonas gingivalis infections are significant risk factors for the onset of Alzheimer's disease (AD). Despite the reliance of P. gingivalis on its biofilm for its survival and virulence, the impact of the extracellular matrix on AD's neuropathological hallmarks has never been examined. In this study, we report a bidirectional relationship between the amyloid-beta (Aβ) peptide, which plays a central role in AD, and the biofilm of P. gingivalis. Using multiple fluorescent markers for biofilm components, we observed that Aβ1-40 inhibited biofilm formation while Aβ1-42 increased extracellular matrix production. Also, using thioflavin T staining and atomic force microscopy, we observed co-aggregation of the biofilm and monomeric Aβ1-40, resulting in faster aggregation and significant changes in aggregate structure. Our findings propose mechanistic explanations for the role of P. gingivalis as a risk factor for AD and offer potential mechanisms for microbial involvement in AD etiology.

IMPORTANCE: While the etiology of Alzheimer's disease has been studied extensively for the past 50 years, its exact causes remain unknown. Our current understanding is that the accumulation of multiple genetic and environmental risk factors would lead to the onset of the disease. Porphyromonas gingivalis is a bacterium that produces biofilm and elicits periodontitis, a chronic infection of the gums that constitutes a risk factor for Alzheimer's disease. While studies have looked at the effects of P. gingivalis in triggering Alzheimer's symptoms in animal models, none have explored the impact of the biofilm, which is essential in this bacterium. Our study seeks to bridge that gap by demonstrating a bidirectional relationship between P. gingivalis biofilm and amyloid beta, one of the brain lesions involved in Alzheimer's disease. By understanding the risk factors involved in Alzheimer's disease and their impact, we aim to provide valuable insights on prevention and treatment.},
}

@article {pmid41543367,
year = {2026},
author = {Bhagunde, P and Penner, N and Willis, BA and Bell, R and Charil, A and Irizarry, MC and Hersch, S and Reyderman, L},
title = {Brain Amyloid Plaque Levels Affect Clinical Progression in Alzheimer Disease: Assessment of Amyloid PET and Change in CDR-SB Utilizing Semi-Mechanistic Model.},
journal = {CPT: pharmacometrics & systems pharmacology},
volume = {15},
number = {2},
pages = {e70173},
doi = {10.1002/psp4.70173},
pmid = {41543367},
issn = {2163-8306},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Disease Progression ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage/pharmacology ; *Plaque, Amyloid/drug therapy/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism/diagnostic imaging/drug effects ; Male ; Aged ; Female ; Double-Blind Method ; Models, Biological ; },
abstract = {Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid-beta (Aβ) protein. In clinical studies, lecanemab has been shown to reduce amyloid markers in early symptomatic Alzheimer's disease and slow decline on clinical endpoints of cognition and function. Nonlinear mixed-effects modeling assessed the correlation between amyloid PET and change in CDR-SB using data from lecanemab phase 2 study (Study 201) and phase 3 study (Study 301; Clarity AD). Data from placebo-treated subjects were used to establish a disease-progression model; the effect of amyloid reduction on disease progression was defined using data from lecanemab-treated subjects. CDR-SB scores were used with beta regression to fit a Richard's function parameterized in terms of baseline CDR-SB, intrinsic rate of disease progression, shape, and precision of the beta distribution. Simulations were conducted to evaluate the impact of lecanemab treatment over 4 years. Baseline CDR-SB was predicted by diagnosis and baseline mini-mental state examination (BMMSE) score. Intrinsic rate of disease progression was predicted by amyloid PET and BMMSE. Amyloid PET was a better predictor of drug effect than lecanemab exposure, demonstrating amyloid reduction as a surrogate marker of efficacy. Simulations projected the difference in CDR-SB between lecanemab and placebo treated subjects continued increasing over 4 years. Patients with low baseline amyloid and less severe disease were projected to have slower disease progression and better outcomes with lecanemab treatment.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
Positron-Emission Tomography
Disease Progression
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage/pharmacology
*Plaque, Amyloid/drug therapy/diagnostic imaging/metabolism
Amyloid beta-Peptides/metabolism
*Brain/metabolism/diagnostic imaging/drug effects
Male
Aged
Female
Double-Blind Method
Models, Biological

@article {pmid41541199,
year = {2026},
author = {Salah, RS and El-Sayed, NF and El-Hussieny, M and Mansour, ST and Othman, M and Fouad, MA and Rashdan, HRM and Ewies, EF and Gharib, HSA and Elsayed, GH},
title = {Design and synthesis of new phosphazine and triazole derivatives for treatment of Alzheimer's disease: modulating ROS/JNK and Wnt/β-catenin signaling pathways.},
journal = {RSC advances},
volume = {16},
number = {4},
pages = {3077-3100},
pmid = {41541199},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and the accumulation of amyloid-β (Aβ) peptides. In this study, a novel series of triazole and phosphazine derivatives were synthesized and evaluated for neuroprotective activity in an aluminum chloride (AlCl3)-induced rat model of AD. Among the synthesized compounds, 3a, 6a, and 6c were structurally characterized and selected for in vivo biological evaluation. Behavioral, biochemical, molecular, and histopathological assessments were conducted to determine their efficacy, with Rivastigmine used as a reference drug. Compounds 3a and 6c significantly improved cognitive and memory performance, decreased Aβ1-42 production, and reduced reactive oxygen species (ROS) generation. Furthermore, both compounds inhibited the activation of JNK and Puma, promoted Beclin-1 expression, and activated Wnt/β-catenin signaling, as evidenced by increased expression levels of Wnt7a, β-catenin, LRP6, and FZD4, alongside decreased expression levels of GSK-3β and BACE1. Molecular docking studies supported these findings, revealing strong binding affinities of the active compounds, particularly 3a, to the JNK3 active site. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 3a to confirm the formation of a stable complex with JNK3. Compounds 3a, 6a, and 6c demonstrated favorable pharmacokinetic profiles, with predicted good oral bioavailability, blood-brain barrier permeability, and non-substrate behavior toward P-glycoprotein. They are expected to maintain therapeutic availability in systemic circulation, as indicated by the predicted plasma protein binding below 90%, moderate to high steady-state volume of distribution, and lack of substrate affinity for cytochrome P450 enzymes CYP2C9 and CYP2D6. These results suggest that compounds 3a and 6c may serve as promising multi-target therapeutic candidates for AD by modulating oxidative stress, apoptosis, autophagy, and Wnt/β-catenin signaling pathways.},
}

@article {pmid41540764,
year = {2026},
author = {Kanwal, A and Azeem, B and Nasir, H and Mumtaz, F and Ashraf, N and Amin, MHJ and Kanwal, W and Khan, BW},
title = {Exploring Adjunctive Novel Therapeutic Approach of KarXT (Xanomeline-Trospium Chloride) for Managing Psychotic Symptoms in Patients With Schizophrenia and Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {1},
pages = {e71182},
pmid = {41540764},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Schizophrenia/drug therapy/complications ; *Psychotic Disorders/drug therapy ; *Antipsychotic Agents/pharmacology/therapeutic use ; Quality of Life ; },
abstract = {BACKGROUND: Acute psychotic symptoms like delusions and hallucinations are of major concern while treating patients with schizophrenia and alzheimer's psychosis, primarily impacting their daily life functioning and quality of life. The traditional antipsychotic medications, commonly prescribed to manage these symptoms, cause significant side effects with limited efficacy, requiring novel therapeutic agents that can overcome this challenge. While there is no definitive cure, symptomatic treatment can help relieve some of the symptoms and improve the quality of life of people with alzheimer's disease (AD).

METHOD: A comprehensive literature search of PubMed, scopus, google scholar, and ClinicalTrials.gov was conducted to identify studies on xanomeline-trospium chloride (KarXT) in schizophrenia and AD psychosis. After screening 802 unique records, 39 studies-including preclinical, clinical, and observational investigations-were included in this narrative review. Only English-language publications up to February 2025 were considered.

RESULT: KarXT, with its dual action on the M1 and M4 receptors and mAChR antagonism, greatly helps reduce the severity of the positive and negative symptoms, as it resulted in an 8.4-point greater reduction on the PANSS scale. Side effects were minimal and did not account for the discontinuation of treatment.

CONCLUSION: Psychosis is a common feature of schizophrenia and AD, most often caused by high concentrations of dopamine in the brain, characterized by hallucinations, delusions, and disorganized thinking, resulting in markedly reduced quality of life for the patient and associated caregiver. Conventional treatments targeting dopamine receptors produce extrapyramidal symptoms and metabolic side effects, leading to noncompliance with medication. KarXT, with its dual action on M1 and M4 receptors and mAChR antagonism, greatly helps reduce the severity of the positive and negative symptoms. The side effects experienced were minimal and did not account for the discontinuation of treatment.An overview of the mechanism of action, clinical trials, and classical findings of KarXT for the management of psychotic symptoms in patients with schizophrenia and alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/complications
*Schizophrenia/drug therapy/complications
*Psychotic Disorders/drug therapy
*Antipsychotic Agents/pharmacology/therapeutic use
Quality of Life

@article {pmid41540706,
year = {2026},
author = {Zhang, S and Huang, T and Yang, C and Chen, J and Lü, T and Zhang, J},
title = {[Sulforaphane reduces reactive astrocyte-mediated neuron apoptosis in vitro by inhibiting the MAPK/NF-κB signaling pathway in Aβ42 oligomer-activated astrocytes].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {1},
pages = {191-199},
pmid = {41540706},
issn = {1673-4254},
mesh = {*Isothiocyanates/pharmacology ; *Astrocytes/cytology/drug effects/metabolism ; Sulfoxides ; *Apoptosis/drug effects ; *Amyloid beta-Peptides/pharmacology ; *Neurons/cytology/drug effects/metabolism ; Signal Transduction/drug effects ; Humans ; Animals ; NF-kappa B/metabolism ; Mice ; Coculture Techniques ; Peptide Fragments/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Cell Line, Tumor ; Interleukin-6/metabolism ; },
abstract = {OBJECTIVES: To explore the effects of sulforaphane (SFN) on Aβ42-activated U87 astrocyte-mediated apoptosis of SH-SY5Y neurons in vitro.

METHODS: U87 cells treated with different concentrations of Aβ42, SFN or both were examined for changes in cell activity, IL-6 and TNF-α mRNA expression, release of IL-6 and TNF-α proteins, and expressions of p-p38, p-p65 and GFAP using CCK-8 assay, RT-qPCR, ELISA and Western blotting. SH-SY5Y neurons were co-cultured with U87 astrocytes treated with Aβ42 alone or in combination with SFN or SB203580 for 24 h, and the changes in Bax protein expression levels and viability of SH-SY5Y cells were examined. The effects of Aβ42, SFN, and their combination were also observed in astrocytes isolated from mouse brain tissues, and the indirect effects of astrocyte treatmentt on viability of the co-cultured primary neurons were assessed.

RESULTS: The viability of U87 astrocytes increased significantly following treatment with 1.25 μmol/L Aβ42 but decreased after Aβ42 treatment above 5 μmol/L. SFN treatments for 24 h below 5 μmol/L did not significantly affect U87 cell viability. Aβ42 treatment significantly increased protein expressions of p-p38, p-p65 and GFAP, mRNA expression levels of IL-6 and TNF-α, and IL-6 and TNF-α levels in culture supernatant of U87 cells. SH-SY5Y cells co-cultured with Aβ42-treated U87 cells showed significantly increased protein expressions of Bax, and exhibited lowered viability following co-culture with 5 μmol/L Aβ42-treated U87 cells. The isolated mouse astrocytes showed lowered viability following Aβ42 treatment above 10 μmol/L, but SFN treatment below 5 μmol/L for 24 did not obviously affect the cell viability. The primary neurons co-cultured with Aβ42-treated mouse astrocytes showed significantly lower cell viability than those co-cultured with the astrocytes treated with Aβ+SFN or Aβ+SB203580.

CONCLUSIONS: SFN attenuates astrocyte-mediated neuron apoptosis by inhibiting the MAPK/NF-κB signaling pathway in Aβ42 oligomer-activated astrocytes.},
}

*Isothiocyanates/pharmacology
*Astrocytes/cytology/drug effects/metabolism
Sulfoxides
*Apoptosis/drug effects
*Amyloid beta-Peptides/pharmacology
*Neurons/cytology/drug effects/metabolism
Signal Transduction/drug effects
Humans
Animals
NF-kappa B/metabolism
Mice
Coculture Techniques
Peptide Fragments/pharmacology
Tumor Necrosis Factor-alpha/metabolism
Cell Line, Tumor
Interleukin-6/metabolism

@article {pmid41540543,
year = {2026},
author = {Singh, NK and Kumar, Y and Chandra, M and PadmaPriya, G and Sharma, Y and Mishra, S},
title = {Betanin: A Natural Phytomolecule for the Intervention of Neurological Disorders.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266398457251014040532},
pmid = {41540543},
issn = {1873-4294},
abstract = {Betanin is widely consumed around the globe either as beetroot directly or as one of the key ingredients in food and pharmaceutical preparations. The health benefits of Betanin, including the treatment of numerous neurological diseases and brain cancer, have been reported extensively. Betanin has gained global attention due to notable anti-inflammatory, antioxidant, and anti-cancer activities. Recently, there has been growing attention on the usage of Betanin to prevent or delay the onset of neurodegenerative disorders. This review recapitulates available information from various recent pre-clinical studies on Betanin in several neurological diseases, such as Parkinson's disease, Alzheimer's disease, aging, brain stroke, anxiety, and neuropathic pain. Betanin exhibits remarkable neuroprotective effects via activation of the Nrf2 signaling pathway, inhibition of the production and expression of pro-inflammatory mediators and reactive oxygen species, along with suppression of the NF-κB signaling pathway. Taking betanin as part of a healthy diet may aid in the management of various brain-related disorders. This review focuses on the neurological conditions for which betanin has shown therapeutic potential, highlighting its beneficial properties, cellular and molecular mechanisms of action, and its relevance in light of current research. Based on the available evidence, betanin could be considered a promising candidate and lead compound in the drug development process for the prevention, treatment, and management of several neurological disorders in the future.},
}

@article {pmid41540503,
year = {2026},
author = {Song, C and Wu, PY and Huffman, WJ and David-Bercholz, J and Bedolla, A and Velagapudi, R and Njoroge, A and Rodriguiz, RM and Wetsel, WC and Rendina, D and Bilbo, SD and Chiang, W and Ogu, JC and Gelbard, HA and Yang, T and Grill, WM and Terrando, N},
title = {Electrical stimulation of the vagus nerve improves amyloid pathology in delirium superimposed on dementia.},
journal = {Bioelectronic medicine},
volume = {12},
number = {1},
pages = {2},
pmid = {41540503},
issn = {2332-8886},
support = {AARF-24-1313412/ALZ/Alzheimer's Association/United States ; 2019-AARG-643070/ALZ/Alzheimer's Association/United States ; R01-AG057525, R01-AG083979A1, RF1-AG079138, R21-AG055877/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Delirium and delirium superimposed on dementia (DSD) are common complications affecting patients suffering from ongoing neurodegenerative pathologies. Peripheral surgical trauma can trigger neuroinflammation and ensuing DSD via mechanisms that remain poorly understood. Given the multifactorial therapeutic effects of neuromodulation, including vagal nerve stimulation, we have tested a minimally invasive approach to combat DSD following orthopedic surgery.

METHODS: We performed orthopedic surgery on 5xFAD and CVN-AD mice and tested the efficacy of minimally invasive percutaneous vagus nerve stimulation (pVNS). We applied immunohistochemical, biochemical, and behavioral assays to evaluate the impact of surgery on postoperative delirium on DSD pathology in Alzheimer’s disease-like mice. To confirm the role of systemic factors in neuroinflammation and amyloid-β dyshomeostasis, we conducted experiments using interleukin-6 (IL-6), a cytokine commonly upregulated in postoperative delirium and in vitro co-culture assays for validation.

RESULTS: In AD-like mice surgery induced acute changes in amyloid-β; perioperative treatment with pVNS effectively reduced amyloid-β load, plaque sphericity, and neuronal loss. The rescue of these pathological hallmarks led to improved delirium-like behavior, as demonstrated by the 5-choice serial reaction time task on postoperative days 1 and 2. pVNS improved microglial morphology, particularly near amyloid-β plaques. Acute isolation of microglial cells from 5xFAD mice after surgery indicated that pVNS partially enhanced key Disease-Associated Microglia (DAM) markers. The contribution of pro-inflammatory cytokines to amyloid-β aggregation was validated using an in vitro transwell culture model following Cytomix exposure, which also caused endothelial barrier disruption. Finally, we isolated IL-6 as a well-established biomarker of postoperative delirium and described its role in DSD pathology following systemic administration.

CONCLUSION: These findings establish a role for neuromodulation after pVNS in regulating perioperative immunity and advance a new paradigm for perioperative interventions in patients at risk for DSD.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s42234-025-00194-5.},
}

@article {pmid41540481,
year = {2026},
author = {Si, X and Tian, S and Chen, Y and Li, X and Wu, G and Yao, Y and Wang, M},
title = {Investigating the molecular mechanisms of glutamine metabolism and mitochondria-related biomarkers in Alzheimer's disease through transcriptomics and experimental validation.},
journal = {European journal of medical research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40001-025-03747-1},
pmid = {41540481},
issn = {2047-783X},
support = {22JR5RA994//Natural Science Foundation of Gansu Province, China/ ; CY2022-MS-A07//Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital, China/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. This study aims to identify biomarkers associated with glutamine metabolism-related genes (GRGs) and mitochondria-related genes (MRGs) in AD through bioinformatics analysis, offering insights for prevention and treatment strategies.

METHODS: Candidate genes were first picked out through differential gene expression profiling, construction of weighted gene co-expression network analysis (WGCNA), and interaction network analysis. Biomarkers were then filtered using machine learning algorithms. For these biomarkers, expression verification and receiver operating characteristic (ROC) curve analysis were carried out. These biomarkers underwent GeneMANIA analysis, subcellular and chromosomal localization, enrichment analysis, along with immune infiltration assessment, establishment of a multi-layered molecular regulatory network, and prediction of potential therapeutic agents by leveraging drug-gene interaction databases. Finally, the consistency was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR).

RESULTS: Initially, 10 candidate genes were identified through bioinformatics analysis. Machine learning, expression validation, and ROC analysis pinpointed SNCA and PPP2R1A as biomarkers (AUC > 0.7). These biomarkers were associated with 20 functionally similar genes and were active in the nucleus and cytoplasm. SNCA was located on chromosome 4, and PPP2R1A on chromosome 19. Enrichment analysis unveiled their involvement in pathways such as olfactory transduction. Additionally, these biomarkers influenced immune cells; for instance, there was a positive correlation between PPP2R1A and type 2 T helper cells (cor = 0.66, P = 1.03 × 10[-5]). A molecular regulatory network demonstrated that these biomarkers were regulated by 134 miRNAs, and 72 potential drugs targeting these biomarkers were identified. RT-qPCR confirmed the expression consistency with bioinformatics results.

CONCLUSION: This study ultimately identified SNCA and PPP2R1A as biomarkers for AD, providing a theoretical foundation and potential targets for the diagnosis and treatment of AD.},
}

@article {pmid41540476,
year = {2026},
author = {Zhang, Y and Zhang, F and Yin, H and Sun, Y and Wang, Y and Ren, Z and Jiang, J and Zeng, L},
title = {hUC-MSC-derived exosomes ameliorate Alzheimer's disease pathology through lncRNA-9969-mediated multi-target protection involving neuronal autophagy and microglial modulation.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01954-4},
pmid = {41540476},
issn = {1758-9193},
support = {YDZJ202301ZYTS536//the Science and Technology Department of Jilin Province/ ; },
abstract = {BACKGROUND: Alzheimer's disease is characterized by intertwined pathologies including neuroinflammation, driven by microglial dysfunction, and metabolic disturbances such as lipid dyshomeostasis. Mesenchymal stem cell-derived exosomes (MSC-Exos) hold therapeutic promise, Still, it is unknown whether they can simultaneously address these co-occurring impairments via specific molecular cargos, such as long non-coding RNAs (lncRNAs).

METHODS: Transcriptome sequencing of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) revealed high expression of the long noncoding RNA ENST00000629969 (hereinafter referred to as lncRNA-9969). We isolated exosomes from hUC-MSCs (WT-Exo) and established human umbilical cord blood mesenchymal stem cells stably knocked down for lncRNA-9969 via siRNA, from which corresponding exosomes (KD-Exo) were isolated. Cross-species analysis identified the mouse homolog of lncRNA-9969 as ENSMUST00000200021 (hereinafter referred to as lncRNA-0021). Cellular experiments employed an Aβ₂₅₋₃₅-induced SH-SY5Y cell model to evaluate the protective effects of exosomes. In animal experiments, 6-month-old APP/PS1 mice received biweekly tail vein injections of WT-Exo or KD-Exo for 4 weeks. Phenotypic and mechanistic analyses were subsequently conducted using the Morris water maze, Western blot, immunofluorescence, qPCR, and transmission electron microscopy.

RESULTS: In Aβ-injured SH-SY5Y cells, WT-Exo significantly attenuated cellular damage and promoted Aβ clearance, whereas the protective effect of KD-Exo was markedly reduced. In APP/PS1 mice, WT-Exo treatment significantly improved spatial memory deficits and upregulated hippocampal expression of synaptic proteins synaptophysin (Syn) and brain-derived neurotrophic factor (BDNF). Molecular mechanism studies demonstrated that lncRNA-0021 directly binds mmu-miR-6361. Through this ceRNA mechanism, exosome-delivered lncRNA activated the mTOR/p70S6K autophagy pathway, regulated lipid metabolism-related genes, promoted microglial polarization toward the protective M2 phenotype, and suppressed pyroptosis. These beneficial changes were not observed in the KD-Exo-treated group.

CONCLUSIONS: hUC-MSC-derived exosomes exert neuroprotective effects by delivering functional lncRNA-9969. Its highly conserved homolog in mice, lncRNA-0021, achieves coordinated multi-target regulation of neuroinflammation, pyroptosis, and metabolic disturbances by sequestering miR-6361 and activating downstream signaling pathways. This study elucidates the central role of exosomal lncRNAs in AD pathology and provides new insights for developing RNA-based multi-target therapeutic strategies.},
}

@article {pmid41540303,
year = {2026},
author = {Abd El-Fattah, MA},
title = {Challenges and Opportunities of Drug Delivery for Treatment of Alzheimer's Disease.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {1},
pages = {78},
pmid = {41540303},
issn = {1530-9932},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Nanoparticles/chemistry ; Brain/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognitive functions. It represents a global health concern with increasing prevalence and devastating outcomes for the quality of life that could ultimately lead to death. AD is associated with deposition of β-amyloid (Aβ) plaques and intracellular buildup of tau proteins forming neurofibrillary tangles (NFTs), which are the main characteristics for AD brain tissues. Approved AD therapy is based mainly on symptomatic relief, and conventional medicaments often fail due to either low bioavailability, limited solubility, or failure to cross blood-brain barrier (BBB). The complexity in AD pathophysiology opens windows for many therapeutic options. So, lecanemab was recently approved by FDA as the first disease-modifying therapy. However, drug delivery to the brain remains challenging due to the nature of BBB. Hence, more extensive research is essential to develop disease-modifying therapies and also to find drug delivery strategies to ensure simplified administration and successful brain delivery. This review article summarizes AD pathogenesis with the corresponding treatment targets. It emphasizes innovative drug delivery strategies and novel formulation approaches to deliver medicines across BBB. The use of recent advancements in drug delivery to deliver medicaments across BBB are highlighted, with focus given to novel drug delivery systems and formulation of nanoparticles for brain targeting. The use of nutraceuticals, gene therapy, and stem cell therapy are is covered.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Drug Delivery Systems/methods
Blood-Brain Barrier/metabolism/drug effects
Animals
Nanoparticles/chemistry
Brain/metabolism/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid41539386,
year = {2026},
author = {Hector, A and Leduc, T and Caiado, MJDC and Delignat-Lavaud, B and Dufort-Gervais, J and Daneault, C and Des Rosiers, C and Bourguignon, C and Lina, JM and Fernandes, K and Brouillette, J and Mongrain, V},
title = {Electrocorticographic, Astrocytic and Transcriptomic Signatures in the Triple Transgenic Mouse Model of Alzheimer's Disease submitted to Stearoyl-CoA Desaturase Inhibition.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110835},
doi = {10.1016/j.neuropharm.2026.110835},
pmid = {41539386},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD) is associated with cognitive deficits and sleep disturbances. Research suggests the involvement of dysfunctions in lipid metabolism in the brain of AD patients and animal models. The inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. This project tested whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associates with modifications in lipids, astrocytic function and the transcriptome. Wild-type (WT) and 3xTg-AD female mice received a SCD inhibitor (SCDi) or vehicle, which was followed by an electrocorticographic (ECoG) recording. Brain slices were stained for lipid droplets, astrocytic markers or processed for spatial transcriptomics. The reduced time spent awake (increased time spent in slow wave sleep) in 3xTg-AD mice was not restored by SCDi treatment. Rhythmic and scale-free ECoG activities were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi changed these ECoG signatures differently in mutant in comparison to WT mice. GFAP-positive cell density and lipid droplet count were elevated in hippocampal CA1, and rescued by SCDi. The treatment also rescued the expression of several genes in a manner mainly overlapping between brain regions. The findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not mitigated by SCD inhibition, but that this treatment can revert changes in hippocampal astrocytes, lipids and in the brain transcriptome. This work will benefit the understanding of the AD pathophysiology and associated sleep disturbances.},
}

@article {pmid41537771,
year = {2026},
author = {Wang, N and Sun, Z and Chen, F and Tian, X and Li, J and He, X},
title = {Mangiferin Alleviates Formaldehyde-Induced Tau Hyperphosphorylation and Cognitive Impairment in Mice via the PI3K/AKT/GSK3β Pathway: Insights From Network Pharmacology and Experimental Validation.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {2},
pages = {e71346},
doi = {10.1096/fj.202503159R},
pmid = {41537771},
issn = {1530-6860},
support = {202401AT070082//Yunnan Fundamental Research Projects/ ; 202301BA070001-032//Yunnan Fundamental Research Projects/ ; },
mesh = {Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; Mice ; *tau Proteins/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Cognitive Dysfunction/chemically induced/metabolism/drug therapy ; *Phosphatidylinositol 3-Kinases/metabolism ; *Xanthones/pharmacology ; Phosphorylation/drug effects ; Male ; Network Pharmacology/methods ; *Formaldehyde/toxicity ; Molecular Docking Simulation ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Hippocampus/metabolism/drug effects ; },
abstract = {Studies have demonstrated that accumulation of formaldehyde (FA) in the body can result in Alzheimer's disease (AD) like changes including cognitive impairment, Aβ deposition, and Tau hyperphosphorylation. Mangiferin (MGF), a natural flavonoid compound, has been suggested in previous reports to have potential in the treatment of AD. This study integrated network pharmacology and in vivo experiments to elucidate the therapeutic potential and mechanisms of MGF in mitigating FA-induced neurotoxicity. Potential overlapping targets between MGF and AD were identified using jvenn. Functional enrichment analysis of these targets was performed with DAVID. A protein-protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape to identify hub genes. Molecular docking simulations with AutoDock were then employed to assess binding affinity. Subsequently, for experimental validation, a mouse model of FA-induced neurotoxicity was established. Spatial memory and cognitive function in mice were evaluated using the Y-maze and novel object recognition tests. The expression levels of key pathway-related proteins in the cortex and hippocampus were analyzed via immunohistochemistry (IHC) and Western blotting (WB). Network analysis identified AKT1 and GSK3β as key targets, and molecular docking confirmed strong binding affinity between MGF and these proteins. Experimental validation demonstrated that MGF dose-dependently improved spatial memory and cognitive performance in FA-exposed mice, reduced neuronal apoptosis, and suppressed Tau hyperphosphorylation at Thr181, Ser396, and Ser404. Mechanistically, MGF activated the PI3K/AKT pathway, leading to GSK3β inactivation through Ser9 phosphorylation. These findings highlight MGF as a promising therapeutic candidate for AD by targeting the PI3K/AKT/GSK3β axis.},
}

Animals
*Glycogen Synthase Kinase 3 beta/metabolism
Mice
*tau Proteins/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Cognitive Dysfunction/chemically induced/metabolism/drug therapy
*Phosphatidylinositol 3-Kinases/metabolism
*Xanthones/pharmacology
Phosphorylation/drug effects
Male
Network Pharmacology/methods
*Formaldehyde/toxicity
Molecular Docking Simulation
Signal Transduction/drug effects
Mice, Inbred C57BL
Hippocampus/metabolism/drug effects

@article {pmid41538772,
year = {2026},
author = {Liao, YS and Wai, T and Liao, TY and Chang, HL and Chang, YL and Fu, LC},
title = {Mild Cognitive Impairment Detection System Based on Unstructured Spontaneous Speech: Longitudinal Dual-Modal Framework.},
journal = {JMIR medical informatics},
volume = {14},
number = {},
pages = {e80883},
pmid = {41538772},
issn = {2291-9694},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; Aged ; Male ; Female ; Longitudinal Studies ; *Speech ; Aged, 80 and over ; Memory, Episodic ; China ; },
abstract = {BACKGROUND: In recent years, the incidence of cognitive diseases has also risen with the significant increase in population aging. Among these diseases, Alzheimer disease constitutes a substantial proportion, placing a high-cost burden on health care systems. To give early treatment and slow the progression of patient deterioration, it is crucial to diagnose mild cognitive impairment (MCI), a transitional stage.

OBJECTIVE: In this study, we use autobiographical memory (AM) test speech data to establish a dual-modal longitudinal cognitive detection system for MCI. The AM test is a psychological assessment method that evaluates the cognitive status of subjects as they freely narrate important life experiences.

METHODS: Identifying hidden disease-related information in unstructured, spontaneous speech is more difficult than in structured speech. To improve this process, we use both speech and text data, which provide more clues about a person's cognitive state. In addition, to track how cognition changes over time in spontaneous speech, we introduce an aging trajectory module. This module uses local and global alignment loss functions to better learn time-related features by aligning cognitive changes across different time points.

RESULTS: In our experiments on the Chinese dataset, the longitudinal model incorporating the aging trajectory module achieved area under the receiver operating characteristic curve of 0.85 and 0.89 on 2 datasets, respectively, showing significant improvement over cross-sectional, single time point models. We also conducted ablation studies to verify the necessity of the proposed aging trajectory module. To confirm that the model not only applies to AM test data, we used part of the model to evaluate the performance on the ADReSSo dataset, a single time point semistructured data for validation, with results showing an accuracy exceeding 0.88.

CONCLUSIONS: This study presents a noninvasive and scalable approach for early MCI detection by leveraging AM speech data across multiple time points. Through dual-modal analysis and the introduction of an aging trajectory module, our system effectively captures cognitive decline trends over time. Experimental results demonstrate the method's robustness and generalizability, highlighting its potential for real-world, long-term cognitive monitoring.},
}

Humans
*Cognitive Dysfunction/diagnosis
Aged
Male
Female
Longitudinal Studies
*Speech
Aged, 80 and over
Memory, Episodic
China

@article {pmid41537461,
year = {2026},
author = {Choi, KY and Kang, S and Cook, S and Li, D and Choi, YY and Seo, EH and Han, X and Park, JE and Lee, S and Lee, S and Chung, JY and Chong, A and Choi, SM and Ha, JM and Song, MK and Lee, JS and Choo, IH and Kim, JH and Song, HC and Kim, BC and Kim, H and Farrer, LA and Gim, J and Jun, GR and Lee, KH},
title = {The Gwangju Alzheimer's & Related Dementias (GARD) cohort: Over a decade of Asia's largest longitudinal multimodal study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e70981},
pmid = {41537461},
issn = {1552-5279},
support = {25-BR-03-05//the KBRI Basic Research Program through the Korea Brain Research Institute, funded by the Ministry of Science and ICT/ ; NRF-2014M3C7A1046041//the Original Technology Research Program for Brain Science of the National Research Foundation funded by the Korean government, MSIT/ ; RS-2024-00407198//Brain Pool program funded by the Ministry of Science and ICT through the National Research Foundation of Korea/ ; 2023-ER1007-01//Korea National Institute of Health research project/ ; //by the Technology Innovation Program (20022810, Development and Demonstration of a Digital System for the evaluation of geriatric Cognitive impairment) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea)/ ; RS-2024-00433283//the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy, Republic of Korea/ ; HR22C141105//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; },
mesh = {Humans ; Longitudinal Studies ; Male ; *Alzheimer Disease/epidemiology/diagnostic imaging/genetics/diagnosis ; Female ; Aged ; *Cognitive Dysfunction/epidemiology/diagnostic imaging ; Disease Progression ; Republic of Korea/epidemiology ; Cohort Studies ; Middle Aged ; Biomarkers ; Magnetic Resonance Imaging ; Aged, 80 and over ; Neuroimaging ; Proteomics ; Genomics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a major public health concern in Korea, with a high prevalence among older adults. A community-based longitudinal study is essential for tracking disease progression, identifying biomarkers, and developing targeted prevention and treatment strategies. The Gwangju Alzheimer's & Related Dementias (GARD) cohort was established to address these needs through a multimodal approach.

METHODS: Participants aged ≥60 years undergo comprehensive clinical evaluations, neuroimaging, and biospecimen collection for multi-omics analyses (genomics, transcriptomics, proteomics, and metagenomics) at baseline and systematic follow-up visits.

RESULTS: From over 17,000 screened individuals, 12,877 were enrolled. Baseline diagnoses include 5,123 cognitively unimpaired (CU), 3,250 mild cognitive impairment (MCI), and 2,125 AD dementia. The resource includes magnetic resonance imaging scans (n = 10,843) and extensive multi-omics data: genomic (n = 10,775), proteomic (n = 116), and microbiome (n = 595).

DISCUSSION: The integrated GARD dataset provides a powerful and scalable resource for identifying novel biomarkers, understanding disease heterogeneity, and advancing precision medicine for AD.

HIGHLIGHTS: Gwangju Alzheimer's & Related Dementias (GARD) is a large-scale, longitudinal, community-based cohort study in South Korea. The study focuses on early detection and monitoring of dementia progression. GARD includes cognitive testing, imaging, biospecimens, and multi-omics data. We aim to identify Korean-specific biomarkers predictive of cognitive decline. Supports East Asian insights and fills gaps in global Alzheimer's research.},
}

Humans
Longitudinal Studies
Male
*Alzheimer Disease/epidemiology/diagnostic imaging/genetics/diagnosis
Female
Aged
*Cognitive Dysfunction/epidemiology/diagnostic imaging
Disease Progression
Republic of Korea/epidemiology
Cohort Studies
Middle Aged
Biomarkers
Magnetic Resonance Imaging
Aged, 80 and over
Neuroimaging
Proteomics
Genomics

@article {pmid41536422,
year = {2025},
author = {Thaliath, A and Pillai, JA},
title = {Non-Cognitive Symptoms in Alzheimer's Disease and Their Likely Impact on Patient Outcomes. A Scoping Review.},
journal = {Current treatment options in neurology},
volume = {27},
number = {},
pages = {},
pmid = {41536422},
issn = {1092-8480},
support = {P30 AG072959/AG/NIA NIH HHS/United States ; },
abstract = {PURPOSE OF REVIEW: Increased understanding of the pathophysiology of Alzheimer's disease (AD) has led to development of disease modifying therapies. The therapies primarily target measures of cognitive decline since AD has been thought of as a cognitive disorder. However, the non-cognitive symptoms seen in AD contribute to overall quality-of-life. This scoping review was undertaken to further our understanding of the non-cognitive features of AD.

RECENT FINDINGS: The non-cognitive symptoms in AD range from changes in sensory perception, systemic changes, and neuropsychiatric manifestations. We targeted the following non-cognitive domains: vision, olfaction, GI, muscle, sleep, circadian rhythm, immune and behavioral symptoms as it relates to AD for this review. Non-cognitive features impact the ability of individuals to perform their activities of daily living, have safety implications and lead to increased caregiver burden. The review explores non-pharmacological and pharmacological measures targeted at the non-cognitive changes in AD.

SUMMARY: Non-cognitive symptoms contribute to significant disease burden in Alzheimer's disease. It is important to screen for and provide supportive care for these symptoms to help improve clinical care. Incorporation of non-cognitive features of AD in clinical trials will help ascertain the true societal and economic impact of AD and that of potential therapeutics.

OPINION STATEMENT: Alzheimer's disease (AD) is primarily recognized as a disorder of cognition; however, non-cognitive symptoms significantly contribute to disease burden and clinical presentation. These manifestations particularly behavioral symptoms and systemic changes beyond the central nervous system impact patients' quality of life and increase caregiver stress. Often, such symptoms necessitate a transition from home-based care to more intensive settings, such as memory care facilities. As AD prevalence rises alongside an aging population, the shortage of dedicated memory care providers in community settings challenges access and quality of care. Improved awareness and early recognition of non-cognitive features among healthcare professionals can aid identification of modifiable systemic issues and allow timely behavioral management during clinical encounters. Treatment of these symptoms requires a multifaceted approach, incorporating pharmacological and non-pharmacological strategies. Non-pharmacological interventions, including tailored behavioral approaches and environmental modifications, can enhance quality of life for individuals with AD and reduce caregiver burden especially where specialized medical resources are limited.},
}

@article {pmid41536056,
year = {2026},
author = {Dong, J and Xu, L and Xu, X and Shi, B and Wang, Q and Xu, J and Xu, C and Kuang, H and Qu, A},
title = {Chiral Spindle-like Nanorods Reprogram Neuroinflammation by Catalyzing α-Ketoglutarate Biosynthesis.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c19753},
pmid = {41536056},
issn = {1520-5126},
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, and breakthroughs in effective intervention strategies are urgently needed. Here, we report that chiral spindle-like Fe7Se8 nanorods (NRs) promote α-ketoglutarate (AKG) biosynthesis, providing a new potential route for AD intervention through modulation of neuroimmune homeostasis. Oral administration of L-NRs significantly restored intestinal microbiota homeostasis in 3 × Tg AD model mice, markedly enriched Lactobacillus johnsonii, and enhanced biosynthesis of the metabolite AKG, which reversed cognitive impairment and neuronal degeneration in 5 × FAD mice. Moreover, AKG levels in the clinical serum and cerebrospinal fluids were found to be significantly lower in patients with AD than in healthy controls. Mechanistic studies revealed that L-NRs efficiently promoted AKG biosynthesis through scavenging reactive oxygen species (ROS) to restore the activities of three enzymes in the biosynthesis pathway. Crucially, these NRs are broken down by gastric juice into smaller nanoparticles and subsequently into ions in the intestines. Further studies explored that AKG crossed the blood-brain barrier via cooperatively mediated transport proteins, targeted microglial phenotypic switching, reprogrammed the neuroinflammatory microenvironment, and ultimately ameliorated cognitive deficits and neuronal pathological alterations. Our findings suggest that AKG might serve as a therapeutic drug for the precise treatment of neurodegenerative diseases.},
}

@article {pmid41535708,
year = {2026},
author = {Yu, MJ and Xiong, RQ and Wu, JW and Li, YC and Xie, JX and Zhou, HP and Ye, GY and Chang, Y and Huang, KB and Pan, SY},
title = {β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41535708},
issn = {1745-7254},
abstract = {Cerebral edema is a severe complication following ischemic stroke. Recent studies have highlighted the crucial role of the glymphatic system (GS) in the clearance of water and macromolecules. GS dysfunction involving the disorders of AQP4 polarization may be crucial in the pathophysiology of cerebral edema. β-Hydroxybutyrate (BHB), the main component of the ketone body, has been shown to alleviate neurological deficits by restoring GS function in subarachnoid hemorrhage models and to reduce Aβ deposition in Alzheimer's disease models. In this study we investigated the effects of BHB on cerebral edema following ischemic stroke and its mechanisms. The mice were fed a ketogenic diet (KD) or a normal diet for 4 weeks before transient middle cerebral artery occlusion (MCAO). Alternatively, the mice received BHB (5 g·kg[-1]·d[-1]) or vehicle post-MCAO. By using brain section analysis, transcranial macroimaging, two-photon in vivo imaging and MRI, we demonstrated that both KD and BHB treatment significantly enhanced GS function under normal and MCAO conditions. BHB reduced cerebral edema and infarct volume post-MCAO. Notably, delayed BHB treatment initiated 10 h post-MCAO still improved GS function, but did not influence infarct volume. Furthermore, we revealed that BHB increased α1-syntrophin expression and H3K27ac levels in α1-syntrophin (Snta1) enhancer, restoring AQP4 polarization. In addition, BHB also reduced HDAC3 expression and elevated p300 expression. These results suggest that a KD and BHB treatment enhance GS function in mice and that BHB also mitigates brain edema after MCAO. The potentiation of GS function by BHB is likely mediated by the inhibition of HDAC3 activity and the increase in p300 activity, which upregulate α1-syntrophin expression and restore AQP4 polarization.},
}

@article {pmid41535445,
year = {2026},
author = {Schnieder, M and von Arnim, CAF},
title = {[Polypharmacy in patients with neuropsychiatric symptoms].},
journal = {Innere Medizin (Heidelberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {41535445},
issn = {2731-7099},
abstract = {Dementia, delirium, and depression are the main geriatric psychiatric syndromes, and their prevalence is increasing significantly due to demographic aging. At the same time, multimorbidity and polypharmacy lead to increased interaction rates and a higher frequency of side effects, as well as reduced adherence. In Germany, the number of dementia cases is projected to rise from the current 1.8 million to 2.8 million by 2050. The most common etiologies are Alzheimer's disease and vascular dementia. Progressive cognitive and motor function loss often results in apraxia and dysphagia, which complicate pharmacotherapy. Acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine are used therapeutically. Newly approved amyloid antibodies (lecanemab, donanemab) show efficacy in the early stages of Alzheimer's disease, but carry the risk of amyloid-associated imaging abnormalities (ARIA). Dementia is considered a predisposing risk factor for delirium, which is characterized by fluctuations in attention and consciousness. Delirogenic factors include polypharmacy as well as other medications such as opioids and benzodiazepines. Due to the increased risk of mortality and stroke, neuroleptics should only be administered to geriatric patients when strictly indicated, in minimal doses, and for a limited duration. Non-pharmacological interventions take precedence. Selective serotonin reuptake inhibitors (SSRIs) are considered the first-line treatment for depressive disorders in older adults, while tricyclic antidepressants should be avoided. Regular medication reviews, reduction of anticholinergic burden, and technical aids to facilitate medication intake are essential for optimizing treatment adherence.},
}

@article {pmid41533472,
year = {2026},
author = {Shah, A and Kalu, U and Chen, D and Slomkowski, M and Hobart, M and Such, P and Grossberg, GT},
title = {Brexpiprazole side-effect profile in people with agitation in Alzheimer's dementia: a plain language summary.},
journal = {Current medical research and opinion},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/03007995.2025.2608578},
pmid = {41533472},
issn = {1473-4877},
}

@article {pmid41533031,
year = {2026},
author = {Tan, FHP and Najimudin, N and Azzam, G and Zainuddin, A and Shamsuddin, S and Mohd Kasihmuddin, MS},
title = {Geroprotective effects of Salvianolic acid A through redox and detoxification pathway activation in an aging Drosophila Alzheimer's model.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {39},
pmid = {41533031},
issn = {1573-6768},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Drosophila melanogaster ; Disease Models, Animal ; *Aging/drug effects/metabolism ; Oxidation-Reduction ; Animals, Genetically Modified ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism/genetics ; *Caffeic Acids/pharmacology ; *Lactates/pharmacology ; Humans ; *Neuroprotective Agents/pharmacology ; Longevity/drug effects ; Peptide Fragments ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β42 (Aβ42) neurotoxic peptides that cause oxidative stress and neurodegeneration. The current study examined the neuroprotective properties of salvianolic acid A (SalA), an antioxidant polyphenol, in a Drosophila melanogaster model of AD. Transgenic flies expressing human Aβ42 were assayed for eye morphology, life span, and locomotor function after SalA diet supplementation. RNA-seq and RT-qPCR were used to quantify transcriptional regulation with SalA treatment. Aβ42 expression resulted in classic AD phenotypes, including retinal degeneration, shortened lifespan, and compromised climbing ability. Partial rescue of the rough-eye phenotype, significant prolongation of lifespan, and improved locomotor function in aging flies were induced by SalA treatment. Transcriptome profiling showed the upregulation of glutathione metabolism-associated, cytochrome P450 activity-associated, and antioxidant defence-associated genes, while muscle development-associated, cell adhesion-associated, and apoptosis-associated genes were downregulated. Network analysis identified a SalA-responsive gene module enriched in detoxification and immune pathways that was conducive to enhanced cellular resistance to Aβ42 toxicity. These findings identify a redox-regulated aging mechanism whereby SalA maintains neuronal and systemic homeostasis during aging. SalA inhibits Aβ42-induced neurotoxicity in Drosophila via promoting redox equilibrium and detoxification. These findings present SalA as a potential multi-target lead drug for AD and other age-related neurodegenerative diseases.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/genetics
Drosophila melanogaster
Disease Models, Animal
*Aging/drug effects/metabolism
Oxidation-Reduction
Animals, Genetically Modified
Oxidative Stress/drug effects
Amyloid beta-Peptides/metabolism/genetics
*Caffeic Acids/pharmacology
*Lactates/pharmacology
Humans
*Neuroprotective Agents/pharmacology
Longevity/drug effects
Peptide Fragments

@article {pmid41531988,
year = {2025},
author = {Benin, BM and Hillyer, T and Csubak, BA and Aguirre, N and Dengler-Crish, CM and Kang, C and Shin, WS},
title = {Investigation of Three Flavonoids as Potent Tau Aggregation Inhibitors and In vivo Demonstration of Myricetin.},
journal = {Pharmacological research. Natural products},
volume = {9},
number = {},
pages = {},
pmid = {41531988},
issn = {2950-1997},
support = {R01 AG076699/AG/NIA NIH HHS/United States ; R03 NS135326/NS/NINDS NIH HHS/United States ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), are characterized by the formation and propagation of neurotoxic tau aggregates, which arise from the misfolding and subsequent aggregation of tau proteins into fibrillary structures. While tau-targeting agents represent a promising therapeutic strategy for the prevention and treatment of various neurodegenerative diseases, they currently constitute a limited subset of the treatments undergoing clinical trials. In this study, we report the potent anti-aggregation and filament disassembly effects of three flavonols: myricetin, quercetagetin, gossypetin. We observed remarkable nanomolar-to-low-micromolar 50% inhibitory concentrations (0.57-1.21μM) and low 50% disassembly concentrations (7.5-14μM) using tau seeds derived from AD mouse model brains. Furthermore, we validated that myricetin treatment was associated with a reduction in overall phosphorylated tau (p-Tau) burden in vivo in the 3xTg AD mouse model. Notably, these reductions were associated with enhanced performance in Y-maze assessments of spatial learning and memory, supporting further preclinical evaluation, including direct brain pharmacokinetic studies and mechanism-driven investigations relevant to tauopathy therapy.},
}

@article {pmid41531938,
year = {2026},
author = {Mandloi, U and Giri, N and Kumar, S and Modi, G},
title = {Theranostic advances in Alzheimer's disease: structure-guided design of near-infrared fluorescent probes targeting amyloid-β and cholinergic dysfunction.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41531938},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with unmet clinical challenges due to the lack of early diagnosis and an efficient treatment. Theranostics, an integrated approach that combines diagnosis and therapy, has emerged as a viable option, particularly with the use of near-infrared fluorescence probes (NIRFPs), which allow real-time in vivo imaging and therapeutic monitoring. This review article discusses recent breakthroughs in the rational design of alkene-bridged donor-π-acceptor (D-π-A) NIRFPs that target AD hallmarks such as amyloid-β (Aβ) aggregation and cholinergic dysfunction. We specifically focused on multifunctional probes like THK-565 (fluorescent compound), and a dihydrotetramethyl-indocyanine theranostic near-infrared probe (DTNP), which exhibit high blood-brain barrier (BBB) permeability, target selectivity, and dual imaging/therapeutic capabilities. Furthermore, emerging probes can distinguish between Aβ and cholinesterase (ChEs) with high resolution and low toxicity. Together, these molecular imaging technologies provide a game-changing platform for detection of early-stage AD and multiple intervention approaches. We explore structure-activity connections, molecular processes, and future directions for the clinical translation of NIRFP-based theranostic agents in AD.},
}

@article {pmid41531926,
year = {2025},
author = {Jerath, R and Malani, V},
title = {The fading self in space-disruption of default spatial representation across neurological disorders.},
journal = {Frontiers in systems neuroscience},
volume = {19},
number = {},
pages = {1655500},
pmid = {41531926},
issn = {1662-5137},
abstract = {Neurological disorders stem from an intermingled change to self-in-space. While many of these disorders present as spatial deficits-contralateral neglect syndrome, for example-they manifest from the same etiology: disruption to the brain's "default spatial representation" (DSR). DSR is a basic internally generated representation of space that delineates where the self is located in space-without attentional focus from an external drive. We review how pathologic disintegration of DSR is associated with anomalous activation and connectivity within distinct large-scale brain networks (e.g., the default mode network and a comprehensive attention-networked system), leading to a heterogeneous presentation of clinically assessed outcomes. The outcomes include psychogenic paralysis of limbs, left-side neglect, rectified sense of other locations, disorders of consciousness, symptoms related to autism spectrum disorder, Alzheimer's disease, schizophrenia, and depersonalization/derealization disorder. By consolidating evidence from neuroimaging, lesion-symptom mapping, and computational assessment, we aim to reconceptualize these disorders not as separate and independent maladies, but as manifestations of a deeper, shared etiology, supporting a network-based assessment strategy for diagnosis and treatment that seeks to restore self-in-space.},
}

@article {pmid41531784,
year = {2025},
author = {Zhang, Y and Ren, Y and Zhu, X and Liu, T and Han, R and Fang, Y and Zhao, Z and Mao, F and Wang, Y and Li, X and Li, X},
title = {Research Progress on Idebenone in Neurodegenerative Diseases.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {8},
number = {6},
pages = {624-633},
pmid = {41531784},
issn = {2475-0360},
abstract = {In recent years, significant progress has been made in understanding the therapeutic potential of idebenone (IDE), a synthetic analogue of Coenzyme Q10, in neurodegenerative diseases (NDs). This review comprehensively examines the pharmacological properties of IDE and its emerging applications in various NDs, with particular emphasis on Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and Huntington's disease. We elucidate IDE's multifaceted neuroprotective mechanisms, including its potent antioxidant activity that reduces reactive oxygen species production, its ability to enhance mitochondrial bioenergetics, and its regulatory effects on cellular metabolism. Additionally, we critically evaluate current clinical research findings and discuss the translational potential of IDE in ND therapeutics. The accumulated evidence strongly supports IDE as a promising mitochondrial-targeted agent capable of mitigating disease symptoms and modifying disease progression in multiple neurodegenerative disorders. This review highlights both the current achievements and future directions for IDE-based interventions in ND treatment.},
}

@article {pmid41531459,
year = {2025},
author = {Fischer, BL and Van Hulle, CA and Norton, DL and Wyman, MF and Ennis, G and Lambrou, NH and Bouges, S and Gooding, DC and Gleason, CE},
title = {Mild Behavioral Impairment is Associated With Incident Cognitive Decline Among Dementia-Free, Racially Diverse Older Adults: Data From the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Study.},
journal = {The American journal of geriatric psychiatry. Open science, education, and practice},
volume = {8},
number = {},
pages = {43-53},
pmid = {41531459},
issn = {2950-3868},
support = {R01 AG074231/AG/NIA NIH HHS/United States ; R01 AG062307/AG/NIA NIH HHS/United States ; R56 AG062307/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG054059/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVES: To determine whether MBI associates with worse cognitive performance over time and with incident cognitive decline in an older, racially/ethnically diverse cohort at early stages of cognitive change.

DESIGN: This observational cohort study followed participants from the Wisconsin Alzheimer's Disease Research Center Clinical Core (WADRC) for up to 13 visits.

SETTING: An urban university research center.

PARTICIPANTS: Participants from the WADRC Clinical Core were included in this convenience sample if they were without dementia, had undergone at least 1 cognitive assessment, and completed measures of cognitive, clinical and affective function.

MEASUREMENTS: MBI was assessed using the Neuropsychiatric Inventory. Linear mixed effects models (LME) were fit to cognitive outcomes Trailmaking Tests A and B (TMT-A, B) and Wechsler Logical Memory (LM). Cox proportional hazard models assessed whether MBI was related to risk for incident global Clinical Dementia Rating Scale (CDR >0).

RESULTS: N = 584 participants with mean age 64.6 years, range 46-92.6 years, 59.4% female and 17% African American. LME results indicated participants with MBI exhibited worse age-associated decline on TMT-B, compared to those without MBI (beta=0.008, p = 0.01, CI: 0.002, 0.01, t(337) = 2.4, p = 0.01). MBI at baseline was associated with a significant hazard ratio (HR) indicating an increased risk of decline on the CDR (HR: 2.84; HR 95% CI: 1.68 - 4.81; p = 0.0001).

CONCLUSIONS: MBI associated with worse cognitive performance and incident cognitive decline in a racially diverse, older adult sample at early stages of cognitive change. Increased awareness of the late life emergence of neuropsychiatric symptoms is warranted to assist in identification and improve prognostication and treatment of neurodegenerative disease.},
}

@article {pmid41531227,
year = {2026},
author = {Samudra, N and Vemuri, M and Weitlauf, J},
title = {Menopause, cognition, and Alzheimer's disease risk.},
journal = {Current opinion in obstetrics & gynecology},
volume = {},
number = {},
pages = {},
doi = {10.1097/GCO.0000000000001087},
pmid = {41531227},
issn = {1473-656X},
abstract = {PURPOSE OF REVIEW: Cognitive symptoms are common throughout the menopause transition. This review outlines a comprehensive clinical approach, grounded in recent findings, to guide clinicians in addressing menopause-related cognitive concerns and neurodegenerative disease risk for midlife women.

RECENT FINDINGS: Research highlights the benefits of lifestyle and psychosocial interventions for cognitive symptoms during the menopause transition. Addressing underlying medical and mental health conditions, as well as difficulties with sleep, chronic stress, and vasomotor symptoms, can ameliorate symptoms and reduce risk for future dementia. Cognitive changes during the menopause transition do not typically indicate dementia. A subset of women, including apolipoprotein ε4 (APOE ε4) carriers and those who experience early menopause, face heightened risk. Alzheimer's disease biomarkers are clinically available and may change in some women during the menopause transition, particularly in APOE ε4 carriers, but our understanding of these changes, as well as their relationship to menopause hormone therapy, is evolving. There is presently insufficient evidence for the role of menopause hormone therapy for the treatment of menopause-related cognitive symptoms or neurodegenerative disease prevention.

SUMMARY: While typically transient, cognitive symptoms in menopause can benefit from addressing comorbid medical and psychosocial conditions. Research into dementia risk related to changes in the menopause transition is ongoing.},
}

@article {pmid41530949,
year = {2026},
author = {Chen, Y and Liu, Y},
title = {Eosinophils: Pathological Mechanisms and Novel Targeted Therapeutic Strategies Across Multiple Disease Spectrums.},
journal = {Journal of leukocyte biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jleuko/qiag009},
pmid = {41530949},
issn = {1938-3673},
abstract = {Eosinophils are a type of white blood cell belonging to the granulocyte family. Their cytoplasm contains eosinophilic granules that hold various biologically active substances. They perform diverse functions, participating in inflammatory responses, immune defense, and tissue repair. Eosinophils are implicated in the pathogenesis of multiple diseases, including infectious diseases, allergic disorders, and hematological conditions. Moreover, increasing research in recent years has revealed significant associations between eosinophils and autoimmune diseases, solid tumors, coronary atherosclerotic heart disease, and even Alzheimer's disease. They participate in disease onset and progression through the release of toxic proteins, cytokines, and chemokines, as well as through interactions with other cells. Focusing on the biological characteristics and functions of eosinophils facilitates the elucidation of disease mechanisms associated with related disorders. This, in turn, provides further direction for eosinophil-targeted research and therapeutic strategies, including the research and development of drugs that modulate their function, targeted therapies, immunotherapies, and cell therapies. This paper provides a comprehensive review of the structure, function, and role of eosinophils in related diseases, along with potential future therapeutic strategies. It aims to deepen the understanding of researchers and clinicians, thereby facilitating their application in further research, as well as in clinical disease diagnosis and treatment analysis.},
}

@article {pmid41530554,
year = {2026},
author = {Taylor, WD and Gerlach, AR and Szymkowicz, SM and Gujral, S and Andreescu, C},
title = {Remission is insufficient: predictors and mechanistic models of recurrence in late-life depression.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41530554},
issn = {1740-634X},
support = {R01 MH121620/MH/NIMH NIH HHS/United States ; R01 MH123662/MH/NIMH NIH HHS/United States ; R33 MH122464/MH/NIMH NIH HHS/United States ; K01 MH133913/MH/NIMH NIH HHS/United States ; K23 MH125074/MH/NIMH NIH HHS/United States ; R01 MH108509/MH/NIMH NIH HHS/United States ; R01 MH121619/MH/NIMH NIH HHS/United States ; },
abstract = {While achieving remission is the goal of acute antidepressant treatment, recurrence of new depressive episodes following remission is unfortunately common in clinical populations with Major Depressive Disorder, including older adults with Late-Life Depression (LLD). The neurobiological factors underlying this risk are poorly understood, limiting our ability to identify potential preventive mechanistic targets. Beyond the limited prognostic utility achieved from individual psychiatric history, it remains challenging to clinically stratify individual risk. This review examines factors influencing the recurrence of depressive episodes following remission in LLD, focusing on cognitive, behavioral, social, and environmental aspects. It additionally considers neuroimaging-based biomarkers related to recurrence risk as well as discussing evidence for and limits of maintenance treatment to prevent recurrence. The paper proposes possible mechanisms contributing to recurrence, including physiological and behavioral responses to stressors, the influence of Alzheimer's disease neuropathology, and conceptualizing repeat depressive episodes within the accelerated aging hypothesis of LLD. A dynamical landscape model of depression recurrence is proposed to elucidate the interplay between different mood states, resilience, and treatment response. This synthesis then highlights avenues for future research, focusing on areas of potential significance ranging from risk stratification to tertiary prevention efforts that may improve both long-term affective and cognitive symptoms.},
}

@article {pmid41530008,
year = {2026},
author = {Feldman, OJ and Herrmann, N and Ruthirakuhan, M and Gallagher, D and L G Verhoeff, NP and Kiss, A and Black, SE and Lanctôt, KL},
title = {Assessment of clinical factors that predict response to nabilone for agitation in Alzheimer's disease: A post hoc analysis of a randomized placebo-controlled trial.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100183},
doi = {10.1016/j.inpsyc.2026.100183},
pmid = {41530008},
issn = {1741-203X},
abstract = {INTRODUCTION: Previously, nabilone showed a medium effect size for treating agitation in moderate-to-severe Alzheimer's disease (AD), but response varied. These post hoc analyses aimed to identify a group of clinical characteristics that predicted treatment response.

METHODS: Data from a double-blind, placebo-controlled crossover trial in AD agitation were used. Nineteen clinical characteristics were categorized (presence/absence) and evaluated for relation to agitation response (change on Cohen-Mansfield Agitation Inventory (CMAI)). Characteristics with a ≥ 8 point response difference between categories were included in a multivariable analysis model to calculate individual predicted response. Linear mixed-effects models with Satterthwaite's approximation evaluated the impact of treatment on the relationship between predicted and observed responses.

RESULTS: Thirty-nine participants (77 % male, mean [SD] age 87 [10.2], standardized Mini-Mental State Exam (sMMSE) 6.5 [6.8]) were enrolled. Variable selection identified five characteristics related to greater nabilone efficacy: higher pain (Pain Assessment in Advanced Dementia score ≥3) (difference [SE] in CMAI response = -18.8 [3.2]), greater appetite and eating disorders (-16.4 [5.5]), greater apathy (-14.0 [5.5]), less cognitive impairment (sMMSE greater than 10) (-16.5 [4.2]) and no concomitant cholinesterase inhibitors (-13.9 [4.4]). For those with a predicted response in the top tertile based on those five characteristics, 82 % responded, compared with 40 % in the lowest tertile. A treatment-by-tertile interaction (F(2,29) = 8.48, p = 0.001) indicated observed treatment response varied across tertiles.

CONCLUSION: A reliable clinical profile of persons with AD related agitation likely to respond to nabilone may be established with additional research.},
}

@article {pmid41528665,
year = {2026},
author = {Kumar, A and Rakshit, D and Saharia, N and Tiwari, P and Mugale, MN and Mishra, A},
title = {Dietary Isoflavone Biochanin A Attenuates Aluminium Chloride-Induced Sporadic Alzheimer's Disease and Associated Neurobehavioral Alterations Through NRF2-HO1 Pathway Activation and NLRP3 Inflammasome Suppression.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {359},
pmid = {41528665},
issn = {1559-1182},
mesh = {Animals ; *Genistein/pharmacology/therapeutic use/administration & dosage ; Aluminum Chloride ; *Alzheimer Disease/chemically induced/metabolism/drug therapy/pathology ; *NF-E2-Related Factor 2/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism/drug effects ; Male ; Signal Transduction/drug effects ; Mice ; Oxidative Stress/drug effects ; *Behavior, Animal/drug effects ; *Heme Oxygenase-1/metabolism ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD), a debilitating neurodegenerative disorder, currently lacks effective curative treatments. Growing evidence implicates aluminium, a widely prevalent environmental metal, in the pathogenesis of AD due to its ability to induce oxidative stress, neuroinflammation, cholinergic dysfunction, and amyloid-beta (Aβ) deposition, ultimately leading to cognitive decline. Biochanin A (BCA), a naturally occurring isoflavone, exhibits well-documented antioxidant, anti-inflammatory, and neuroprotective activities, including acetylcholinesterase (AChE) inhibition. However, its specific therapeutic potential in AD models has remained largely unexplored. This study evaluates the protective effects of BCA against aluminium chloride (AlCl3)-induced AD-like pathology in mice. Animals received daily oral administration of AlCl3 (100 mg/kg) for 6 weeks, with or without concurrent BCA treatment (5, 10, and 20 mg/kg). During the final week, comprehensive neurobehavioral assessments were conducted. Thereafter, hippocampal tissues were analyzed for biochemical, molecular, and elemental analyses, and intact brains were examined histologically. AlCl3 exposure significantly impaired neurobehavioral performance, elevated oxidative stress, disrupted cholinergic function, intensified neuroinflammation, promoted amyloid aggregation, and induced neurodegeneration. Notably, BCA supplementation dose-dependently ameliorated these pathological alterations. BCA treatment improved neurobehavioral deficits (P < 0.05), reduced oxidative markers (P < 0.01), restored cholinergic function by lowering AChE activity (P < 0.01), attenuated inflammatory mediators (P < 0.01), reduced amyloid and aluminium deposition (P < 0.001), and alleviated AlCl3-induced neurodegeneration. Overall, our findings indicate that BCA confers neuroprotection primarily through activation of the NRF2-HO-1 signaling pathway and through suppression of the NLRP3 inflammasome, highlighting its promise as a potential therapeutic candidate for AD.},
}

Animals
*Genistein/pharmacology/therapeutic use/administration & dosage
Aluminum Chloride
*Alzheimer Disease/chemically induced/metabolism/drug therapy/pathology
*NF-E2-Related Factor 2/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Inflammasomes/metabolism/drug effects
Male
Signal Transduction/drug effects
Mice
Oxidative Stress/drug effects
*Behavior, Animal/drug effects
*Heme Oxygenase-1/metabolism
Amyloid beta-Peptides/metabolism
Neuroprotective Agents/pharmacology
Mice, Inbred C57BL

@article {pmid41527747,
year = {2026},
author = {Heo, RJ and Negida, A and Barrett, MJ and Chrenka, EA and Bayram, E and Kane, JPM and Werner, AM and Rossom, RC and Wyman-Chick, KA},
title = {Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411418},
doi = {10.1177/13872877251411418},
pmid = {41527747},
issn = {1875-8908},
abstract = {BackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26-0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71-0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62-0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further.},
}

@article {pmid41527739,
year = {2026},
author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W},
title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411546},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.},
}

@article {pmid41527682,
year = {2026},
author = {Zohud, O and Lone, IM and Midlej, K and Iraqi, FA},
title = {The complexity of dementia development and its comorbidities: The collaborative cross-mouse population for multivarious tasks approach.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70131},
pmid = {41527682},
issn = {2576-2095},
support = {//A core fund from Tel Aviv University/ ; },
abstract = {The rising incidence of dementia and associated neurodegenerative disorders poses a growing public health challenge. These conditions have traditionally been studied as isolated central nervous system disorders; however, emerging evidence suggests that broader systemic factors, including chronic inflammation, immune dysregulation, metabolic dysfunction, and genetic susceptibility, may also play a role. This review examines the interconnection between autoimmune diseases and metabolic syndromes in the pathogenesis and exacerbation of neurodegeneration. Conditions such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus have been associated with a heightened risk of developing dementia through chronic immune activation, blood-brain barrier disruption, and neuroinflammatory signaling. Similarly, metabolic disorders such as diabesity promote insulin resistance and oxidative stress, accelerating cognitive decline. The review also discusses glaucoma as a neurodegenerative condition with autoimmune features, underscoring the need for expanded classification and treatment strategies. A key focus is the utilization of the Collaborative Cross (CC) mouse model, which enables the study of gene-environment interactions across genetically diverse backgrounds. Findings from CC mice reveal strain-dependent susceptibility to inflammation, cognitive impairment, and gut-brain axis dysfunction, providing a translational bridge to human variability. This review highlights the importance of integrating precision-based approaches to dementia research that consider systemic influences. Advancing our understanding of these multiorgan interactions holds potential for designing precision-based therapeutic approaches to postpone the onset or reduce the incidence of neurodegenerative conditions.},
}

@article {pmid41527663,
year = {2025},
author = {Barbati, SA and Carota, G and Partsinevelos, K and Di Pietro, L and Privitera, A and Cardaci, V and Graziani, A and Mangione, R and Lazzarino, G and Tavazzi, B and Di Pietro, V and Maiani, E and Bellia, F and Amorini, AM and Lazzarino, G and Baba, SP and Caruso, G},
title = {Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.},
journal = {AIMS neuroscience},
volume = {12},
number = {4},
pages = {444-513},
pmid = {41527663},
issn = {2373-7972},
abstract = {Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.},
}