@article {pmid42035056,
year = {2026},
author = {Ashley, CC and Constantino, NJ and Pettit-Mee, RJ and Snipes, JA and Saito, K and Irmen, RE and Zhang, R and Neary, EM and Lanning, MJ and Karch, CM and Johnson, LA and Morganti, JM and Macauley, SL},
title = {Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {42035056},
issn = {1742-2094},
support = {R01 AG068330/AG/NIA NIH HHS/United States ; R01 AG093847/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) is increasingly recognized as a disorder of early immunometabolic dysfunction, yet how amyloid-β (Aβ) pathology reshapes brain metabolism and neuroinflammation remains poorly defined. Here, we demonstrate interstitial fluid (ISF) lactate levels progressively increase with amyloid plaque accumulation in APPswe/PSEN1dE9 (APP/PS1) mice, a model of cerebral amyloidosis. Stable isotope-resolved metabolomics revealed metabolic reprogramming in APP/PS1 mice, characterized by increased glycolysis at the expense of TCA cycle intermediates and neurotransmitter biosynthesis. Spatial interrogation of lactate production demonstrated lactate dehydrogenase A (Ldha), the enzyme required for lactate generation, is highly enriched in the peri-plaque microenvironment. Approximately 98% of cortical amyloid plaques were Ldha + , with Ldha preferentially localized to diffuse Aβ deposits rather than the dense core of amyloid plaques. Although most plaque-associated Ldha appeared extracellular, higher-resolution analyses demonstrated a pronounced enrichment of Ldha within peri-plaque microglia, identifying microglia as a key cellular source of plaque-associated lactate. Consistent with this, single-cell and single-nucleus transcriptomic analyses in both mouse and human brains identified microglia as the highest expressers of LDHA, with expression further increased in AD and enriched within specific microglial populations. Notably, LDHA was concentrated within a subset of glycolytic microglia (MG7) associated with cytokine production and innate immune signaling, which emerge early with amyloid pathology and decline with disease progression. Functionally, in vitro Aβ42 aggregation assays demonstrated that lactate alters Aβ aggregation kinetics and fibril stability. Critically, this immunometabolic signature was reversible; pharmacologic inhibition of lactate dehydrogenase (LDH) with stiripentol, an FDA-approved anti-seizure medication, reduced ISF Aβ levels by approximately 50% and selectively depleted peri-plaque microglia, including Cd68[+] and Clec7a[+] populations. Together, these data demonstrate that amyloid pathology drives early metabolic reprogramming in microglia that elevates brain lactate levels, sustains neuroinflammation, and modulates Aβ dynamics, identifying lactate metabolism as a tractable therapeutic target in presymptomatic Alzheimer’s disease.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03825-z.},
}

@article {pmid42297218,
year = {2026},
author = {Bastos, IM and Moreira, DR and Rebelo, S and Silva, VLM},
title = {Current progress in the use of pyrazole-containing compounds for neuroprotection as a strategy to counteract neurodegeneration.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118161},
doi = {10.1016/j.bcp.2026.118161},
pmid = {42297218},
issn = {1873-2968},
abstract = {Pyrazoles, a versatile class of five-membered heterocyclic compounds, have attracted significant attention due to their broad biological activities, including neuroprotection. This review examines the role of pyrazole-containing compounds in protecting neuronal tissues against various forms of damage, such as oxidative stress, excitotoxicity, and neuroinflammation, which are critical contributors to neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. The targets and molecular mechanisms through which pyrazoles exert their neuroprotective effects, including the modulation of signaling pathways, enzyme inhibition, and antioxidant activity, are also comprehensively discussed. Furthermore, recent advances in the design of pyrazole-bearing compounds with enhanced neuroprotective properties are highlighted through the presentation of key structure-activity relationships (SARs), emphasizing their therapeutic potential in the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This review provides an up-to-date overview of pyrazoles, either as standalone scaffolds or in combination with other ring systems, in neuroprotection, thereby paving the way for future research and drug development in this promising field.},
}

@article {pmid42297456,
year = {2026},
author = {Alghamdi, A and Balafas, S and Bos, JHJ and van Munster, BC and Rafie, K and Dolga, AM and Hak, E},
title = {Association between the use of anti-herpetic drugs and subsequent initiation of Alzheimer's disease drug treatment: Dutch population-based inception cohort study.},
journal = {BMJ open},
volume = {16},
number = {6},
pages = {e114033},
doi = {10.1136/bmjopen-2025-114033},
pmid = {42297456},
issn = {2044-6055},
mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/drug therapy/epidemiology ; Netherlands/epidemiology ; *Antiviral Agents/therapeutic use ; Retrospective Studies ; Male ; Middle Aged ; Aged, 80 and over ; Valacyclovir/therapeutic use ; Acyclovir/therapeutic use ; Famciclovir/therapeutic use ; Proportional Hazards Models ; Memantine/therapeutic use ; Donepezil/therapeutic use ; },
abstract = {OBJECTIVES: To examine whether exposure to anti-herpetic drugs (AHDs: acyclovir, valacyclovir, famciclovir) is associated with reduced risk of Alzheimer's disease (AD) treatment initiation.

DESIGN: Population-based retrospective matched cohort study.

SETTING: University Groningen community pharmacy database IADB.nl, covering approximately 125 Dutch pharmacies (1994-2024).

PARTICIPANTS: 262 757 adults aged 50-80 years without prior dementia or AD treatment. Exposed individuals with antiherpetic prescriptions (n=23 887) were matched 1:10 to unexposed controls (n=238 870) by age, sex and calendar time.

INTERVENTION: AHDs: acyclovir, valacyclovir, famciclovir.

MAIN OUTCOME MEASURES: Initiation of AD drug treatment, defined as at least two prescriptions for rivastigmine, donepezil, galantamine or memantine within 1 year. Cox proportional hazards models estimated HRs with 95% CIs, adjusted for comorbidities and medications. Analyses were stratified by period (1994-2018 vs 2019-2024) and drug type.

RESULTS: During follow-up, 2495 participants initiated AD treatment. The age of the participants was 65 (SD 9), and 59% were female. Any AHD exposure was associated with 90% reduced hazard of AD treatment (HR 0.09, 95% CI 0.07 to 0.13, p<0.001). Similar association was found in both periods: HR 0.14 (95% CI 0.09 to 0.20) in period one and HR 0.05 (95% CI 0.03 to 0.10) in period 2. All three AHDs were associated with a lower likelihood of future AD drug prescription: valacyclovir HR 0.10, acyclovir HR 0.09, famciclovir HR 0.07. The incidence rate of AD treatment initiation was substantially lower among AHD users compared with unexposed individuals overall (0.69/1000 person-years (py) vs 4.96/1000 py, p<0.001), with this association evident in both period 1 (0.65/1000 py vs 3.74/1000 py, p<0.001) and period 2 (0.81/1000 py vs 8.22/1000 py, p<0.001).

CONCLUSIONS: AHD exposure was consistently associated with markedly lower risk of AD treatment initiation, with similar findings observed in recent years. These findings support the hypothesis that herpesvirus reactivation may contribute to AD pathogenesis and suggest antiviral therapy could have preventive implications. Confirmation through prospective studies and randomised trials is needed.},
}

Humans
Female
Aged
*Alzheimer Disease/drug therapy/epidemiology
Netherlands/epidemiology
*Antiviral Agents/therapeutic use
Retrospective Studies
Male
Middle Aged
Aged, 80 and over
Valacyclovir/therapeutic use
Acyclovir/therapeutic use
Famciclovir/therapeutic use
Proportional Hazards Models
Memantine/therapeutic use
Donepezil/therapeutic use

@article {pmid42297902,
year = {2026},
author = {Saeed, F and Aldera, S},
title = {Explainable EEG-based machine learning for early diagnosis of Alzheimer's disease and frontotemporal dementia.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-57069-1},
pmid = {42297902},
issn = {2045-2322},
support = {KSRG-2024-467//King Salman Center for Disability Research/ ; IMSIU-DDRSP2601//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; IMSIU-DDRSP2601//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; },
abstract = {The quick and accurate diagnosis of Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) is a significant and unresolved challenge in clinical neurology, with early identification being crucial for prompt intervention and disease management. This study presents AutoSSM-ICA-EEG, an automated and interpretable framework that incorporates Fast Independent Component Analysis (FastICA) for artifact removal and relevant feature extraction, few-shot AutoML for efficient hyperparameter optimization and dynamic architecture adaptation, and State-Space Modeling (SSM) for temporal EEG dynamics, facilitating concurrent classification of dementia subtypes and regression of clinical severity. Three distinct datasets were utilized: (1) OpenNeuro ds006036 (open-eyes/photic stimulation EEG; AD, FTD, and Healthy Controls; n = 88), functioning as the primary tri-class benchmark; (2) OpenNeuro ds004504 (closed-eyes resting-state EEG; AD and HC; n = 65), employed for cross-condition generalization; and (3) ADFSU (resting-state EEG; AD and HC; external institution, UNESP Brazil), utilized for cross-institution transfer assessment. Rigorous subject-level leave-one-subject-out (LOSO) cross-validation was uniformly implemented throughout all four evaluation protocols, ensuring that all preprocessing, ICA decomposition, and model tuning were performed solely within each training fold to avert data leakage. In the primary tri-class benchmark, the model attained an accuracy of 87.5%, macro sensitivity of 87.5%, macro specificity of 95.4%, macro F1-score of 88.7%, and macro AUC of 0.99. The regression analysis of MMSE severity produced a R[2] of 0.81 ± 0.04, with a mean absolute error (MAE) of 1.64 ± 0.31 and a root mean square error (RMSE) of 1.71 ± 0.21. Cross-condition generalization (Closed→Open and Open→Closed) and cross-institution transfer (ADFSU↔OpenNeuro; AD sensitivity = 83.9%) further validate the framework's resilience beyond a singular dataset or recording situation. ICA-refined SHAP channel-level explainability identifies Ch11 and Ch13 as the principal neurophysiological biomarkers for subtype classification and MMSE severity regression, respectively, with Ch17 serving as the most sensitive predictor of disease duration - corroborating established frontotemporal EEG signatures of neurodegeneration. These findings establish AutoSSM-ICA-EEG as a potential, neurophysiologically interpretable paradigm for EEG-based dementia screening, subject to prospective multi-site clinical validation.},
}

@article {pmid42297920,
year = {2026},
author = {Ashkavandi, S and Moazedi, AA and Semnanian, S and Abdolahpour, S and Gholami, M},
title = {Dose- and state-dependent enhancement of hippocampal CA1 pyramidal neuron excitability by GM1 ganglioside in male rats with cholinergic lesions.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58002-2},
pmid = {42297920},
issn = {2045-2322},
abstract = {Cholinergic degeneration contributes to hippocampal circuit dysfunction in Alzheimer's disease (AD). Ganglioside GM1 modulates membrane signaling and synaptic function, yet its acute effects on hippocampal neuronal activity under cholinergic-deficient conditions remain unclear. Using in vivo single-unit recordings in urethane-anesthetized male rats, extracellular single-unit activity was recorded from CA1 pyramidal neurons before and after systemic GM1 administration. We examined whether systemic GM1 alters spontaneous firing of CA1 pyramidal neurons in a nucleus basalis magnocellularis (NBM) lesion model of cholinergic hypofunction. GM1 (2, 5, 10 mg/kg, i.p.) produced dose-dependent increases in firing rate. Linear mixed-effects modeling, accounting for multiple neurons per animal, revealed a significant main effect of Time (F1,79 = 41.33, p < 0.001, partial η[2] = 0.34) and a significant Dose × Time interaction (F3,79 = 3.28, p = 0.025, partial η[2] = 0.11). Notably, NBM-lesioned animals exhibited amplified responses, particularly at 2 mg/kg (Δ = 7.22 ± 1.82 Hz), whereas control animals showed minimal change at this dose. GM1-induced increases remained within reported physiological firing ranges under urethane anesthesia. These findings demonstrate that GM1 enhances hippocampal CA1 excitability in a dose- and state-dependent manner, with heightened responsiveness in cholinergic-compromised networks. The results support the concept that membrane-targeting interventions may modulate dysfunctional circuits depending on baseline network state.},
}

@article {pmid42297931,
year = {2026},
author = {Dou, X and Hu, D and Wang, J and Zhong, Y and Yu, C and Zhan, H and Chen, Y and Zhou, R and Zhang, X and Zhang, B and Zhou, J and Tian, M and Zhang, H and Yan, Y and Jin, C},
title = {Baseline amyloid deposition phenotypes inform the spatial distribution of early amyloid clearance with lecanemab in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42297931},
issn = {1619-7089},
support = {2021YFA1101700, 2022YFE0118000//Key Technologies Research and Development Program/ ; 82030049, 32027802//National Natural Science Foundation of China/ ; 82394433, 82361148130//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVE: Lecanemab effectively reduces brain amyloid-β (Aβ) burden in early Alzheimer's disease (AD). However, Aβ deposition is spatially heterogeneous.The aim of this study is to test whether baseline β-amyloid (Aβ) deposition phenotype influences lecanemab-related Aβ clearance on Aβ-PET.

METHODS: An Aβ Subtype and Stage Inference (SuStaIn) model was trained to identify Aβ progression phenotypes using cross-sectional Aβ-PET SUVRs from seven brain regions in 303 individuals (249 Aβ+/tau + PET-confirmed Alzheimer's disease and 54 Aβ-/tau- controls). This trained model was then applied to 39 lecanemab-treated patients with paired baseline and 6‑month Aβ-PET. Global and regional Aβ burden was quantified in Centiloids (CL) and SUVR, respectively. Subtype differences in ΔCL and ΔSUVR were tested. By defining baseline topology and clearance topology using posterior-to-anterior dominance indices (Topo_occ-fron = SUVR of occipital lobe - SUVR of frontal lobe), topology-clearance coupling was assessed using correlation and regression analysis. Additionally, spatial topological correspondence was quantified by modeling ROI-level clearance as a function of ROI-level baseline SUVR within a mixed-effects model with a subject-level random intercept.

RESULTS: SuStaIn identified two dominant phenotypes consistent with an occipital-onset pattern (subtype 1) and a precuneus-frontal-onset pattern (subtype 2). In the lecanemab cohort, CL decreased by a mean ΔCL of - 27.77 ± 24.51. ΔCL did not differ between subtype 1 (n = 16) and subtype 2 (n = 17), whereas baseline CL strongly predicted ΔCL (r = -0.68, P < 0.001). ROI-wise ΔSUVR differences were not significant after FDR correction, while the ΔSUVR was significantly correlated with baseline SUVR (r = -0.64, P < 0.0001). In subtype-assigned patients (n = 33), a posterior-dominant baseline topology predicted greater posterior clearance. The changed Topo_occ-fron is correlated with baseline values (r = 0.514, P < 0.01) and remained significant after adjusting for baseline CL (β=-0.273, P < 0.01). ROI-level clearance magnitude increased with baseline regional SUVR (mixed-effects β = 0.264, p < 0.001), quantifying high spatial correspondence between deposition and clearance.

CONCLUSION: While baseline Aβ phenotype did not influence the magnitude of early global amyloid removal, it predicted the spatial pattern of regional clearance. Quantitative topological correspondence between baseline deposition and early clearance provides in vivo evidence of target engagement and supports topology-informed PET monitoring beyond global CL.},
}

@article {pmid42297936,
year = {2026},
author = {Barichello, T and Scaini, G and Tayyab, M and Dal-Pizzol, HR and Petronilho, F and Dal-Pizzol, F},
title = {Hospital-treated infection associated with Alzheimer's disease pathology: underlying mechanisms.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42297936},
issn = {1476-5578},
support = {R01AG072491//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG072491/AG/NIA NIH HHS/United States ; },
abstract = {IMPORTANCE: Growing epidemiological and mechanistic evidence indicates that infections substantially increase the risk of Alzheimer's disease (AD) and related dementias. Systemic immune activation and pathogen persistence may act as upstream triggers accelerating neurodegenerative cascades.

OBJECTIVE: To synthesize recent evidence on infection-driven mechanisms contributing to AD pathology, emphasizing how systemic and central immune activation influence amyloid-beta (Aβ) aggregation, tau pathology, blood-brain barrier (BBB) dysfunction, and neuroinflammation.

This expert review integrates data from large epidemiological cohorts, neuropathological analyses, and mechanistic studies in both human and animal models to address innate and adaptive immune mechanisms linking infection to AD pathogenesis.

EXPOSURES: Systemic and central nervous system (CNS) infections, including sepsis, pneumonia, viral, and chronic bacterial infections, as well as hospital-treated infections, that trigger inflammatory and immune signaling cascades impacting the brain's structural and molecular integrity.

RESULTS: Infections activate the innate immune system through toll-like receptors and inflammasomes (NOD-like receptor family pyrin domain-containing 3 (NLRP3), linear ubiquitin assembly complex (LUBAC)), driving chronic neuroinflammation, pyroptosis, and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck that cross-seeds Aβ and tau aggregation. Additionally, cytokine-induced upregulation of interferon-induced transmembrane protein 3 (IFITM3) enhances γ-secretase activity, thereby increasing Aβ production. Therefore, peripheral inflammation compromises BBB integrity, while extracellular vesicles propagate inflammatory cargoes across the neurovascular unit. Consequently, the expansion of cytotoxic CD8⁺ T cells and the alteration of Th1/Th17 profiles are linked to adaptive immunity and neurodegeneration. Moreover, epidemiologic data show reduced AD risk following herpes zoster, Tdap/Td (tetanus, diphtheria, and acellular pertussis (Tdap) and tetanus and diphtheria (Td) vaccines), and pneumococcal vaccination, supporting immune modulation as a preventive strategy.

CONCLUSIONS AND RELEVANCE: Infection-driven immune activation represents a key modifiable pathway in AD pathogenesis, highlighting novel diagnostic and therapeutic targets focused on the inflammasome.},
}

@article {pmid42297977,
year = {2026},
author = {Özata, G and Wise, RM and Cardona-Alberich, A and Mayeen, NF and Müller, SA and Lichtenthaler, SF and Zecca, L and Burbulla, LF},
title = {Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42297977},
issn = {2045-2322},
mesh = {Humans ; *Microglia/metabolism/immunology/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurodegenerative Diseases/genetics/immunology/pathology/metabolism ; *Carrier Proteins/genetics/metabolism ; Lysosomes/metabolism ; Mutation ; },
abstract = {Microglia are the brain's resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer's and Parkinson's disease (PD), where their early activation and sustained inflammatory mediator release contribute to neuronal loss. However, their role in rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by WDR45 mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant WDR45 in BPAN pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.},
}

Humans
*Microglia/metabolism/immunology/pathology
*Induced Pluripotent Stem Cells/metabolism/cytology
*Neurodegenerative Diseases/genetics/immunology/pathology/metabolism
*Carrier Proteins/genetics/metabolism
Lysosomes/metabolism
Mutation

@article {pmid42297981,
year = {2026},
author = {Ding, DY and Bot, VA and Chen, KL and Groves, JW and Pálovics, R and Masuda, D and Farinas, A and Oh, HS and Wagner, V and Lu, N and , and Cruchaga, C and Isakova, A and Schott, JM and Wyss-Coray, T},
title = {Plasma proteomic signatures of cellular aging predict human disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42297981},
issn = {1546-170X},
support = {AG072255//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; ARUK-PG2017-1946//Alzheimer's Research UK (ARUK)/ ; SG-666374-UK BIRTH COHORT/ALZ/Alzheimer's Association/United States ; },
abstract = {Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer's Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.},
}

@article {pmid42298074,
year = {2026},
author = {Fancy, NN and Willumsen, N and Chau, VMN and Boulger, SL and Whitwell, HJ and Wang, W and Avot, B and Thomas, M and Talbot-Martin, J and Tsartsalis, S and Khozoie, C and McGarry, A and Schneegans, E and Yagoubi, R and Cheung, TKD and Papageorgopoulou, M and Adair, E and Cooper, B and Davey, K and Smith, AM and Scotton, W and Hardy, J and Matthews, PM and Jackson, JS},
title = {Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42298074},
issn = {1432-0533},
mesh = {Humans ; *Membrane Glycoproteins/genetics/metabolism ; *Receptors, Immunologic/genetics/metabolism ; *Alzheimer Disease/genetics/pathology/metabolism ; Microglia/pathology/metabolism ; *Brain/pathology/metabolism ; Female ; Male ; Amyloid beta-Peptides/metabolism ; *Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism ; Aged ; Aged, 80 and over ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; },
abstract = {TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer's disease (AD). Genetic polymorphisms reducing expression of the functionally related protein CD33 are protective. Here we have contrasted cellular pathology in human post-mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865444 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by relative normalisation of differences in β-amyloid load in TREM2var carriers of the protective CD33 allele. These functional differences were mirrored by differential microglial transcriptomic responses to β-amyloid. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H compared to CV, and there was a reduction in expression of neuroplasticity pathways in TREM2var. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with phagocytosis and from CV by differences in inflammatory gene expression including those involved in NF-kappaB signalling. Differential gene expression with increasing β-amyloid also suggested upregulation of β-amyloid production and binding pathways in excitatory neurons in TREM2var heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from CV samples for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var, which showed evidence of increased β-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between CV and TREM2var and between the TREM2var risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 inhibition or expression.},
}

Humans
*Membrane Glycoproteins/genetics/metabolism
*Receptors, Immunologic/genetics/metabolism
*Alzheimer Disease/genetics/pathology/metabolism
Microglia/pathology/metabolism
*Brain/pathology/metabolism
Female
Male
Amyloid beta-Peptides/metabolism
*Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism
Aged
Aged, 80 and over
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide

@article {pmid42298083,
year = {2026},
author = {Al-Shami, AS and Anwar, MM},
title = {The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42298083},
issn = {1568-5608},
abstract = {Neurodegenerative and chronic pulmonary diseases represent major global health challenges and have widely been investigated separately. Emerging evidence indicates the existence of a lung-brain axis, through which pulmonary pathology and environmental exposures can influence neurological health. The current review highlights the mechanistic and clinical evidence linking chronic lung inflammation, air pollution, and immune dysregulation to the onset and progression of Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). A pathway-based framework is presented in which lung inflammation, systemic cytokine release, oxidative stress, blood-brain barrier disruption, immune priming, and protein misfolding mediate lung-to-brain communication. Associations between chronic obstructive pulmonary disease, asthma, particulate matter exposure, and adverse neurological outcomes including cognitive decline, brain atrophy, disease progression, and elevated neurodegenerative risk are emphasized. Specific mechanisms are addressed, including immune-mediated effects in multiple sclerosis, inhalation-driven protein aggregation in Parkinson's disease, and vascular and oxidative injury contributing to dementia and amyotrophic lateral sclerosis. COVID-19 is considered a clinical model of acute lung-brain axis disruption, demonstrating inflammation-driven neurocognitive consequences, and its role in this context was also highlighted. Additionally, potential preventive and therapeutic strategies are discussed, highlighting pulmonary health and environmental exposure reduction as modifiable factors that may help mitigate neurological disease. This integrative review underscores the clinical relevance of the lung-brain axis and calls for interdisciplinary strategies to improve neurological outcomes through pulmonary and environmental interventions.},
}

@article {pmid42298113,
year = {2026},
author = {Fyfe, I},
title = {Autophagy protein links ageing and Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42298113},
issn = {1759-4766},
}

@article {pmid42298115,
year = {2026},
author = {Duan, X and Huang, D and Zhong, H and Guo, X and Lu, X and Wu, J and Huang, L},
title = {The Association Between Alzheimer's Disease-Related Biomarkers And Parkinson's Disease Based On Single-Cell Sequencing Analysis Combined With Mendelian Randomization.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42298115},
issn = {1559-1166},
support = {2022-1501//Research Programs of Sichuan Provincial Cadre Healthcare Commission/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/cerebrospinal fluid/metabolism ; *tau Proteins/genetics/cerebrospinal fluid ; *Parkinson Disease/genetics/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid ; Mendelian Randomization Analysis ; Amyloid beta-Peptides/cerebrospinal fluid/genetics ; Single-Cell Analysis ; Peptide Fragments/cerebrospinal fluid/genetics ; },
abstract = {Parkinson's disease (PD) and Alzheimer's disease (AD) are both neurodegenerative disorders sharing overlapping pathological mechanisms. Several studies suggest that AD biomarkers may have diagnostic and predictive value in PD, but causal evidence remains insufficient. This study aimed to explore the association between AD-related biomarkers and PD. Bidirectional two-sample Mendelian randomization (MR) was performed using GWAS summary statistics of AD-related biomarkers and PD to assess causal relationships. Subsequently, single-nucleus RNA sequencing (snRNA-seq) of postmortem midbrain tissues was employed to examine the expression of AD biomarkers in PD patients and to explore underlying cellular signaling pathways. Forward MR revealed a significant causal association between PD and decreased CSF p-tau levels. PD progression showed significant causal associations with decreased CSF Aβ42 and increased CSF total tau. Reverse MR indicated that elevated CSF total tau may increase PD risk. SnRNA-seq analysis demonstrated that MAPT (encoding tau) was predominantly expressed in dopaminergic neurons, with differentially expressed genes enriched in PD- and neurodegeneration-related pathways. Our findings provide preliminary, hypothesis-generating evidence at the genetic level suggesting potential associations between CSF tau, Aβ42, and PD or its progression. Bidirectional MR analyses suggest that CSF total tau may be associated with increased PD risk, while exploratory snRNA-seq analysis indicates that MAPT is predominantly expressed in dopaminergic neurons with enrichment in PD-related pathways. Given the limited number of instrumental variables for several exposures, the small snRNA-seq cohort, and the absence of protein-level validation, these findings should be interpreted with caution. Large-scale prospective clinical studies with protein-level biomarker assessment, tau-PET imaging, and independent multi-cohort transcriptomic validation are warranted before CSF total tau can be considered a candidate biomarker for PD progression.},
}

Humans
*Alzheimer Disease/genetics/cerebrospinal fluid/metabolism
*tau Proteins/genetics/cerebrospinal fluid
*Parkinson Disease/genetics/cerebrospinal fluid/metabolism
Biomarkers/cerebrospinal fluid
Mendelian Randomization Analysis
Amyloid beta-Peptides/cerebrospinal fluid/genetics
Single-Cell Analysis
Peptide Fragments/cerebrospinal fluid/genetics

@article {pmid42298214,
year = {2026},
author = {Fang, S and Chen, S},
title = {Biomarker Based ARIA Stress Test: A Proposed Conceptual Framework for Dynamic Biomarker-Guided ARIA Risk Stratification in Anti-Amyloid Immunotherapy for Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42298214},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/therapy/blood/drug therapy/complications ; Biomarkers/blood ; Amyloid beta-Peptides/blood ; *Immunotherapy/adverse effects/methods ; Glial Fibrillary Acidic Protein/blood ; tau Proteins/blood ; Neurofilament Proteins/blood ; Animals ; },
abstract = {While anti-amyloid immunotherapy has shown clinical benefit, amyloid-related imaging abnormalities (ARIA), comprising vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), represent the principal safety limitation. This paper presents a theoretical construct not yet based on empirical data. As a theoretical construct, we systematically synthesize current published findings on ARIA pathophysiology, plasma biomarker biology (glial fibrillary acidic protein [GFAP], amyloid-beta [Aβ] 42/40 ratio, neurofilament light chain [NfL], and phosphorylated tau [p-tau217]), and clinical trial outcomes. We propose that ARIA is fundamentally a kinetic-not static-pathological event, driven by the velocity of immune-mediated amyloid clearance. The Neuro-Pharmacological Kinetic Stress Test (NPKST) measures plasma biomarker velocity (rate of change per unit time) at Days 3-4 and 7 following the first therapeutic dose. A rapid spike in plasma GFAP velocity (ΔpGFAP/Δt), a precipitous decline in Aβ42/40 ratio velocity, and early NfL elevation constitute early biochemical signatures of individuals at high risk for clinically significant ARIA before macroscopic MRI changes are detectable. The Biomarker Velocity Composite Index (BVCI) stratifies patients into Low, Intermediate, and High Velocity tiers, each linked to specific dosing modification protocols. The cardiac stress test analogy provides the conceptual scaffold: the first therapeutic dose serves as the 'pharmacological stress,' and the BVCI captures the individual's dynamic neuro-immune-vascular response phenotype. This proposed theoretical framework, if validated through future pilot studies and the KINETIC-ARIA trial, would shift ARIA prevention from reactive MRI surveillance to proactive biomarker-guided risk management. Long-term monitoring of potential ARIA effects is warranted.},
}

Humans
*Alzheimer Disease/therapy/blood/drug therapy/complications
Biomarkers/blood
Amyloid beta-Peptides/blood
*Immunotherapy/adverse effects/methods
Glial Fibrillary Acidic Protein/blood
tau Proteins/blood
Neurofilament Proteins/blood
Animals

@article {pmid42298279,
year = {2026},
author = {Siengsukon, CF and Hand, LK and Nelson, E and Glaser, A and Ludwig, R and Russell, JA and Phadnis, MA and Dai, J and Bruce, J and Vidoni, ED and Drerup, M and Morris, J and Burns, JM},
title = {The impact of cognitive behavioral therapy for insomnia on cognitive performance and amyloid beta in older adults: A randomized controlled trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71591},
pmid = {42298279},
issn = {1552-5279},
support = {R01AG058530/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; T32 AG078114/AG/NIA NIH HHS/United States ; T32HL007028/NH/NIH HHS/United States ; T32HD057850//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Amyloid beta-Peptides/metabolism ; Female ; *Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism ; Aged ; Male ; *Cognition/physiology ; Neuropsychological Tests ; Alzheimer Disease ; Aged, 80 and over ; Executive Function ; },
abstract = {INTRODUCTION: Insomnia is associated with increased risk for Alzheimer's disease (AD). It is unknown how cognitive behavioral therapy for insomnia (CBT-I) impacts two hallmarks of AD progression, cognitive performance and beta-amyloid (Aβ) burden.

METHODS: Cognitively normal older adults with symptoms of insomnia were randomized into CBT-I treatment (n = 100) or control (n = 100) groups. Cognitive performance was assessed at baseline, 6-weeks, and 1-year (1 year). Aβ burden was assessed in a subsample (n = 50).

RESULTS: No differences were observed between groups in change in cognitive performance, including speed of information processing (mean difference, 0.017; 95% confidence interval [CI], -0.1036 to 0.1376; p = 0.78), executive function (-0.0881; 95% CI, -0.2945 to 0.1182; p = 0.40), and memory (0.4068; 95% CI, -2.3965 to 3.2101; p = 0.77). No group differences were observed in Aβ deposition.

DISCUSSION: CBT-I did not improve cognitive performance or Aβ deposition by one year. Longer follow up is needed to understand the potential impact of CBT-I on AD risk.

CLINICAL TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NCT03954210) on 5/17/2019.},
}

Humans
*Cognitive Behavioral Therapy/methods
*Amyloid beta-Peptides/metabolism
Female
*Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism
Aged
Male
*Cognition/physiology
Neuropsychological Tests
Alzheimer Disease
Aged, 80 and over
Executive Function

@article {pmid42298288,
year = {2026},
author = {Yang, M and Wang, Y and Deng, J and Wu, Q and Wang, Z and Meng, Q and Wang, P and Yang, J},
title = {A High-Affinity NIR Fluorescent Probe for Aβ Oligomers Enables Theranostics Through Disrupting Membrane Interaction and Aggregation.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00058},
pmid = {42298288},
issn = {1948-7193},
abstract = {Amyloid-β (Aβ) oligomers serve as pivotal biomarkers and therapeutic targets in Alzheimer's disease (AD) due to their early emergence in pathogenesis and high level of neurotoxicity. In this work, we introduce a class of D-π-A amphiphilic fluorescent probes engineered for simultaneous detection and therapeutic modulation of Aβ oligomers. The lead compound, API-QB, exhibits a near-infrared (NIR) wavelength upon interaction with Aβ oligomers and demonstrates high selectivity and sensitivity toward Aβ oligomers in both solution and simulated brain environments. Importantly, API-QB is able to inhibit Aβ aggregation by interacting with oligomers. Furthermore, probe API-QB can reduce the toxicity of Aβ oligomers by inhibiting the interaction between oligomers and cell membranes and suppressing the production of reactive oxygen species generated by Aβ oligomers. Therefore, probe API-QB, which features NIR emission at 720 nm, a Kd of 6.38 nM, and a 47-fold fluorescence enhancement upon binding to Aβ oligomers, represents an attractive multifunctional candidate for integrated diagnostic imaging and therapeutic intervention in AD.},
}

@article {pmid42298289,
year = {2026},
author = {Amouyel, P and Andrieu, S and Bradshaw, A and Carmona, RC and Dumont, M and Grinberg, LT and Iwatsubo, T and Hansson, O and Jack, CR and Jicha, GA and Mahinrad, S and McDade, E and Mummery, CJ and Petersen, RC and Robinson, S and Schneider, JA and Shellcross, L and Smith, AG and Snyder, HM and Tapply, B and Teunissen, C and van der Flier, WM and Vellas, B and Wallon, D and Williamson, JD and Wilcock, D and Carrillo, MC},
title = {Provider and patient perspectives on the diagnosis and treatment of Alzheimer's disease: A global perspective from the Global Alzheimer's Leadership Series (GoALS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71536},
pmid = {42298289},
issn = {1552-5279},
mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; },
abstract = {Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real-world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision-making, clear and transparent communication, and the need for real-world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.},
}

*Alzheimer Disease/diagnosis/therapy
Humans

@article {pmid42298291,
year = {2026},
author = {Guo, Y and Wang, R and Sindi, S and Middleton, LT and Kivipelto, M},
title = {Sleep and dementia: Assessing established dementia-related factors using multivariable Mendelian randomization.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71592},
pmid = {42298291},
issn = {1552-5279},
mesh = {Humans ; *Mendelian Randomization Analysis ; *Dementia/genetics/epidemiology ; *Sleep Initiation and Maintenance Disorders/genetics ; Risk Factors ; *Sleep/genetics ; United Kingdom ; *Alzheimer Disease/genetics ; Polymorphism, Single Nucleotide ; },
abstract = {INTRODUCTION: The relationship between sleep, other dementia risk factors, and dementia remains unclear. We aim to explore these associations using a two-sample Mendelian randomization (MR) approach.

METHODS: We identified genetic instrumental variables for sleep characteristics from the UK Biobank and obtained summary-level genetic association data for dementia outcomes, including Alzheimer's disease (AD), from the FinnGen consortium. We applied inverse-variance weighted (IVW) MR to examine the associations between sleep characteristics and dementia outcomes. Multivariable MR was subsequently employed to assess the influence of additional dementia-relevant factors on these relationships.

RESULTS: Genetic variants for insomnia, among the sleep characteristics, were associated with elevated AD risk (odds ratio [OR]IVW = 3.02, 95% confidence interval [CI]: 1.28-7.10, p = 0.01). Yet this association was largely attenuated after adjusting for education and low-density lipoprotein (LDL).

DISCUSSION: These findings indicate that the association between insomnia and AD is complex and indirect, potentially operating through social-behavioral factors (education) and biological pathways such as LDL cholesterol.},
}

Humans
*Mendelian Randomization Analysis
*Dementia/genetics/epidemiology
*Sleep Initiation and Maintenance Disorders/genetics
Risk Factors
*Sleep/genetics
United Kingdom
*Alzheimer Disease/genetics
Polymorphism, Single Nucleotide

@article {pmid42298542,
year = {2026},
author = {Oosterlynck, M and Fichter, L and Leroux, E and Eddarkaoui, S and Bouillet, T and Lefebvre, C and Nguyen, M and Maurage, CA and Accart, B and Dupré, E and Landrieu, I and Danis, C and Lehmann, S and Vialaret, J and Buée, L and Hirtz, C and Colin, M},
title = {Tau profiling of brain extracellular vesicles reveals PHF6 peptide as core for pathological tau seeding in Alzheimer's disease.},
journal = {Journal of biomedical science},
volume = {33},
number = {1},
pages = {},
pmid = {42298542},
issn = {1423-0127},
support = {18-CE44-0016//ANR, France, ToNIC/ ; HORIZON-MSCA-2022-DN-01//European Union/ ; T-PEP-23-969176//Rainwater Charitable Foundation & Alzheimer's Association/ ; 22-CE92-0061//ANR, France, NanoTarget/ ; 21-CE18-0046//ANR, France, Tauseed/ ; AAPSM2020#3056//France Alzheimer/ ; 24-INBS-0015//ANR, France/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism/genetics ; *Extracellular Vesicles/metabolism ; *Brain/metabolism/pathology ; Female ; Male ; Oligopeptides ; },
abstract = {BACKGROUND: Tauopathies are neurodegenerative diseases all characterized by tau lesions in the brain. Nevertheless, a clinical and pathophysiological heterogeneity is present among them. This includes the dominant tau isoform found within aggregates (3R and/or 4R tau) along with different brain regions being affected. For some tauopathies, especially in Alzheimer's disease, a specific spatio-temporal staging of tau lesions is present. This staging has been the basis for the prion-like propagation hypothesis, which describes a cell-to-cell transfer of pathological tau species resulting in new aggregates formation in recipient neurons. Human extracellular vesicles isolated from the brain-derived fluid (BD-EVs) of Alzheimer's disease patients contain seeds that contribute to this tau pathology spreading. However, the nature of these tau species responsible for this nucleation activity remains unknown. Additionally, heterogeneity in seeding activity of BD-EVs of Alzheimer's disease, progressive supranuclear palsy and Pick's disease patients is known.

METHODS: Here, EVs were isolated from human frozen tissue (Alzheimer's disease, Progressive Supranuclear Palsy, Pick disease and non-demented controls). We used a tau immunoprecipitation followed by high-resolution mass spectrometry to define their proteomic profile and test their seeding capacity in vitro.

RESULTS: We show that the tau profile present within BD-EVs is different among tauopathies. Interestingly, multiple tau peptides located in the microtubule binding region were specifically enriched in Alzheimer's disease extracellular vesicles. Of these, mainly the PHF6 (VQIVYK) containing proteins mediate tau seeding activity.

CONCLUSIONS: PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism/genetics
*Extracellular Vesicles/metabolism
*Brain/metabolism/pathology
Female
Male
Oligopeptides

@article {pmid42298558,
year = {2026},
author = {Deng, L and Li, H and Yang, S and Chen, F and Qiao, J and Bao, H and Wang, X and Fang, S and Xu, B and Tang, Z},
title = {Advances in nano-TCM for Alzheimer's disease: lipid-based carriers integrated with innovative delivery strategies.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04654-1},
pmid = {42298558},
issn = {1477-3155},
support = {JYB2025XDXM612//The Pilot Project for Disciplinary Breakthroughs of Ministry of Education ('Prevention and Treatment of Multi-System Comorbid Diseases with Traditional Chinese Medicine')/ ; 2025ZD1801004//Innovative Drug Research and Development National Science and Technology Major Project/ ; ZYYCXTD-D-202405//2024 Traditional Chinese Medicine Innovation Team and Talent Support Program Project/ ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, neuroinflammation, and oxidative stress. However, current therapies remain largely symptomatic. Traditional Chinese Medicine (TCM)-derived monomers exhibit considerable anti-AD potential owing to their multitarget neuroprotective activities. However, their therapeutic translation is severely limited by poor stability, low bioavailability, and restricted brain delivery across the blood-brain barrier (BBB). This review summarizes the pathological basis of AD, the neuroprotective mechanisms of representative TCM-derived monomers, and the major BBB-related barriers that hinder effective brain delivery. Particular emphasis is placed on lipid-based nanocarriers, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), as platforms for improving drug stability, BBB transport, and brain accumulation. We further highlight innovative delivery strategies that integrate ligand-mediated targeting with biomimetic modification, particularly cell membrane camouflage and exosome-inspired engineering. These approaches may confer immune evasion, prolonged circulation, enhanced biocompatibility, and improved lesion-oriented delivery. Finally, we discuss the challenges facing the clinical translation of lipid-based nanocarriers, including large-scale production, quality control, regulatory considerations, and long-term safety. Collectively, these lipid-based nanoplatforms provide a promising framework for advancing next-generation nano-TCM therapeutics for AD. Future progress will depend on optimized carrier design, rigorous mechanistic validation, comprehensive long-term safety assessment, and clinically relevant translational studies.},
}

@article {pmid42298621,
year = {2026},
author = {Gezginer, I and Karakatsani, ME and Nanda, P and Chalasani, P and Kindler, D and Storz, R and Belau, M and Ni, R and Schratt, G and Deán-Ben, XL and Razansky, D},
title = {Transcranial pulse stimulation modulates spectral signatures of Alzheimer's disease in the 3×Tg-AD mouse model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02109-1},
pmid = {42298621},
issn = {1758-9193},
abstract = {BACKGROUND: Large-scale brain network dysfunction is increasingly recognized as an important feature of Alzheimer's disease (AD), offering insight into disease mechanisms and opportunities for targeted therapeutic intervention. The spectral features of this dysfunction remain poorly understood, and how neuromodulatory interventions interact with and reshape these frequency-resolved network signatures has yet to be explored.

METHODS: Triple-transgenic (3×Tg-AD) mice underwent resting-state functional MRI to assess functional connectivity, signal power, and variance across frequency bands after acute and longitudinal transcranial pulse stimulation (TPS), a low-intensity single-pulse neuromodulatory intervention. Novel object recognition testing was used to evaluate exploratory drive and short-term recognition memory following repeated TPS or sham treatment.

RESULTS: AD mice exhibited widespread functional connectivity loss accompanied by reduced low-frequency resting-state power and variance, together with a redistribution of spectral energy from slow-5 (0.01-0.027 Hz) to slow-4 (0.027-0.073 Hz) activity. TPS modulated these abnormalities by increasing low-frequency power, rebalancing slow-5/slow-4 fractional power, and strengthening network coherence, with the most prominent effects in cingulate, insular, piriform, and striatal regions. TPS effects showed a non-linear, region-dependent emergence across stimulation trains, with the strongest and most consistent modulation appearing after repeated stimulation. Similar spectral rebalancing was observed both after acute and longitudinal stimulation, persisting for up to 5 days. In addition, hippocampal regions that showed minimal acute responses exhibited delayed spectral changes at 24 h, with further modulation at 120 h. TPS-treated 3×Tg-AD mice did not show the decline in object exploration observed in sham-treated animals and showed an exploration-adjusted increase in novel object preference.

CONCLUSIONS: Frequency-specific neural dynamics are sensitive markers of AD-related dysfunction and may provide a useful framework for tracking disease-related network abnormalities. TPS selectively modulates low-frequency oscillatory activity and network coherence and is accompanied by preliminary behavioral changes, including preserved exploratory engagement and an exploration-adjusted increase in novel object preference in a separate behavioral cohort. This highlights the potential of combining neuromodulation with spectral network analysis to monitor disease-related network dysfunction and treatment-associated responses.},
}

@article {pmid42298651,
year = {2026},
author = {Sanderson-Cimino, M and Gross, AL and Gaynor, LS and Paolillo, EW and Saloner, R and Albert, MS and Apostolova, LG and Boersema, B and Boxer, AL and Boeve, BF and Casaletto, KB and Heuer, HW and Forsberg, LK and Hallgarth, SR and Diaz, VE and Clark, LR and Eloyan, A and Farias, ST and Maillard, P and Gonzales, MM and Hammers, DB and La Joie, R and Cobigo, Y and Wolf, A and Hampstead, BM and Mechanic-Hamilton, D and Miller, BL and Rabinovici, GD and Ringman, JM and D'Orazio, LM and Rosen, HJ and Ryman, SG and Prestopnik, JL and Salmon, DP and Smith, GE and DeCarli, C and Rajan, KB and Jin, LW and Hinman, JD and Johnson, DK and Harvey, DJ and Fornage, M and Carrillo, MC and Dickerson, BC and Kramer, JH and Staffaroni, AM and , },
title = {Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02100-w},
pmid = {42298651},
issn = {1758-9193},
support = {AG053760/AG/NIA NIH HHS/United States ; AG063911,/AG/NIA NIH HHS/United States ; AG057195/AG/NIA NIH HHS/United States ; NS092089//National Institute of Neurological Disorders and St/ ; NS120384/NS/NINDS NIH HHS/United States ; },
abstract = {INTRODUCTION: List-learning tasks (LLTs) are important for characterizing memory in Alzheimer's disease and related dementias. However, as the Uniform Data Set Neuropsychological Battery (UDS-NB) historically did not require a specific LLT, centers have administered different LLTs. The newest UDS version (v4.0) requires one of two LLTs. To support harmonized UDS memory research, we developed a memory composite incorporating UDS memory tests and multiple LLTs.

METHODS: Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogeneous sample (n = 8716) that completed the UDS-NB and one of five LLTs. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, amyloid/tau PET positivity, and plasma phosphorylated tau. Analyses were replicated in a racially/ethnically diverse cohort (n = 839).

RESULTS: Psychometric properties were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity.

CONCLUSIONS: This composite supports memory research across cohorts that administer the UDS and LLTs. A user-friendly UI is freely available to create the score in other datasets.},
}

@article {pmid42298675,
year = {2026},
author = {Fan, X and Yang, Y and Zhao, Y and Liao, J},
title = {Sedentary behavior type matters: compositional analysis of 24-hour movement behaviors and cognitive function in older adults.},
journal = {Journal of activity, sedentary and sleep behaviors},
volume = {},
number = {},
pages = {},
doi = {10.1186/s44167-026-00105-2},
pmid = {42298675},
issn = {2731-4391},
support = {72061137003, ES/T014377/1//UK-China Health and Social Challenges Ageing Project (UKCHASCAP): present and future burden of dementia, and policy responses/ ; },
abstract = {BACKGROUND: Sleep, sedentary behaviors (SB) and physical activity are independently associated with cognitive function in older adults, yet the joint relationship of these 24-hour movement behaviors with cognitive function is less well studied. Additionally, the association between SB and cognitive function may differ depending on whether SB is mentally active or inactive. This study aimed to examine the associations between 24-hour movement behavior compositions and cognitive function in older adults, explore the differential associations of different sedentary behavior (SB) types with cognitive function, and assess the predicted cognitive differences associated with time reallocation among these behaviors.

METHODS: Data were drawn from 2516 US adults aged ≥ 60 years in the 2011-2014 National Health and Nutrition Examination Survey. Sleep, total SB, light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) were all assessed via wrist-worn accelerometry. Total SB was disaggregated into TV watching (inactive SB), computer use (active SB), and other SB using individual proportional weights derived from the Global Physical Activity Questionnaire (GPAQ). Cognitive function was evaluated using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning (memory), Animal Fluency (language), and Digit Symbol Substitution (executive function) tests. Standardized scores were combined into a global cognition score. Weighted compositional linear regression and isotemporal substitution models were applied.

RESULTS: In the 4-component model, greater relative time in MVPA and total SB were positively associated with global cognition (β = 0.191 and β = 0.260, respectively; both P ≤ 0.001), whereas relative sleep and LPA were negatively associated with global cognition. In the 6-component model, disaggregating total SB revealed divergent associations: computer use was positively associated with all cognitive domains (global: β = 0.045, P < 0.001), while TV watching was negatively associated with global cognition (β=-0.050, P = 0.047) and language. Notably, neither "other SB" nor sleep remained significantly associated with cognition in this expanded model. Isotemporal substitution analyses indicated that reallocating time to MVPA or computer use was associated with predicted higher global cognition scores, revealing a pronounced asymmetric trajectory where reducing these behaviors predicted steep cognitive declines.

CONCLUSIONS: Engaging in MVPA or mentally active SB may help preserve cognitive function in older adults, whereas mentally inactive SB is associated with poorer cognition. Optimizing 24-hour time use by replacing passive sedentary behaviors with MVPA or cognitively engaging activities represents a promising strategy.},
}

@article {pmid42298873,
year = {2026},
author = {Fiorenzato, E and Cauzzo, S and Musso, G and Biundo, R and Ceolin, C and Cosma, C and Fogliano, CA and Meissner, WG and Misenti, V and Moz, S and Nasi, ML and Vianello, F and Manara, R and Montagnana, M and Sergi, G and Antonini, A and , },
title = {Plasma p-tau217 Versus p-tau181 in Parkinson's Disease: Differential Associations with Alzheimer's Disease-Related Neurostructural Changes and Cognitive Function.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70392},
pmid = {42298873},
issn = {1531-8257},
support = {//Ministero dell'Istruzione, dell'Università e della Ricerca, National Recovery and Resilience Plan (NRRP)./ ; //NextGenerationEU (DM 1557 11.10.2022)./ ; },
abstract = {BACKGROUND: Plasma phosphorylated-tau at threonine-217 (p-tau217) and threonine-181 (p-tau181) are scalable, minimally invasive biomarkers of Alzheimer's disease (AD) pathology. In Parkinson's disease (PD), AD co-pathology may contribute to its clinical heterogeneity. However, the existing literature has predominantly focused on p-tau181, with comparatively limited investigation of p-tau217.

OBJECTIVE: The aim is to evaluate plasma p-tau217 and p-tau181 as biomarkers of AD co-pathology across the PD cognitive spectrum, relative to a cohort of dementia-free older adults.

METHODS: Plasma p-tau217 and p-tau181 were measured in 70 PD patients and 83 older adults. Associations with cognitive impairment, disease severity (Hoehn-and-Yahr), and neurostructural measures-including global atrophy, hippocampal volume, and a magnetic resonance imaging-based AD signature-were assessed using correlation and dominance analyses.

RESULTS: Both p-tau217 and 181 were higher in PD with cognitive impairment and dementia compared with cognitively normal PD. P-tau217 showed stronger associations than p-tau181 with AD-like neurostructural changes, multidomain cognitive deficits, greater disease severity, and reduced functional independence.

CONCLUSIONS: Plasma p-tau217 and p-tau181 may serve as scalable markers of AD-related processes associated with neurostructural, clinical, and cognitive outcomes in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42298895,
year = {2026},
author = {Yin, F and Wang, X and Chen, X and Sun, J and Zhang, K and Dong, X and Wang, W and Zeng, P and Li, B and Nie, L and Luo, D and Li, Y and Luo, T and , },
title = {Decoding Choroid Plexus Pathology in Alzheimer's Disease: A Longitudinal Radiomics Approach for Prodromal Identification and Risk Stratification.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {6},
pages = {e70987},
doi = {10.1002/cns.70987},
pmid = {42298895},
issn = {1755-5949},
support = {cstc2022ycjh-bgzXM0230//Chongqing Municipal Science and Technology Bureau/ ; 2023ZDXM006//Chongqing Medical Scientific Research Project/ ; CSTC2021 jscx-gksb-N0008//Key Project of Technological Innovation and Application Development of Chongqing Science and Technology Bureau/ ; CYYY-BSCX202506//Doctoral Research Innovation Project of the First Clinical College, Chongqing Medical University/ ; U19AG024904/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid ; Radiomics ; *Choroid Plexus/diagnostic imaging/pathology ; Female ; Male ; Aged ; Longitudinal Studies ; Magnetic Resonance Imaging/methods ; Cognitive Dysfunction/diagnostic imaging/pathology ; Disease Progression ; *Prodromal Symptoms ; Machine Learning ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; Risk Assessment ; Cohort Studies ; },
abstract = {AIMS: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and its identification of its prodromal stages remains a challenge. The choroid plexus (CP) plays a crucial role in AD pathology. This study aims to develop the CP radiomics model to distinguish AD from mild cognitive impairment (MCI) patients and predict the risk of MCI progression to AD.

METHODS: Radiomics features of CP were derived from magnetic resonance imaging (MRI) data, utilizing scans derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and a local institutional cohort. A range of 12 classic machine learning algorithms was utilized for model construction. Additionally, we assessed the partial correlations of CP radiomics features with the Mini-Mental State Examination (MMSE) score and with CSF biomarkers.

RESULTS: In the MCI versus AD classification task, the CP model attained a best AUC of 0.794. This performance was further boosted to an AUC of 0.907 upon integration with clinical features. In the model predicting MCI-to-AD conversion, the CP model achieved an AUC of 0.745, which increased to 0.908 after incorporating clinical features. Furthermore, the high-risk group, as defined by the radiomics model, had a significantly shorter time to AD conversion (HR = 2.201, p < 0.001). CP radiomics features showed significant correlations with MMSE and CSF biomarkers (p < 0.05).

CONCLUSION: The machine learning model based on CP radiomics features effectively differentiates AD from MCI patients and predicts the risk of MCI progression to AD, offering new insights into the role of the CP in AD pathophysiology.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid
Radiomics
*Choroid Plexus/diagnostic imaging/pathology
Female
Male
Aged
Longitudinal Studies
Magnetic Resonance Imaging/methods
Cognitive Dysfunction/diagnostic imaging/pathology
Disease Progression
*Prodromal Symptoms
Machine Learning
Biomarkers/cerebrospinal fluid
Aged, 80 and over
Risk Assessment
Cohort Studies

@article {pmid42299007,
year = {2026},
author = {Imai, N and Yano, H and Ikegame, Y and Yasuda, S and Morishima, R and Okumura, A and Kumagai, M and Shinoda, J and Izumo, T},
title = {Cerebral Hyperperfusion with Lecanemab in Alzheimer's Disease Assessed by Amyloid PET and Arterial Spin Labeling.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050453079260226065149},
pmid = {42299007},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by cognitive decline, amyloid-β deposition, and decreased Cerebral Blood Flow (CBF). Lecanemab, a monoclonal antibody targeting amyloid-β, slows cognitive decline in AD; however, its effects on CBF remain unclear. This study aimed to characterize CBF changes following lecanemab treatment and their association with baseline amyloid burden.

METHODS: Thirty patients with AD treated with lecanemab were analyzed retrospectively. Baseline amyloid deposition was quantified using the Centiloid scale, and patients were stratified into low, middle, and high groups. CBF was analyzed at baseline and at 8, 12, and 26 weeks using arterial spin labeling (ASL). Monoclonal antibody-triggered cerebral hyperperfusion (MATCH) was defined as a >20% CBF increase at week 8.

RESULTS: Seven patients were MATCH-positive (median CBF: 133.5% [125.5-167.8] of baseline). All MATCH-positive patients exhibited a decrease in CBF at week 12 compared to week 8. MATCH occurred in 6 of 10 patients in the middle Centiloid group. The low Centiloid group showed stable CBF, while the high Centiloid group showed a decreasing trend. The MATCHpositive group showed a significant deterioration in Instrumental Activities of Daily Living scores.

DISCUSSION: A transient CBF increase was closely associated with the middle Centiloid group. These CBF responses, including MATCH, may reflect amyloid removal, hyperperfusion, amyloidrelated imaging abnormalities, or immune responses.

CONCLUSIONS: CBF changes differed according to baseline amyloid burden. Understanding these therapy-related CBF changes is crucial for elucidating AD pathology, and ASL provides a practical, non-invasive method for longitudinal CBF monitoring in routine clinical practice.},
}

@article {pmid42299008,
year = {2026},
author = {Singh, NK and Singh, A},
title = {Mechanistic Perspectives of Icariin against Neuroinflammation: Taming Glial Activation.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575448388260306051328},
pmid = {42299008},
issn = {1875-5607},
abstract = {Glial-mediated neuroinflammation significantly contributes to major neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Inhibition of glial-mediated neuroinflammation is effective in treating neurodegenerative diseases. Although no permanent cure exists, considerable research aims to identify natural compounds that may slow the disease progression. Icariin is a naturally occurring flavonoid derived from the herb Herba epimedii and has been shown to have several medicinal benefits, including anti-aging, antioxidant, anti-inflammatory, and anti-apoptotic properties. Recent studies have indicated that Icariin, a potent prenylated flavonol glycoside, exhibits neuroprotective effects against glial-mediated neuroinflammation. Icariin attenuates glial pro-inflammatory responses and prevents neurotoxicity in cellular and animal models. Additionally, Icariin is speculated to facilitate neuronal functioning and survival in experimental conditions. The present review highlights the remarkable role of glial cells in neuroinflammatory processes subsequently neurodegeneration, and the potential of icariin to suppress glial-mediated neuroinflammation. We hope that this review will accelerate the pharmacological development of icariin as a potential therapeutic compound against glial-mediated neuroinflammation, which triggers the pathogenesis of several neurodegenerative disorders.},
}

@article {pmid42299012,
year = {2026},
author = {Watson, A and Shahid, M and Eldeeb, M},
title = {The Role of Helicobacter pylori CagA Protein in Inhibiting Amyloid Protein Aggregation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273445389260303041529},
pmid = {42299012},
issn = {1996-3181},
abstract = {Amyloids are β-sheet-rich protein aggregates with various implications in biology. Beyond their functional contributions, such as biofilm formation, amyloids are best known for their involvement in a number of human pathologies, including Alzheimer's Disease, Parkinson's Disease, and Type-two Diabetes (T2D), where they accumulate as toxic aggregates. Mounting lines of research investigations aimed at inhibiting amyloids encompass various strategies targeting different stages of amyloid formation and toxicity. Recent studies have unveiled a previously unrecognized function of the Helicobacter pylori virulence protein CagA as a potent inhibitor of amyloid formation. Herein, we highlight these findings, summarizing the current evidence suggesting that the N-terminal region of CagA interferes with multiple stages of fibril formation across a wide range of substrates, including bacterial amyloids and human disease-associated proteins. Further, depending on the protein, CagA appears to block primary nucleation, elongation, or secondary nucleation, and its activity has been mapped in part to Domain II. Together, these findings suggest that CagA functions beyond its canonical role in host signaling as a versatile regulator of protein aggregation. By highlighting this promising finding, we briefly discuss the broader implications in the context of host microbe interactions, the potential for microbial proteins to influence key molecular processes in mediating neurodegeneration, and the therapeutic potential of bacterial factors as amyloid inhibitors.},
}

@article {pmid42299049,
year = {2026},
author = {},
title = {Correction to "The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis".},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70591},
doi = {10.1111/acel.70591},
pmid = {42299049},
issn = {1474-9726},
}

@article {pmid42299128,
year = {2026},
author = {Song, Y and Xie, S and Li, T and Li, Y and Nie, S and Wang, Z and Ma, J and Jia, J},
title = {Amyloid beta aggregation seeding activity as a new biomarker for Alzheimer's disease.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {42299128},
issn = {2542-5641},
abstract = {BACKGROUND: Blood-based biomarkers would greatly facilitate the clinical diagnosis of Alzheimer's disease (AD) as minimally invasive measurements. While several blood biomarkers for AD have emerged, the potential of plasma β-amyloid (Aβ) aggregation seeding activity remains underexplored. In this study, we aim to evaluate the ability of this biomarker to distinguish AD and mild cognitive impairment (MCI) due to AD from cognitively unimpaired (CU) individuals and non-AD dementia.

METHODS: A total of 549 participants were recruited from Xuanwu Hospital, Capital Medical University, between December 2020 and May 2024. Plasma Aβ aggregation seeding activity was measured using a real-time sonication-based protein misfolding cyclic amplification assay across discovery (n = 120: 30 CU, 30 MCI due to AD, 30 AD, 30 non-AD dementia) and validation (n = 429: 118 CU, 46 MCI due to AD, 141 AD, 124 non-AD dementia) stages. The diagnostic performance of plasma Aβ aggregation seeding activity as a biomarker was assessed using receiver operating characteristic (ROC) curves.

RESULTS: In the validation stage, plasma Aβ aggregation seeding activity exhibited high diagnostic accuracy with optimal cutoff values (Thioflavin T fluorescence %) of 42.91 for distinguishing AD from CU (area under the ROC curve [AUC] = 0.93, 95% confidence interval [CI]: 0.91-0.96), 42.02 for AD from non-AD dementia (AUC = 0.91, 95% CI: 0.88-0.94), 43.17 for MCI due to AD from CU (AUC = 0.92, 95% CI: 0.87-0.96), and 43.24 for MCI due to AD from non-AD dementia (AUC = 0.90, 95% CI: 0.85-0.94). Plasma Aβ seeding activity significantly correlated with cognitive functions (Mini-Mental State Examination scores [MMSE]: rs = -0.68, P <0.001; Clinical Dementia Rating scores [CDR]: rs = 0.71, P <0.001).

CONCLUSIONS: These findings indicate that plasma Aβ aggregation seeding activity could serve as a promising minimally invasive biomarker for identifying both AD and MCI due to AD. This biomarker potentially facilitates early detection and differential diagnosis of AD at different clinical stages.},
}

@article {pmid42299502,
year = {2026},
author = {Liu, M and Hong, H and Zhang, X and Ren, J and Tang, C},
title = {Targeting the Nrf2 Signaling Pathway: A Review of Traditional Chinese Medicine for Alzheimer's Disease.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-29},
doi = {10.1142/S0192415X26500400},
pmid = {42299502},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by [Formula: see text]-amyloid (A[Formula: see text]) deposition, Tau protein hyperphosphorylation, and chronic neuroinflammation. Current pharmacological interventions demonstrate limited therapeutic efficacy. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a pivotal regulator of oxidative stress and neuroinflammation, plays a critical role in AD pathogenesis. Recent studies have revealed that traditional Chinese medicines (TCMs) and their bioactive constituents can modulate the Nrf2 signaling pathway to mitigate oxidative stress, suppress neuroinflammation, enhance A[Formula: see text] clearance, and reduce Tau protein phosphorylation. By doing so, TCMs exert multi-targeted anti-AD effects. This review systematically summarizes the mechanisms and recent advances concerning the active ingredients of Nrf2 pathway-modulating TCMs, herbal medicines, and TCM formulations for the prevention and treatment of AD. Furthermore, it critically evaluates current research limitations and prospects for future research directions to provide a theoretical foundation for the development of novel anti-AD therapeutics derived from TCMs.},
}

@article {pmid42299696,
year = {2026},
author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, B and Brown, JR and Braxton, DS and Henry, SN and McCoin, CS and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Jarome, TJ and Najt, CP and Drake, JC},
title = {Age-Dependent Remodeling of the Sciatic Nerve Proteome in 5xFAD Mice Can Be Attenuated by Exercise or Donepezil Treatment to Maintain Neuromuscular Function.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70595},
pmid = {42299696},
issn = {1474-9726},
support = {R01AG080731/AG/NIA NIH HHS/United States ; K02AG088474/AG/NIA NIH HHS/United States ; R00AG070104/AG/NIA NIH HHS/United States ; R01AG062548/AG/NIA NIH HHS/United States ; R01AG069781/AG/NIA NIH HHS/United States ; P20GM144269/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Donepezil/pharmacology/therapeutic use ; Mice ; *Proteome/metabolism ; *Sciatic Nerve/metabolism/drug effects ; *Physical Conditioning, Animal ; *Aging ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy ; Muscle, Skeletal/drug effects ; Male ; },
abstract = {Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age-related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months, identifying proteome remodeling coincides with functional declines at 4 months particularly in pathways linked to mitochondrial turnover, calcium handling, and inflammation. We hypothesized either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates, were given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil. We assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in vivo at 4 months. Both exercise and donepezil attenuated in vivo nerve-stimulated muscle torque and CNAP dysfunction. Further, both exercise and donepezil attenuated the proteomic remodeling of the sciatic nerve through both shared and independent mechanisms that converged on mitochondria-centric pathways. Our findings in the 5xFAD model of AD support the notion that early phenotypes of AD are evident in the periphery that may have implications for timing of interventions.},
}

Animals
*Donepezil/pharmacology/therapeutic use
Mice
*Proteome/metabolism
*Sciatic Nerve/metabolism/drug effects
*Physical Conditioning, Animal
*Aging
Mice, Transgenic
*Alzheimer Disease/metabolism/drug therapy
Muscle, Skeletal/drug effects
Male

@article {pmid42299743,
year = {2026},
author = {Bélanger, E and Couch, E and Carroll, M and Gadbois, EA and Jutkowitz, E and Van Houtven, CH and Wetle, TT},
title = {Long-Term Perceptions of the Value of Amyloid PET Scans Among Cognitively Impaired Medicare Beneficiaries and Their Care Partners.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {6},
pages = {e70226},
doi = {10.1002/gps.70226},
pmid = {42299743},
issn = {1099-1166},
support = {R01AG053934/NH/NIH HHS/United States ; //American College of Radiology Imaging Network/ ; /ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/psychology/economics ; Male ; Female ; Aged ; United States ; Aged, 80 and over ; Medicare ; *Alzheimer Disease/diagnostic imaging ; *Caregivers/psychology ; Qualitative Research ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid ; },
abstract = {OBJECTIVES: The objective of this study was to examine the long-term perceptions of the value of receiving an amyloid PET scan, a test used to diagnose Alzheimer's disease, among Medicare beneficiaries with cognitive impairment and their care partners.

METHODS: An exploratory qualitative research design was used. A total of 100 in-depth semi-structured interviews were conducted with a purposeful sample of CARE-IDEAS participants two to three years post-scan. A team of coders applied qualitative content analysis to identify content about the value of the scan, which was then analyzed using thematic analysis, and stratified by diagnostic category (mild cognitive impairment vs. dementia) and scan results (elevated amyloid vs. not elevated).

RESULTS: A majority of amyloid PET scan recipients and their care partners emphasized major benefits of receiving the scan including increased certainty about diagnosis, the ability to prepare for the future, potentially accessing treatment or trials, the ability to contribute to research, and limited procedural risks. Some participants also reported concerns about the cost of the scan, the lack of effective treatment options and clear prognostic information, the limited impact on their lives or treatment plans, and the emotional toll of living with the results. Their views and endorsements of the scan were shaped by their health and personal circumstances (e.g., seen as less relevant among those with rapidly declining health), and by their preference for more information and involvement in decision-making.

CONCLUSION: The perspectives of persons living with cognitive impairment and their care partners about the value of amyloid PET scans differed across disease trajectories and personal circumstances. These experiences should be taken into consideration when advising symptomatic patients on the benefits and drawbacks of biomarkers for Alzheimer's disease.},
}

Humans
*Positron-Emission Tomography/psychology/economics
Male
Female
Aged
United States
Aged, 80 and over
Medicare
*Alzheimer Disease/diagnostic imaging
*Caregivers/psychology
Qualitative Research
*Cognitive Dysfunction/diagnostic imaging
Amyloid

@article {pmid42299769,
year = {2026},
author = {Cox, CW and Farina, CL and Reisenberg, CE and Charles, R},
title = {Bridging disciplines through Alzheimer care: A faculty-guided summer interprofessional education experience for prelicensure nursing students.},
journal = {Nursing},
volume = {56},
number = {7},
pages = {57-62},
doi = {10.1097/NSG.0000000000000409},
pmid = {42299769},
issn = {1538-8689},
mesh = {Humans ; *Students, Nursing/psychology ; *Alzheimer Disease/nursing ; *Education, Nursing, Baccalaureate/organization & administration ; *Interprofessional Relations ; *Interprofessional Education/organization & administration ; Curriculum ; },
abstract = {Interprofessional education (IPE) is essential for preparing nursing students to engage in collaborative, team-based care. However, coordinating IPE experiences is challenging for several reasons, including the limited number of health profession programs with summer enrollment. The Accelerated Bachelor of Science in Nursing (ABSN) program at the authors' university operates year-round on a four-semester schedule, making it difficult to ensure consistent IPE opportunities for every cohort, particularly those beginning in summer. To address this gap and advance best practices, the authors present a redesigned virtual simulation structured as an IPE experience that offers meaningful interdisciplinary engagement for summer-entry ABSN students.},
}

Humans
*Students, Nursing/psychology
*Alzheimer Disease/nursing
*Education, Nursing, Baccalaureate/organization & administration
*Interprofessional Relations
*Interprofessional Education/organization & administration
Curriculum

@article {pmid42299837,
year = {2026},
author = {Leem, S and Yang, Y and Woods, AJ and Fang, R},
title = {Prediction of Alzheimer's disease risk factors from retinal images via deep learning: Development and validation of biologically relevant morphological associations in the UK Biobank.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457650},
doi = {10.1177/13872877261457650},
pmid = {42299837},
issn = {1875-8908},
abstract = {BackgroundThe systemic, metabolic, lifestyle factors have established associations with Alzheimer's disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear.ObjectiveTo determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability.MethodsUsing 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD pathology or incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, body mass index, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls.ResultsPredictive performance of DL ranged from AUROC between 0.5654 and 0.9480 for categorical factors and R[2] between -0.0291 and 0.7620 for continuous factors, outperforming most of the morphometry-based machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of AD-related risk factors and preclinical AD-associated changes.ConclusionsCFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.},
}

@article {pmid42299852,
year = {2026},
author = {Beh-Pajooh, A},
title = {Identification of candidate diagnostic biomarkers and gene networks for moderate stages of Alzheimer's disease in fusiform gyrus exhibiting neurofibrillary tangles.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452277},
doi = {10.1177/13872877261452277},
pmid = {42299852},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder whose incidence grows with age and its development is gradual. However, if detected earlier there is much hope to prevent further exacerbation. In this study, NGS transcriptomics data from cases and controls with Braak scores of III-IV were investigated that all possessed neurofibrillary tangles (NFTs) in their fusiform gyrus.ObjectiveThe aim of this study was to discover the underlying mechanisms at gene level which could explain cognitive impairment by considering the presence of NFTs in both groups.MethodsDifferentially expressed genes (DEGs) were determined and ROC AUC were evaluated by leave-one-out cross-validation method on the diagnostic DEGs to detect candidate gene biomarkers. WGCNA was employed to identify co-expression modules with their trait association. Finally, in silico hybridization of lncRNAs from potential biomarkers with important AD-related microRNAs was carried out.ResultsHighly ranked potential diagnostic gene biomarkers revealed assessed AUC ranges of 80-90% in which RASGRF2-AS1 demonstrated the highest value. WGCNA demonstrated upregulated genes in favor of dephosphorylation of tau, proper proteostasis and vascular health in resilient controls whereas dysfunctional proteostasis, chronic protein misfolding, heightened cellular stress and tetrahydrobiopterin deficiency were attributed to cognitive impairment in AD patients. In silico analyses predicted some lncRNAs with a high possibility of acting as sponge for AD-related microRNAs.ConclusionsThis study discovered potential diagnostic gene biomarkers and transcriptional signatures that could explain the mechanisms of cognitive decline by considering the existence of NFTs, which could provide further insight for diagnosis and treatment of the disease.},
}

@article {pmid42299870,
year = {2026},
author = {Churchill, N and Le, TT and Nianogo, RA},
title = {Alzheimer's disease and related dementias state policies and mortality in the United States: A descriptive study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453609},
doi = {10.1177/13872877261453609},
pmid = {42299870},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease and related dementias (ADRD) were the sixth leading cause of death among people aged 65 + in 2022 and are currently the leading cause of disability and morbidity in older adults. In 2025, an estimated 7.2 million Americans aged 65 years and older were living with Alzheimer's disease (AD), with prevalence projected to rise.ObjectiveWe describe 1) the trends in the adoption of ADRD policies that were implemented in the U.S. from 2008-2020, as well as 2) the trends in ADRD mortality during 1999-2022.MethodsWe presented mortality data for the age-adjusted rate of ADRD mortality per 100,000 people in 1999-2022 from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER). We also collected policy data from state websites from 2008-2020.ResultsPolicies were implemented for all 50 states, starting in 2008 and ending in 2020. ADRD mortality steadily rose during 1999-2022. The first states to implement ADRD in 2008 were Iowa and Kentucky. The largest number of states added policies in 2013. South Dakota, Wyoming, Ohio, and Kansas were the last states to implement policies.ConclusionsOur study documented that all the states in the United States implemented a policy to reduce ADRD cases. We also observed that ADRD mortality steadily rose between 1999 and 2022. This rise may reflect increased reporting of ADRD as a cause of death, or policies needing more time to meet national reduction goals.},
}

@article {pmid42299956,
year = {2026},
author = {Leri, M and Nosi, D and Ami, D and Bovio, F and Forcella, M and Carnemolla, F and Mereghetti, P and Fusi, P and Natalello, A and Stefani, M and Taddei, N and Bucciantini, M},
title = {Oleuropein and hydroxytyrosol enhance mitochondrial function and biogenesis in SH-SY5Y cells through estrogen-like mechanisms.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00178e},
pmid = {42299956},
issn = {2042-650X},
abstract = {Age-related hormonal and metabolic changes critically increase vulnerability of neurons to neurodegeneration and cognitive decline. Estrogens are known to support neuronal survival, synaptic plasticity, and mitochondrial function, yet hormone replacement therapies have shown inconsistent neuroprotective outcomes. Safe alternatives are therefore highly desirable. In this study, we characterize Oleuropein aglycone (OleA) and hydroxytyrosol (HT), two of the main bioactive phenolic compounds found in extra virgin olive oil (EVOO), as multitarget neuromodulators with estrogen-like and neuroprotective potential. Unlike most studies on phytoestrogens, which have focused on single pathways such as estrogen receptor activation, our findings reveal a broader spectrum of actions. OleA and HT simultaneously modulate ERβ and IGF1R signaling, regulate Ca[2+] dynamics through ryanodine, AMPA, and NMDA receptors, remodel the neuronal lipidome, and promote mitochondrial biogenesis and metabolic efficiency. Moreover, they influence amyloid-binding alcohol dehydrogenase (ABAD) expression, a mitochondrial target implicated in Alzheimer's disease. By converging on receptor signaling, lipid metabolism, and mitochondrial function, these compounds provide a systems-level perspective on neuronal protection. This multitarget activity, which mimics estrogen-like signaling, positions the investigated EVOO-derived phenolic compounds as safe dietary agents to counteract the neuronal decline associated with estrogen loss during ageing.},
}

@article {pmid42300138,
year = {2026},
author = {Wolf, EJ and Zhao, X and Hao, S and Lawhorn, C and Carbaugh, J and Fortier, CB and Milberg, WP and Logue, MW and Miller, MW},
title = {PTSD Severity-Related Accelerated Aging, Hippocampal Volume, and CLDN5 DNA Methylation.},
journal = {Biopsychosocial science and medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001501},
pmid = {42300138},
issn = {2998-8756},
abstract = {OBJECTIVE: The claudin-5 (CLDN5) gene is critical for blood brain barrier integrity and may link traumatic stress, accelerated aging, and neurological disease. Building on prior research showing associations between trauma exposure and PTSD with CLDN5 DNA methylation (DNAm), we tested if candidate CLDN5 DNAm loci were associated with advanced epigenetic aging in blood and brain tissue and with hippocampal volume.

METHODS: 1302 trauma-exposed individuals (Mage=44.23, SD=13.71; 76% male) underwent psychiatric diagnostic interviews and blood draws for obtaining epi/genetic information; 473 underwent magnetic resonance imaging of the brain. Data from 109 PTSD brain bank decedents with DNAm from ventromedial prefrontal cortex (vmPFC) were also examined (Mage-at-death=45.20, SD=14.21; 62% male).

RESULTS: All candidate loci were associated with metrics of epigenetic age in blood (p-adj range: .0396 to 4.5e-05) and these associations largely extended to postmortem vmPFC. There was an indirect association between PTSD severity and CLDN5 DNAm in blood at cg21872764 via GrimAge residuals (indirect β=.033, P=.040) that was diminished when the direct PTSD association was modeled. The CLDN5 probe cg17411190 in blood was negatively related to left and right hippocampal volume (p-adj=.042) and with volume of multiple hippocampal substructures. The association between PTSD severity and hippocampal volume was indirect via blood DNAm at cg17411190 (indirect β=-.011, P=.045).

CONCLUSIONS: PTSD severity-related accelerated aging may be associated with altered CLDN5 DNAm, which may signal neurodegeneration, such as reduced hippocampal volume. CLDN5 DNAm in blood may serve as a useful proxy for brain CLDN5 DNAm. Given that prior environmental enrichment and antidepressant studies show initial efficacy in altering CLDN5 expression, future studies could evaluate if PTSD treatment alters CLDN5 epigenetics and reduces risk for neurodegeneration.},
}

@article {pmid42300178,
year = {2026},
author = {Cheng, L and Wang, Y and Ma, Y and Zheng, C and Wang, Z and Wu, F and Fang, B},
title = {Daily supplementation with egg yolk lipids from two eggs alleviated cognitive impairment in 5 × FAD mice by restoring neuronal and synaptic function and regulating gut microbiota.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00928j},
pmid = {42300178},
issn = {2042-650X},
abstract = {Eggs are recommended by dietary guidelines as an effective vehicle for DHA intake, yet direct evidence on the health effects and optimal dosage of egg yolk lipids against Alzheimer's disease (AD) remains limited. This study evaluated DHA-enriched egg yolk lipids in 5 × FAD mice at doses of 1 and 2 g kg[-1] day[-1] for eight weeks, corresponding to human consumption of 1 or 2 eggs daily. The high-dose intervention (2 g kg[-1]) ameliorated cognitive deficits and neuronal damage by upregulating BDNF and NGF, improving synaptic plasticity (PSD95, SYN, Drebrin), increasing dendritic spine density, restoring cholinergic and glutamatergic neurons, and suppressing microglial activation-induced neuroinflammation (IL-6, IL-1β, IFN-γ). Metabolomic and gut microbiota analysis revealed increased levels of neuroprotective metabolites (PC (20 : 2/22 : 6), neuroprotectin D1) and enhanced abundance of AD-beneficial genera including Muribaculaceae and Lachnospiraceae. This study provides direct experimental evidence supporting DHA-enriched egg yolk lipids as a dietary intervention strategy for AD, with an effective dosage of 2 g kg[-1].},
}

@article {pmid42300320,
year = {2026},
author = {Oğuz, E and Güller, P},
title = {2-Quinolinone Derivatives as Dual Cholinesterase Inhibitors: Experimental and Computational Insights.},
journal = {Medicinal chemistry (Shariqah (United Arab Emirates))},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734064499561260531131802},
pmid = {42300320},
issn = {1875-6638},
abstract = {BACKGROUND: Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are two cholinesterases that play important roles as therapeutic targets in the cholinergic system associated with neurodegenerative diseases such as Alzheimer's disease.

OBJECTIVE: The purpose of this study was to assess the in vitro inhibitory potencies of 2- quinolinone derivatives against hAChE and hBuChE and to estimate the interaction types in silico. Besides, drug-likeness characteristics (ADME) and density functional theory (DFT) calculations of the compounds were used to support the in vitro inhibition studies.

METHODS: IC50-[inhibitor] graphs and Lineweaver-Burk graphs were generated. Molecular docking studies were performed by AutoDock. While ADME properties were predicted by SwissADME, DFT calculations of the compounds were made by ORCA software.

RESULTS: QU4 and QU6 were found to be the most effective inhibitors of AChE and BuChE with Ki values of 35.672±9.75 μM and 13.38±3.5 μM, respectively. The binding energy of QU3 against hAChE was estimated as -7.51 kcal/mol, while QU2 exhibited a binding energy of -9.11 kcal/mol against BuChE; these values are more negative than that of the reference inhibitor tacrine for both enzymes. Additionally, according to drug-likeness analysis, the derivatives except QU7 showed high blood-brain barrier permeability.

DISCUSSION: The results suggest that QU4 and QU6 derivatives may have potential for cholinesterase inhibition.

CONCLUSION: Overall, the findings of this study guide the development of more potent and selective inhibitors by appropriate structural modifications of the 2(1H)-quinolinone skeleton.},
}

@article {pmid42300608,
year = {2026},
author = {Khorrami, S and Alifarsangi, A and Mohammed, LJ and Amshawee, AM and Zarrabi, A},
title = {Metal-based nanoparticles' potential in Alzheimer's disease diagnosis, therapy and theranostics.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr04613k},
pmid = {42300608},
issn = {2040-3372},
abstract = {Metal-based nanoparticles are emerging as a versatile platform to overcome critical challenges in the diagnosis and treatment of Alzheimer's disease (AD). This review provides a comprehensive synthesis of recent advances, structured around the three core domains of AD management: diagnostics, therapeutics, and theranostics. We discuss how the unique physicochemical properties of metals and metal oxides enable highly sensitive biosensing of amyloid and tau biomarkers, as well as high-contrast imaging modalities. The review then evaluates strategies for engineering metal-based nanoparticles to bypass the blood-brain barrier and achieve targeted accumulation, alongside their therapeutic roles in drug delivery, photothermal therapy, and modulating protein aggregation. Finally, we assess integrated theranostic systems that combine real-time imaging with targeted intervention. The key conclusion is that platforms based on metal-based nanoparticles, through their multifunctionality, offer a realistic pathway toward minimally invasive early diagnosis and targeted therapy. However, the field's future direction must prioritize rigorous standardization and advanced preclinical validation to translate these promising nanotechnologies from bench to bedside, ultimately advancing precision neurotheranostics for AD.},
}

@article {pmid42300694,
year = {2026},
author = {Rodrigues, AC and Valério, FG and Moura, CB and Da Silva, AMP and Tudella, GCN and Almeida, SS and Gomes, AC and Oliveira, CEM and Apóstolos-Pereira, SL and Santos, DH},
title = {Impacts of menopausal hormone therapy on Alzheimer's disease biomarkers: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456766},
doi = {10.1177/13872877261456766},
pmid = {42300694},
issn = {1875-8908},
abstract = {BackgroundSex-specific vulnerability to Alzheimer's disease (AD) has been increasingly recognized, with menopause representing a decisive neuroendocrine transition. Estrogen and progesterone modulate synaptic plasticity, glucose metabolism, and amyloid-tau homeostasis, yet the impact of their decline and replacement remains controversial. AD biomarkers provide objective means to assess menopausal hormone therapy (MHT) mechanistic effects beyond cognitive endpoints.ObjectiveTo determine how MHT influences validated AD biomarkers in peri- and postmenopausal women.MethodsA systematic review was conducted following PRISMA guidelines (PROSPERO CRD420251149404). PubMed, Embase, Web of Science, and Cochrane Library were searched through September 2025 for interventional and observational studies evaluating MHT and AD biomarkers after non-surgical menopause. Eligible biomarkers included cerebrospinal fluid (CSF) and plasma markers, and amyloid-, tau- or FDG-PET imaging. Study quality was assessed using RoB-2 and ROBINS-I tools, and evidence certainty with GRADE.ResultsFourteen studies met inclusion criteria. Early or continuous transdermal 17β-estradiol was linked with lower CSF and plasma p-tau181 and preserved glucose metabolism in AD-vulnerable cortical regions. Neuroimaging studies showed decreased amyloid deposition and sustained metabolic benefits years after discontinuation. Conversely, oral conjugated equine estrogens and estrogen-progestin regimens led to neutral or unfavorable biomarker trends, particularly when initiated more than five years after menopause.ConclusionsMHT's effects on AD biomarkers depend on timing, formulation and hormonal composition. Early transdermal estradiol appears to reinforce neuroprotective biomarker profiles, whereas delayed or combined therapies may nullify these benefits. Genotype-stratified trials with harmonized biomarker reports are needed to define optimal neuroprotective windows for women.},
}

@article {pmid42300696,
year = {2026},
author = {Franco-Macías, E and Noval-Padillo, JÁ and Hervás-Navidad, R and Espejo-Martínez, B and Serrano-Gutiérrez, C and Rodrigo-Herrero, S and Méndez-Barrio, C and Mendoza-Vázquez, G and Carrera-Muñoz, I and Marín-Romero, B and Garzón-Maldonado, F and Carazo-Barrios, L and Rodríguez-Jiménez, L and Martínez-Nogueras, Á and Agüera-Morales, E and Conde-Gavilán, C and Jover, AM and García-Navarro, C and Iglesias-Espinosa, M and Romera-Morales, DJ and Cuartero-Rodríguez, E and García-Roldán, E and González-Acosta, M and Almodóvar-Sierra, Á and Marín-Cabañas, M and Bernal Sánchez-Arjona, M and García-Sánchez, MI and Arriola-Infante, JE and Arrabal-Gómez, C and Oliver-Martos, B and Serrano-Castro, PJ and Fatela-Cantillo, D},
title = {Plasma p-tau217 measured by the Elecsys automated immunoassay: Prospective validation in a heterogeneous memory clinic cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261459067},
doi = {10.1177/13872877261459067},
pmid = {42300696},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a leading blood-based biomarker for the diagnosis of Alzheimer's disease (AD) and can be measured using fully automated, random-access platforms. The Elecsys plasma p-tau217 assay requires further validation, particularly in heterogenous populations seen in memory clinics.ObjectiveTo validate plasma p-tau217 in comparison with p-tau181 and to evaluate its association with other soluble core 1 AD biomarkers, as well as markers of neurodegeneration and neuroinflammation.MethodsBiobank data from two prospective blood-based biomarkers validation studies were analyzed. Cerebrospinal fluid (CSF) p-tau181/Aβ42 ratio served as the reference standard for AD diagnosis. The diagnostic performance of plasma p-tau217 and p-tau181 was compared. In patients with AD, p-tau217 was further evaluated for its association with CSF (Aβ42/Aβ40 ratio, p-tau181, t-tau) and plasma [APOE ε4 protein (APOE ε4p), NfL (neurofilament light chain), GFAP (glial fibrillary acidic protein)] biomarkers.ResultsAmong 303 patients with mild cognitive impairment or mild dementia, plasma p-tau217 outperformed plasma p-tau181 (AUC 0.93 versus 0.87). By the two threshold diagnostic strategy, an upper cutoff (>0.312 pg/mL, specificity 95%) and a lower cutoff (<0.177 pg/mL, sensitivity 95%) were established, with 27% of cases falling into an indeterminate range. Plasma p-tau217 showed strong correlations with CSF Aβ42/Aβ40 and p-tau181/Aβ42 ratios, as well as with plasma GFAP, and only moderate correlations with CSF t-tau and p-tau181, and plasma NfL.ConclusionsPlasma p-tau217 measured using Elecsys demonstrates good diagnostic performance and strong associations with other soluble Core 1 AD and neuroinflammation biomarkers.},
}

@article {pmid42300698,
year = {2026},
author = {Selmanovic, E and Gibbons, LE and Folkerth, RD and Keene, CD and Nolan, A and Crane, P and Postupna, N and Lee, CS and Latimer, CS and Ariza-Torres, J and Hof, PR and Dams-O'Connor, K},
title = {Traumatic brain injury and late-life Alzheimer's disease neuropathology: Quantitative investigation in the Adult Changes in Thought study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457138},
doi = {10.1177/13872877261457138},
pmid = {42300698},
issn = {1875-8908},
abstract = {BackgroundTraumatic brain injury (TBI) is associated with increased dementia risk, yet its relationship to Alzheimer's disease (AD) neuropathology is unclear. Prior autopsy studies show inconsistent results, constrained by limited TBI ascertainment, semi-quantitative neuropathology methods, and selection bias.ObjectiveTo examine whether TBI with loss of consciousness (TBI-LOC) is associated with quantitative measures of tau and amyloid-β42 (Aβ42) pathology in a community-based autopsy cohort.MethodsThe analytic sample included 810 Adult Changes in Thought study brain donors with baseline TBI-LOC ascertainment and quantitative neuropathology data, weighted to represent the full living cohort (n = 5763). Modified Poisson regression estimated rate ratios (RRs) and 95% confidence intervals (CIs) for associations of TBI-LOC with percent-positive AT8 tau immunoreactivity and soluble Aβ42 (GuHCl and RIPA fractions) across brain regions. Models were adjusted for age at death, sex, education, and enrollment cohort; sensitivity analyses included unweighted and quantile models.ResultsWeighted models showed lower frontal tau (RR = 0.50, p = 0.047) and lower soluble Aβ42 in temporal and occipital cortices (p = 0.019-0.037) among donors with baseline TBI-LOC. In unweighted sensitivity analyses, lower temporal RIPA Aβ42 remained significant (p < 0.001), and select inverse associations were observed in duration-stratified analyses, particularly in small >1 h LOC subgroups. Quantile analyses of pathology burden similarly suggest reduced parietal Aβ42 (p = 0.02-0.04); effects were small and driven by sparse subgroups.ConclusionsTBI-LOC was not associated with greater tau or amyloid burden, and inverse associations likely reflect data sparsity rather than biological protection. These findings suggest that links between TBI and late-life cognitive decline may involve non-AD pathological processes.},
}

@article {pmid42300702,
year = {2026},
author = {Deconne, TM and Suerken, CK and Lipford, ME and Lockhart, SN and Bateman, JR and Espeland, M and Rudolph, MD and Rundle, MM and Sutphen, C and Register, TC and Mielke, MM and Pewowaruk, R and Gepner, AD and Baker, LD and Craft, S and Hughes, TM},
title = {Structural and load-dependent arterial stiffness are differentially associated with cognition or biomarkers of Alzheimer's disease and related dementias: The healthy brain study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458779},
doi = {10.1177/13872877261458779},
pmid = {42300702},
issn = {1875-8908},
abstract = {BackgroundArterial stiffness is an emerging risk factor for Alzheimer's disease (AD) and related dementias (ADRD) and is assessed by measuring pulse wave velocity (PWV). Recent mathematical modeling has allowed for the delineation of arterial stiffness caused by structural remodeling (S) and blood pressure, termed "load-dependent" stiffening (LD). While we recently demonstrated that S-PWV and LD-PWV are differentially associated with risk for cognitive decline and AD/ADRD brain imaging biomarkers, the associations between paired measures of S-PWV and LD-PWV with cognitive function, AD/ADRD brain imaging biomarkers, and plasma AD biomarkers have not been assessed.ObjectiveTo conduct a comprehensive analysis combining cross-sectional data from the Wake Forest Alzheimer's Disease Research Center. We hypothesized that higher S-PWV would be associated with worse cognitive function. We also hypothesized that S-PWV and LD-PWV would be differentially associated with brain imaging biomarkers of ADRD and plasma AD biomarkers.MethodsMultivariable linear regression models were used to relate S-PWV and LD-PWV to all outcomes.ResultsAs hypothesized, higher S-PWV, but not LD-PWV, was associated with lower global cognitive function. Higher S-PWV and LD-PWV were differentially associated with AD/ADRD brain MRI biomarkers. We did not observe any significant associations with plasma or PET AD biomarkers in this cohort.ConclusionsS-PWV was associated with lower cognition, while S-PWV and LD-PWV were differentially associated with brain MRI biomarkers. Interventions specifically targeting arterial stiffness may preserve cognition and brain health in AD/ADRD.},
}

@article {pmid42300704,
year = {2026},
author = {Van Rosmalen, L and Brück, CC and Wolters, FJ and Handels, R and De Kok, IMCM},
title = {Primary and secondary prevention strategies for reducing population-level dementia burden: A microsimulation modeling study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457937},
doi = {10.1177/13872877261457937},
pmid = {42300704},
issn = {1875-8908},
abstract = {BackgroundThe growing burden of dementia and Alzheimer's disease may be mitigated by a combination of primary and secondary preventive strategies, including lifestyle interventions and targeted disease-modifying therapy at the individual-level.ObjectiveOur aim is to estimate the effects of primary and secondary prevention on a population level in terms of life years lived with and without dementia.MethodsWe used the previously developed and validated microsimulation model MISCAN-Dementia, modified to evaluate the impact of individual-level primary and secondary preventative interventions in the Dutch population aged 55 years and older, between 2025 and 2050. We expanded this model with prevention-specific effectiveness and eligibility, based on observed trial effects (primary analysis) and assuming a range of combinations of eligibility and effects (secondary analyses).ResultsExtrapolating results from available randomized controlled trials, combined primary and secondary preventative interventions result in a 6.1% decrease of life years lived with moderate to severe dementia until 2050, compared to no additional prevention. Dementia-free life years increased by 3.1%. The magnitude of risk reduction was the primary driver of impact, with the most optimistic assumptions resulting in a stabilization of dementia prevalence by 2050.ConclusionsA combination of primary and secondary preventative strategies likely is needed to achieve optimal effects on the future burden of dementia. These approaches differ in the time needed to achieve maximal population-level impact, with the overall magnitude of effect primarily determined by the size of the intervention's impact.},
}

@article {pmid42300721,
year = {2026},
author = {Song, BX and Schecter, J and Vieira, E and Gallagher, D and Diniz, BS and Fischer, CE and Flint, AJ and Herrmann, N and Kennedy, JL and Mah, L and Mulsant, B and Pollock, BG and Rajji, TK and Ma, C and Lanctôt, KL and , },
title = {Angiogenesis markers and cognitive response in a randomized trial of cognitive remediation plus transcranial direct current stimulation in older adults at risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457934},
doi = {10.1177/13872877261457934},
pmid = {42300721},
issn = {1875-8908},
abstract = {BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f[2] = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ[2]LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.},
}

@article {pmid42300733,
year = {2026},
author = {Liu, H and Cheng, Y and Fan, C},
title = {Association between Gompertz law-based biological age and dementia: A longitudinal study of middle-aged and older Chinese adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457952},
doi = {10.1177/13872877261457952},
pmid = {42300733},
issn = {1875-8908},
abstract = {BackgroundWhile chronological age is a major but non-specific risk factor for dementia, measures of biological age based on physiological biomarkers may more accurately reflect systemic aging.ObjectiveWe aimed to assess the association between a Gompertz law-based biological age (Light BioAge) and incident dementia in a national cohort of middle-aged and older adults in China, and to evaluate the potential modifying role of lifestyle.MethodsWe conducted a longitudinal analysis of 5641 participants (≥45 years) from China Health and Retirement Longitudinal Study. Light BioAge was computed at baseline (2011) using a validated algorithm incorporating chronological age, serum creatinine, fasting glucose, and high-sensitivity C-reactive protein. Dementia in 2018 was determined via cognitive tests, informant reports, and functional assessment. Logistic regression models were used to estimate odds ratios (ORs).ResultsDuring the follow-up, 788 (13.97%) participants were identified as having dementia. Each 1-year increment in Light BioAge was associated with 4% higher risk of dementia (OR 1.04, 95% CI 1.03-1.05). Compared to low BioAge, participants with high BioAge had a more than two-fold higher risk of dementia (OR 2.38, 95% CI 1.85-3.04). This association persisted across strata of favorable and unfavorable lifestyles. Joint exposure analysis revealed that individuals with both high BioAge and an unfavorable lifestyle faced the highest risk (OR 2.96, 95% CI 2.05-4.27).ConclusionsAccelerated biological aging, quantified by Light BioAge, is a robust independent risk factor for dementia. Favorable lifestyle interventions offer potential strategies. However, findings require caution given the observational design and non-clinical dementia measure.},
}

@article {pmid42300742,
year = {2026},
author = {Balohé, M and Thivet, J and Blanc, F and Krein, L and Jeon, YH and Botzung, A and Sanna, L and Ravier, A and Demuynck, C and Muller, C and Chabran, É},
title = {Language and communication disorders in dementia with Lewy bodies versus Alzheimer's disease: Objective screening and subjective perspectives of patients, their caregivers and clinicians.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458679},
doi = {10.1177/13872877261458679},
pmid = {42300742},
issn = {1875-8908},
abstract = {BackgroundLanguage and communication disorders in dementia with Lewy bodies (DLB) remain understudied and have rarely been explored from the caregiver's perspective. Comparative studies with Alzheimer's disease (AD) are also limited.ObjectiveTo provide an initial overview of language and communication profiles in DLB, compared to AD and healthy elderly controls (HC); to assess subjective complaints reported by patients, caregivers and healthcare professionals; and to explore their relationships with rapid language screening. A further aim was to aid non-specialist professionals in identifying patients needing speech therapy referral.MethodsSeventeen DLB patients, 15 AD patients, and 11 HC completed the Diagnostic Tool for Language Assessment and the alpha version of the Communication Support Needs Assessment Tool for Dementia (CoSNAT-D), alongside a semi-directed interview (SDI). Proxy-ratings were also collected from caregivers and healthcare professionals (HP) for the CoSNAT-D and SDI.ResultsCompared to HC, DLB patients showed significantly poorer performance in repetition, verbal working memory, sentence comprehension and dictation, and reported more communication difficulties. Compared to AD patients, DLB patients had greater impairments in phonemic fluency, and more frequent reports of discomfort, vocal changes, and difficulties with writing and handwriting execution. Perceptions of communicative difficulties and their functional impact varied across patients, caregivers, and HP.ConclusionsThis study has identified distinct language and communication deficits in DLB versus AD and HC. Discrepancies between patient and caregiver perceptions were frequent in both groups and may contribute to increased caregiver burden. Findings highlight the potential value of rapid screening tools to better support patients and their caregivers.},
}

@article {pmid42300750,
year = {2026},
author = {Wang, X and Zhang, W and He, J and Zhang, X and Wang, R and Li, Z},
title = {Adverse events of Alzheimer's disease patients treated with memantine-based therapies: A disproportionality analysis of the FAERS database based on the MY FAERS platform.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458818},
doi = {10.1177/13872877261458818},
pmid = {42300750},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is commonly treated with memantine alone or in combination with cholinesterase inhibitors (ChEIs) or second-generation antipsychotics (SGAs), but the safety of these combinations remains unclear.ObjectiveTo characterize FDA Adverse Event Reporting System (FAERS)-based signals of disproportionate reporting associated with memantine-based combination therapies in patients with AD.MethodsA disproportionality analysis was conducted using data from FAERS from 2014Q1 to 2025Q2 via the MY FAERS platform. Reporting odds ratios (RORs) with 95% confidence intervals (CI) were calculated to identify safety signals. Sensitivity analyses were conducted using ChEIs or SGAs monotherapy as reference groups to assess the robustness.Results2531 patients prescribed memantine were identified, comprising memantine monotherapy (n = 1965), memantine-ChEIs combination (n = 482), and memantine-SGAs combination (n = 84). Compared to memantine monotherapy, the memantine- ChEIs combination showed disproportionate reporting signals for skin (ROR, 3.46; 95% CI, 2.05-5.85), gastrointestinal (ROR, 2.53; 95% CI, 1.92-3.33), musculoskeletal (ROR, 2.13; 95% CI, 1.29-3.50), psychiatric (ROR, 1.60; 95% CI, 1.27-2.00), general (ROR, 1.53; 95% CI, 1.18-1.97), and nervous system disorders (ROR, 1.48; 95% CI, 1.19-1.84). The memantine-SGAs combination was strongly associated with the signals of general (ROR, 3.97; 95% CI, 1.74-9.05), psychiatric (ROR, 2.14; 95% CI, 1.32-3.49), nervous system disorders (ROR, 2.03; 95% CI, 1.20-3.43), and hip fracture (ROR, 15.84; 95% CI, 3.72-67.41). Sensitivity analyses confirmed robustness across subgroups.ConclusionsMemantine-based combination therapies were associated with distinct safety signals of disproportionate reporting compared with monotherapies. These findings should be interpreted as pharmacovigilance signals that warrant cautious interpretation and further validation in well-designed observational or prospective studies.},
}

@article {pmid42300919,
year = {2026},
author = {Peesapati, S and Chakraborty, S},
title = {Modeling the organizational heterogeneity of cholesterol-enriched microdomains in the neuronal membranes of gray and white matter of Alzheimer's brain: a computational lipidomics study.},
journal = {Soft matter},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6sm00153j},
pmid = {42300919},
issn = {1744-6848},
abstract = {Alzheimer's disease (AD) is a leading cause of death among the elderly, with no existing treatment. The development of therapies is further hindered by a limited understanding of the molecular pathogenesis and the absence of reliable early-detection biomarkers. Neuroimaging and lipidomic studies reveal structural and biochemical alterations in both gray and white matter in AD patients, including disruptions in membrane organization and neuronal signaling pathways. In the present work, we employed lipidomics-guided modeling of membranes in gray and white matter regions under healthy and diseased (AD) conditions, and used all-atom molecular dynamics (MD) simulations to examine how AD-associated alterations in lipid composition influence the structure, spatial organization, and micro-heterogeneity of neuronal plasma membranes. The data suggest that Alzheimer's disease-associated lipid alterations in gray matter (GM) and white matter (WM) impact membrane thickness and microdomain distribution, highlighting the critical role of lipid composition in maintaining neuronal membrane homeostasis and function. Higher-order cholesterol-ceramide-sphingomyelin-enriched domains are more abundant in the neuronal membranes of the GM region under diseased conditions. Under AD-mimicking conditions, lipidomic analyses demonstrate that neuronal membranes in GM experience more substantial compositional and structural remodeling than those in WM. Our results show significant changes in membrane microdomain distribution across the lipid bilayers, and, interestingly, these changes are more pronounced in the gray matter than in the white matter. This study establishes a framework for modeling the tissue-specific lipidomics data to understand how disease-driven compositional changes affect the structure, organization, and dynamics of biological membranes.},
}

@article {pmid42300978,
year = {2026},
author = {Malaiya, A and Kenwat, R and Mamgain, A and Paliwal, SR and Sulakhiya, K and Maiti, S and Paliwal, R},
title = {Next-generation intranasal delivery nano-platforms for targeted brain therapy of Alzheimer's disease.},
journal = {Nanomedicine (London, England)},
volume = {21},
number = {12},
pages = {1775-1795},
doi = {10.1080/17435889.2026.2685131},
pmid = {42300978},
issn = {1748-6963},
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Administration, Intranasal ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Brain/drug effects/metabolism ; *Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Drug Carriers/chemistry ; *Nanoparticle Drug Delivery System/chemistry ; Biological Availability ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a growing global health burden. Effective drug delivery to the brain is largely constrained by the selective nature of the blood-brain barrier (BBB), which limits therapeutic efficacy of conventional oral medications. Intranasal administration has emerged as a noninvasive and promising route for direct nose-to-brain transport, circumventing BBB restrictions.

AREA COVERED: This review explores the potential of intranasal drug delivery as an alternative approach for targeted brain therapy in Alzheimer's disease. It comprehensively discusses the mechanisms of nasal absorption, physiological and formulation-related barriers, and the role of advanced nanocarrier platforms in overcoming these limitations. Emphasis is placed on recent innovations involving polymeric, lipid-based, and vesicular carriers, along with the incorporation of mucoadhesive and permeation-enhancing agents.

EXPERT OPINION: The present focus is enhancing bioavailability, prolonging drug residence time, and minimizing systemic toxicity. Surface modifications of nanocarriers further facilitates mucosal adhesion and enables effective nose-to-brain transport of encapsulated therapeutic agents. However, clinical translation remains challenging due to interindividual variability in nasal physiology, scalability constraints, and regulatory complexities. Future progress will depend on the rational design of multifunctional nanocarriers, integration of mucoadhesive and stimuli-responsive components, and the use of precision-based formulation strategies.},
}

Humans
*Alzheimer Disease/drug therapy/pathology
Administration, Intranasal
Blood-Brain Barrier/metabolism/drug effects
Animals
*Brain/drug effects/metabolism
*Nanoparticles/chemistry
*Drug Delivery Systems/methods
Drug Carriers/chemistry
*Nanoparticle Drug Delivery System/chemistry
Biological Availability

@article {pmid42301182,
year = {2026},
author = {Kim, A and Tolentino, DA and Choi, S and Song, Y},
title = {Enhancing dementia caregiver self-efficacy through culturally tailored, video-based education for Hispanic caregivers: A quality-improvement project.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {},
number = {},
pages = {},
pmid = {42301182},
issn = {2327-6924},
abstract = {BACKGROUND: Family caregivers of persons living with Alzheimer's disease and related dementias experience significant psychological and physical burden. Hispanic caregivers face additional challenges, including language barriers and limited access to culturally appropriate educational resources.

LOCAL PROBLEM: In a primary care clinic in Los Angeles, Hispanic dementia caregivers had limited access to culturally tailored education, contributing to low caregiver self-efficacy and ongoing caregiver burden.

METHODS: This quality-improvement project used a pre-post design over 8 weeks. Hispanic caregivers of persons living with dementia were recruited during routine clinic visits. Caregiver self-efficacy and burden were measured using the Revised Scale for Caregiving Self-Efficacy and the Zarit Burden Interview at baseline and 4 weeks post-intervention.

INTERVENTIONS: Participants attended a 1-hour, nurse practitioner-led session featuring culturally adapted, Spanish-language dementia education videos. Caregivers also received printed materials with QR codes for continued access to the videos at home.

RESULTS: Eight caregivers completed pre- and post-intervention assessments. Self-efficacy scores improved following the intervention, whereas caregiver burden scores showed minimal change at 4-week follow-up.

CONCLUSION: A culturally tailored, video-based education program was feasible and improved caregiver self-efficacy among Hispanic caregivers. Integrating culturally responsive education into primary care may enhance caregiver support and dementia care in underserved populations.},
}

@article {pmid42301394,
year = {2026},
author = {Wyman, MF and Lennon, DB and Montoure, J and McLester-Davis, LWY and Hammock, C and Lambrou, N and Lawrence, S and Miller, DA and Petri, F and Zuelsdorff, M and Gleason, CE},
title = {Awareness of Family Caregiver Resources and Alignment with Traditional Culture in a Midwest Tribal Nation in the United States.},
journal = {Journal of community health},
volume = {},
number = {},
pages = {},
pmid = {42301394},
issn = {1573-3610},
support = {IK2 HX003080/HX/HSRD VA/United States ; UL1TR002373//Institute for Clinical and Translational Research, University of Wisconsin, Madison/ ; P30 AG062715/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; R01 AG062307/AG/NIA NIH HHS/United States ; R01 AG074231/AG/NIA NIH HHS/United States ; },
abstract = {Family caregivers helping adults with functional needs, including older adults, can benefit from training, support groups, and other services. However, these resources are often underutilized. Caregiving is particularly common in Indigenous communities, but little is known about how Indigenous caregivers consider utilization of supportive resources. To guide efforts to increase utilization, this study sought to describe awareness and attitudes regarding caregiver services within a Midwest Tribal Nation in the United States. Working within a tribally-led, community-based participatory research framework, an online survey was offered to all Tribal members and affiliates aged ≥ 18 years, covering caregiver status, resource awareness and source of information, and beliefs about service use alignment with traditional cultural values. We examined associations between selected factors and awareness. Participants (N = 481) had a mean age of 52.78 (16.6) years, were primarily female (75.5%), and resided both on and off reservation. Almost half (n = 203; 43%) were current caregivers, of whom the majority helped an older adult (n = 173; 83.6%) and/or someone with memory loss (n = 127; 61.4%). Current caregivers, older adults, and reservation residents reported the highest levels of awareness. A significant proportion of respondents (17%) indicated no awareness of any of the 7 resources queried. Primary sources of information for caregivers included independent research and social networks; for non-caregivers, Tribal communications were cited most frequently. Perceptions of alignment of resource use with traditional culture varied by service. Findings add to our understanding of Indigenous family caregiving and can inform public outreach and interventions to increase use of caregiver services.},
}

@article {pmid42301495,
year = {2026},
author = {Maiti, P and Hall, TC and Paladugu, L and Kolli, N and Learman, C and Rossignol, J and Dunbar, GL},
title = {Correction: A comparative study of dietary curcumin, nanocurcumin, and other classical amyloid‑binding dyes for labeling and imaging of amyloid plaques in brain tissue of 5×-familial Alzheimer's disease mice.},
journal = {Histochemistry and cell biology},
volume = {164},
number = {1},
pages = {},
doi = {10.1007/s00418-026-02497-3},
pmid = {42301495},
issn = {1432-119X},
}

@article {pmid42301522,
year = {2026},
author = {Welikovitch, LA and Oakley, DH and Bennett, RE and Serrano-Pozo, A and Zhu, H and Ruiz-Uribe, NE and Zwang, TJ and Chibnik, LB and Gomez-Isla, T and Frosch, MP and Marks, DS and Salloway, S and Bernick, C and Greeley, D and Latimer, CS and Nolan, A and Hutchison, RM and Rubel, CE and Bussiere, T and Plowey, ED and Keene, CD and Hyman, BT},
title = {Neuropathological study of the effects of aducanumab anti-Aβ immunotherapy on patients with Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42301522},
issn = {1432-0533},
support = {24AARF-1192364/ALZ/Alzheimer's Association/United States ; R01AG071567/NH/NIH HHS/United States ; UW ADRC P30 AG066509/NH/NIH HHS/United States ; P30AG062421//Massachusetts Alzheimer Disease Research Center/ ; W81XWH-21-S-TBIPH2//US Department of Defense/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/therapy/immunology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; *Amyloid beta-Peptides/metabolism/immunology ; Male ; Aged ; *Brain/pathology/drug effects/metabolism ; Aged, 80 and over ; Neurofibrillary Tangles/pathology ; *Immunotherapy/methods ; Plaque, Amyloid/pathology ; tau Proteins/metabolism ; },
abstract = {Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer's disease (AD). We examined postmortem brain tissue of individuals who participated in aducanumab clinical trials and investigated the drug's effects on Aβ pathology and other AD phenotypes. The medial temporal lobe of six aducanumab clinical trial participants-who had extensive exposure to aducanumab and happened to die between 7 weeks and 5 years after their last antibody infusion-was compared with that of nine untreated AD patients matched for age, APOE genotype, and Braak neurofibrillary tangle stage, to determine how aducanumab impacts AD pathobiology. Patients treated with aducanumab displayed a robust reduction in Aβ burden. As observed in previous studies, Aβ was associated with non-arterial microvessels in aducanumab-treated patients, suggesting a redistribution of Aβ within the neuropil. Neuritic phospho-tau decreased in parallel with fewer Aβ plaques, but the density of PHF-1[+] and AT8[+] neurofibrillary tangles remained unchanged relative to the average untreated AD donor. Measures of microglial and astroglial reactivity were also comparable to those in untreated AD controls. These findings confirm aducanumab's potent ability to target and remove brain Aβ. On average, Aβ plaques increased in proportion to the length of time after the last dose, consistent with the idea that plaques gradually redeposit post-treatment. The selective reduction of neuritic, but not neurofibrillary tangle phospho-tau implies that Aβ-targeted antibodies such as aducanumab alleviate plaque-associated dystrophy but may not address established tangles. This study describes the long-term outcomes of anti-Aβ immunotherapy in AD.},
}

Humans
*Alzheimer Disease/pathology/drug therapy/therapy/immunology
*Antibodies, Monoclonal, Humanized/therapeutic use
Female
*Amyloid beta-Peptides/metabolism/immunology
Male
Aged
*Brain/pathology/drug effects/metabolism
Aged, 80 and over
Neurofibrillary Tangles/pathology
*Immunotherapy/methods
Plaque, Amyloid/pathology
tau Proteins/metabolism

@article {pmid42301613,
year = {2026},
author = {Rathbun, AM and Chen, C and Tian, Q and Tanaka, T and Ferrucci, L and Shardell, MD},
title = {Characterization of the plasma proteomic profile of dual trajectories in cognitive status and physical performance.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42301613},
issn = {2509-2723},
support = {K01 AG064041/AG/NIA NIH HHS/United States ; R01 AG079854/AG/NIA NIH HHS/United States ; R01 AG048069/AG/NIA NIH HHS/United States ; R01 AG069915/AG/NIA NIH HHS/United States ; RF1 NS128360/NS/NINDS NIH HHS/United States ; },
abstract = {Dual declines in cognitive status and physical performance increase dementia risk but shared biological mechanisms between processes remain unclear. We investigated plasma proteomic signatures underlying dual decline in older adults from the Invecchiare in Chianti cohort (n = 774; age ≥ 60). Group-based trajectory models with up to 15 years of data on cognitive status (global Mini-Mental State Examination scores) and 4-m gait speed identified three trajectories that included no decline, physical decline, or dual decline groups. At baseline, 1301 plasma proteins were measured with aptamer-based proteomics (SomaScan). Adjusted multinomial regressions identified proteins associated with group membership. Additional analyses included Reactome functional enrichment and partial least squares discriminant analysis (PLS-DA). Collectively, eight proteins were associated with differences across trajectory groups. Higher PI3, GDF15, TFF3, CCL15, TNNT2, and AGRP were associated with greater odds of dual decline, whereas higher CKM and GHR were linked to lower odds. PLS-DA confirmed and extended these findings. The top discriminators by variable-importance were PTN, TFF3, GDF15, IGFBP-2, and CHRDL1. Hierarchical clustering found PTN, IGFBP-2, PI3, GDF15, and TFF3 formed a coherent module. Functional enrichment highlighted overrepresentation of regulation of IGF transport and uptake by IGF binding proteins across decline trajectories and exploratory enrichment of post-translational protein phosphorylation and diseases of homeostasis. Older adults with dual declines showed a proteomic profile marked by cellular stress, inflammation, barrier injury, reduced IGF-1 bioavailability, and cardiovascular-metabolic strain. These findings support system-level hypotheses of dual decline and warrant replication, longitudinal proteomics, and evaluation of module-level markers.},
}

@article {pmid42301786,
year = {2026},
author = {Lucena-Agell, D and Fernández, Ó and París-Ogáyar, R and Estévez-Gallego, J and Ondrúšková, D and Álvarez-Bernad, B and Bonato, F and Larraga, J and de Elguea, DO and Cano, GJ and Scheers, M and Imai, H and Yagi, T and Iwamoto, H and Carlos Martínez-Guil, J and Singh, AJ and Keyzers, RA and Vanderwal, CD and Altmann, KH and Van der Eycken, J and Palomo, V and Fang, WS and Gago, F and Lánský, Z and Braun, M and Oliva, MÁ and Kamimura, S and Fernando Díaz, J},
title = {An atlas of microtubule lattice parameters regulated through ligand binding to the microtubule-stabilizing sites.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {25},
pages = {e2532791123},
doi = {10.1073/pnas.2532791123},
pmid = {42301786},
issn = {1091-6490},
support = {PID2022-136765OB I00//Ministerio de Ciencia, Innovación y Universidades (MCIU)/ ; PID2021-123399OB I00//Ministerio de Ciencia, Innovación y Universidades (MCIU)/ ; short term fellowship 11234//European Molecular Biology Organization (EMBO)/ ; MOSBRI 2024 296//MOSBRI/ ; },
mesh = {*Microtubules/metabolism/chemistry ; Ligands ; Animals ; Binding Sites ; Microtubule-Associated Proteins/metabolism/chemistry ; Tubulin/metabolism/chemistry ; Macrolides/chemistry/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology/chemistry ; Protein Binding ; Guanosine Triphosphate/metabolism ; },
abstract = {Microtubules are dynamic cytoskeletal polymers whose lattice architecture regulates force generation, nucleotide hydrolysis, and recognition by motor proteins and microtubule-associated proteins (MAPs). Microtubule-stabilizing agents (MSAs), including taxanes and laulimalide/peloruside-site ligands, suppress depolymerization by binding to defined lattice sites, yet stabilization is not structurally neutral. How ligand chemistry reshapes lattice organization and function remains unresolved. Here, we address three mechanistic questions. First, do distinct ligand classes induce defined lattice states? Using X-ray fiber diffraction, we show that MSAs selectively stabilize two preferred longitudinal conformations, a compact state (~4.06 nm monomer rise) and an expanded state (~4.17 nm), while modulating lateral organization reflected in shifts in mean MT radius. These axial spacings cluster around discrete values across chemotypes, indicating stabilization of preexisting conformational minima rather than continuous distortion. Second, are these states interconvertible upon changes in ligand occupancy? Time-resolved diffraction reveals that longitudinal transitions occur within seconds of ligand addition even at substoichiometric occupancy, whereas, lateral equilibration proceeds slower, consistent with redistribution within heterogeneous protofilament organizations. Third, do such structural states alter nucleotide hydrolysis and motor/MAP behavior? Expanded lattices are associated with reduced apparent GTP hydrolysis rates under steady-state assembly conditions and altered kinesin motility, whereas compact lattices preferentially promote tau binding and distinct motor interaction profiles. Together, these findings establish longitudinal lattice conformation as a regulatory parameter and position MSAs as chemical tools that bias a dynamic structural landscape with predictable catalytic and transport consequences.},
}

*Microtubules/metabolism/chemistry
Ligands
Animals
Binding Sites
Microtubule-Associated Proteins/metabolism/chemistry
Tubulin/metabolism/chemistry
Macrolides/chemistry/pharmacology
Bridged Bicyclo Compounds, Heterocyclic/pharmacology/chemistry
Protein Binding
Guanosine Triphosphate/metabolism

@article {pmid42301817,
year = {2026},
author = {Jing, R and Mahapatra, S and Bimali, A and Herlory, M and Walczak, MA},
title = {Protocol for expressing and purifying recombinant full-length Tau by combining affinity chromatography with preparative HPLC.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104617},
doi = {10.1016/j.xpro.2026.104617},
pmid = {42301817},
issn = {2666-1667},
abstract = {Deposits of microtubule-associated protein full-length Tau (Tau2N4R) are implicated as a hallmark of Alzheimer's disease. Its biochemical and structural characterization is key to understanding disease progression, aggregate toxicity, and designing therapeutics. We present a protocol for expressing and purifying Tau2N4R by combining affinity chromatography with preparative high-performance liquid chromatography (HPLC). We describe steps for linking an N-terminal hexahistidine tag and a cleavable SUMO tag to Tau2N4R. This purification ensures an ultrapure Tau2N4R that gives rise to heparin-induced and cofactor-free in vitro fibrillation.},
}

@article {pmid42301821,
year = {2026},
author = {Boyanova, S and Katsouri, L and Krupic, J and Hair, K and Wang, SH and Wiseman, FK},
title = {Considerations for the selection and phenotyping of mouse models for the study of Alzheimer's disease.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104633},
doi = {10.1016/j.xpro.2026.104633},
pmid = {42301821},
issn = {2666-1667},
abstract = {All models are incomplete and must balance the need for experimental efficiency with the complexity of the natural world. To select and use models for the study of human disease, it is critical to understand what is of fundamental scientific importance and which limitations are thus of greatest concern. Here, we highlight key considerations for the design of research studies using mouse models of aspects of Alzheimer's disease for both mechanistic and proof-of-principle intervention studies. This primer considers mouse model choice, including the strengths and limitations of genetically altered, pathological aggregates injection, and human iPSC-chimera systems. We also review key principles of experimental design, husbandry, and technical considerations for the phenotyping of clinically disease-relevant features, with a focus on behavior and cognition.},
}

@article {pmid42301867,
year = {2026},
author = {Hilal, O and Lin, KW},
title = {Lumipulse Blood Biomarker Test for Diagnosis of Alzheimer Disease.},
journal = {American family physician},
volume = {113},
number = {6},
pages = {597-598},
pmid = {42301867},
issn = {1532-0650},
}

@article {pmid42302007,
year = {2026},
author = {Zhang, Y and Gong, Q and Yu, J and Zhang, L and Hu, Y},
title = {Analysis signals of disproportionate reporting associated with donanemab: A retrospective pharmacovigilance study using the FAERS database.},
journal = {Science progress},
volume = {109},
number = {2},
pages = {368504261461675},
doi = {10.1177/00368504261461675},
pmid = {42302007},
issn = {2047-7163},
mesh = {*Pharmacovigilance ; *Adverse Drug Reaction Reporting Systems/statistics & numerical data ; Retrospective Studies ; Databases, Factual ; Humans ; United States ; United States Food and Drug Administration ; Bayes Theorem ; Antibodies, Monoclonal, Humanized ; },
abstract = {ObjectiveThis study aims to identify signals of disproportionate reporting (SDR) associated with donanemab by analyzing data from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database.MethodsA retrospective analysis was conducted on reports related to donanemab in the FAERS database from the third quarter of 2024 to the second quarter of 2025. Four signal detection methods were employed: reporting odds ratio (ROR), proportional reporting ratio (PRR), Multi-item gamma poisson shrinkage (MGPS), and Bayesian confidence propagation neural network (BCPNN). Additionally, descriptive analysis was performed on the time to onset of reports associated with donanemab.ResultsA total of 646 reports identified donanemab as the primary suspect drug. We identified common SDRs listed on the drug label, including amyloid related imaging abnormality-oedema/effusion, amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits, headache, and infusion-related reactions. In addition, some SDRs not previously listed on the drug label, such as back pain, feeling hot, and influenza like illness, were also detected. The median time to onset for donanemab-related adverse events was 31.5 days (interquartile range: 25-58 days).ConclusionThis study provides a comprehensive analysis of SDRs associated with donanemab. These results are merely statistical indicators and require further validation through clinical trials.},
}

*Pharmacovigilance
*Adverse Drug Reaction Reporting Systems/statistics & numerical data
Retrospective Studies
Databases, Factual
Humans
United States
United States Food and Drug Administration
Bayes Theorem
Antibodies, Monoclonal, Humanized

@article {pmid40471467,
year = {2025},
author = {Angulo, MC},
title = {The Power of Neuroglia in Driving Brain Function.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {184},
pmid = {40471467},
issn = {1573-6903},
support = {EQU202103012626//Fondation pour la Recherche Médicale/ ; ANR-20-CE16-0001-01//Agence Nationale de la Recherche/ ; 00147199/WB-2023-50772//Fondation de France/ ; R24183KD//Fédération pour la Recherche sur le Cerveau/ ; R24190KK//France Sclérose en Plaques/ ; },
abstract = {Neuroglial cells are essential regulators of central nervous system (CNS) function in development, brain function, and disease. This mini-review summarizes recent advances that reveal how astrocytes, oligodendrocyte lineage cells, and microglia contribute to key brain processes. Astrocytes modulate synaptic plasticity and memory through gliotransmitter release, calcium signaling, and circuit-specific interactions, with dysfunctions implicated in disorders such as Alzheimer’s disease and depression. Oligodendrocytes and their precursors influence cognition through myelination, and disruptions in myelin plasticity and oligodendrogenesis can lead to significant cognitive deficits. Microglia, beyond their classical immune roles, are emerging as central sculptors of neural circuits, regulating synaptic pruning, neuronal survival, and extracellular matrix remodeling. Their dysfunction is increasingly associated with both neurodevelopmental and neurodegenerative disorders. Collectively, these findings highlight the powerful and multifaceted roles of neuroglial cells in shaping brain function and pathology. As tools to study and manipulate neuroglial activity continue to evolve, targeting neuroglial mechanisms offers exciting new therapeutic opportunities for a wide range of CNS disorders.},
}

@article {pmid40569486,
year = {2025},
author = {Singh, A and Tiwari, V and Roy, S},
title = {Multifaceted role of oxidative stress in neurological disorders.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {640},
pmid = {40569486},
issn = {1573-4978},
abstract = {The intricate relationship between oxidative stress and neurological disorders stems from multiple factors inherent to central nervous system function. Neural tissue’s high oxygen consumption, elevated iron content, and hydrogen peroxide generation create conditions favorable for oxidative imbalance. The susceptibility of neuronal membranes to oxidative damage is particularly noteworthy due to their high polyunsaturated fatty acid composition. This vulnerability, coupled with disrupted redox homeostasis marked by excessive reactive oxygen species (ROS) and compromised antioxidant mechanisms, contributes to the pathogenesis of major neurodegenerative conditions, including Parkinson’s, Alzheimer’s, and Huntington’s diseases. The interplay between mitochondrial dysfunction, protein aggregation, and neuroinflammation further exacerbates oxidative damage, creating a self-perpetuating cycle of cellular stress. These processes trigger various cell death pathways, including apoptosis and necrosis, ultimately leading to progressive neuronal loss. Understanding the complex network of cellular and molecular mechanisms affected by oxidative stress is crucial for developing targeted therapeutic strategies. Current research focuses on both endogenous antioxidant systems and novel neuroprotective compounds that could potentially modulate these pathways. Future investigations into these biochemical pathways are essential for elucidating disease mechanisms, identifying biomarkers for early detection, and developing more effective therapeutic interventions in the field of neurodegeneration.},
}

@article {pmid40571761,
year = {2025},
author = {Richards, SEV and Yang, M and Deik, AA and Ricq, EL},
title = {APOE Genotype Impacts Polyunsaturated Neutral Lipid Storage and Ferroptosis Vulnerability in Astrocytes.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {211},
pmid = {40571761},
issn = {1573-6903},
support = {R21 AG068769-01/AG/NIA NIH HHS/United States ; },
abstract = {Astrocytes play a critical role in regulating the metabolism of cholesterol and other lipids in the brain. Increasing evidence suggests that dysfunctional lipid metabolism and lipid peroxide-mediated cell death, or ferroptosis, are involved in the pathophysiology of late-onset Alzheimer’s disease. The Alzheimer’s disease risk allele of APOE, APOE4, is expressed in astrocytes and is associated with increased accumulation of cholesterol as well as highly polyunsaturated and peroxidation-prone neutral lipids in lipid droplets. However, a direct connection between APOE4 genotype-dependent lipid dysregulation and sensitivity to ferroptotic cell death has not yet been explored. Here, we show that APOE4 and APOE knockout astrocytes accumulate cholesterol and polyunsaturated lipid-rich droplets in lysosomes and have increased vulnerability to ferroptotic cell death. APOE2 astrocytes are also enriched in polyunsaturated lipids but are less vulnerable to lipid peroxidation. Pharmacological manipulation of neutral lipid content modestly impacted ferroptosis sensitivity. In contrast, modulation of lysosomal lipid content via blockade of autophagy or promotion of cholesterol efflux with methyl-β-cyclodextrin strongly protects APOE4 cells from lipid-peroxide mediated cell death. In humanized APOE4 mice, reduction of brain lipid peroxidation selectively impacted cholesterol ester storage. Taken together, these findings suggest that correction of APOE4-mediated lipid trafficking defects may reduce risk for ferroptotic in astrocytes.},
}

@article {pmid40928715,
year = {2025},
author = {Mallahzadeh, A and Owjfard, M and Fereydoonnezhad, T and Karimi, F},
title = {Therapeutic spectrum of Piperine in ischemic stroke: a literature review.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {885},
pmid = {40928715},
issn = {1573-4978},
abstract = {Ischemic stroke rate is increasing globally and causing a burden on society. The FDA- approved treatments (tissue plasminogen activator and mechanical thrombectomy) come with a series of limitations, such as a narrow therapeutic time window and failure to restore the dying neurons. The area around the ischemic core, known as the penumbra, can be saved and the number of dying neurons could be reduced. This goal can be achieved through reducing inflammation, oxidative stress, and cell apoptosis, All which result as secondary damage following cerebral ischemia. Therefore, identifying new pharmacological agents that possess neuroprotection are of significant interest. Piperine is an alkaloid from the Piperaceae family and has shown benefits for various neurological diseases including Alzheimer’s, Parkinson and epilepsy. Piperine has shown to inhibit inflammation, apoptosis, and oxidative stress, all of which contribute to worse stroke outcomes. Piperine’s impact on blood pressure is also noteworthy since controlling blood pressure, both before and after stroke management, is necessary. Few pre-clinical studies have demonstrated that piperine holds the potential to alleviate stroke severity. While the precise mechanism remains unclear, studies indicate that these beneficial effects are due to its immunomodulatory and neuroprotective mechanisms. Piperine has also been shown to enhance the bioavailability of various pharmacological agents and it could be used in combination with other neuroprotective agents to yield optimum results in stroke management. Despite the promising evidence, utilizing piperine in the stroke setting has not yet been established and future studies are required to shed light on its effects on stroke. This review explores the mechanisms by which piperine may impact stroke, highlighting its underlying mechanisms as supported by existing literature and laboratory findings.},
}

@article {pmid41160236,
year = {2025},
author = {Srivastava, R and Gupta, MK},
title = {Gut bacteria-derived metabolites and their implications in mental health and neurological diseases.},
journal = {World journal of microbiology & biotechnology},
volume = {41},
number = {11},
pages = {423},
pmid = {41160236},
issn = {1573-0972},
abstract = {Gut bacteria generate various metabolites that can significantly affect brain function and behavior through the microbiota–gut–brain axis. This article highlights the role of short-chain fatty acids, tryptophan derivatives, bile acids, and neurotransmitter-like metabolites in regulating neuroinflammation, synaptic plasticity, and neuronal signaling. The article also explores the potential mechanistic pathways through which these chemical signals act on the central nervous system, such as vagus nerve signaling, immune modulation, and blood–brain barrier integrity. The emerging studies suggested that the alterations to metabolites are linked to mental health disorders, including depression, anxiety, and autism spectrum disorders, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although preclinical and clinical studies provide early promise and insight into the relevance of metabolites in the brain, substantial gaps remain concerning the effects induced by metabolites at the mechanistic level, how the effect is dependent on the context, and how it varies between individuals. The article also highlights and focuses on the translational potential of clinical research, targeting the utilization of microbial metabolites for diagnostics and treatments, including methodological limitations on biomarkers, interventional reliability, and personalized interventions. The review illustrates both the potential and the shortcomings of metabolite-centric research in neuropsychiatric and neurological disorders. Future investigations should prioritize integrative approaches that combine metabolomics, neuroimaging, and clinical outcomes to infer causality and clinical relevance. Overall, metabolites derived from gut bacteria represent an attractive but underappreciated territory for advancing precision medicine for mental health and neurology.},
}

@article {pmid41212305,
year = {2026},
author = {Li, Z and Jia, L and Huai, S},
title = {Bidirectional causal association between cathepsins and neuropsychiatric disorders: univariate and multivariate Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1775-1787},
pmid = {41212305},
issn = {1433-8491},
abstract = {BACKGROUND: Neuropsychiatric disorders are among the most common diseases worldwide and are characterized by complex pathogenic mechanisms. Cathepsins (CTS) are crucially involved in the pathogenesis and treatment of numerous diseases. Increasing evidence suggests a relationship between cathepsins and neuropsychiatric disorders. However, the causal associations remain unclear. METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) analysis, applying univariable (UVMR) and multivariable MR (MVMR) to evaluate the causal association between nine cathepsins and five neuropsychiatric disorders. Data for this study were derived from genome-wide association studies (GWAS). The MR analysis primarily used five methods: Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger regression, Simple mode, and Weighted mode. Additionally, sensitivity tests were employed to assess the robustness of the MR results. RESULTS: MR analyses indicated that CTSH is associated with an increased risk of Alzheimer’s disease (AD) (UVMR: OR, 1.041; 95% CI, 1.013–1.069; p = 0.004; MVMR: OR, 1.040; 95% CI, 1.014–1.066; p = 0.003; replication UVMR: OR, 1.046; 95% CI, 1.014–1.082; p = 0.011). Findings that were significant in only one MR approach, such as the putative causal effects of CTSF on AD and bipolar disorder (BIP), of CTSL2 on major depressive disorder (MDD), and of CTSH and CTSE on Parkinson’s disease (PD) should be interpreted with caution. CONCLUSION: CTSH can be considered a plasma biomarker for AD, offering new insights and potential directions for the prevention and treatment of AD. Additionally, during the treatment of BIP and PD, attention should be paid to CTSF and CTSE expression levels to maintain physiological homeostasis.},
}

@article {pmid41372737,
year = {2025},
author = {Shah, A and Doshi, G},
title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41372737},
issn = {2240-2993},
abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.},
}

@article {pmid41417171,
year = {2026},
author = {Garnier-Villarreal, M and Johnson, DK},
title = {Bayesian multivariate longitudinal piecewise regression: detecting early onset of cognitive decline.},
journal = {Journal of behavioral medicine},
volume = {49},
number = {2},
pages = {225-238},
pmid = {41417171},
issn = {1573-3521},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG03991/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG072972/AA/NIAAA NIH HHS/United States ; P01 AG03991/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG072972/AA/NIAAA NIH HHS/United States ; },
abstract = {The current paper defines and tests a hierarchical multivariate change point model (HMLCP) to detect a random change point in longitudinal data (subject-specific). Given the large number of random effects that are estimated, we implemented the HMLCP using Bayesian methods. First, we present model parameterization and then applied it in a sample of older adults, to identify the onset of cognitive decline with neurocognitive data collected at the Knight Alzheimer Disease Center. These data presented an ideal case study to test a multivariate random change-point model with a diagnosed sample, to see if the model can detect the disease progression of AD. HMLCP model was sensitive to detect the presence of disease several years before clinical diagnosis. Further, the HMLCP allowed us to describe the sample disease progression, and predict change points at the level of the individual. We demonstrate HMLCP’s flexibility by comparing results from the whole sample with individual subjects and conclude that the HMLCP is a powerful model for estimating multivariate-multilevel unknown change point trajectories.},
}

@article {pmid41563458,
year = {2026},
author = {Jellinger, KA},
title = {The enigma of vascular dementia: current state and emerging perspectives.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41563458},
issn = {1435-1463},
abstract = {Vascular dementia (VaD) is a neurocognitive disorder attributed to different types of cerebrovascular disease (CVD) and characterized by complex and multifold pathophysiological mechanisms. The most common forms in the elderly brain are multi-infarct, subcortical and strategic infarct dementias caused by atherosclerosis, small vessel disease, and cerebral amyloid angiopathy (CAA), hereditary forms being rare. VaD prevalence, accounting for 5% to 20% of all dementias, in comparison to Alzheimer disease and mixed dementias declines due to recent improvement of cardiovascular risk factors. Its diagnosis relies on thorough clinical evaluations based on current classification criteria, neuroimaging, and fluid biomarkers. Epidemiological research has delineated multiple risk factors that contribute to the etiology of VaD. Its pathogenesis is complex and multifactorial, brain hypoperfusion and hypoxia being due to cerebrovascular pathologies. The lesions affect neuronal networks involved in many cognitive domains, e.g., thalamo-cortical, striato-subfrontal, and limbic systems. The sequence of events leading to VaD is defined by its clinical subtypes that are influenced by genetic disposition, aging, unhealthy lifestyle, and other factors, many of which are modifiable, highlighting the need for preventive measures and early intervention strategies. Newly developed biomarkers may help differentiate VaD from other dementias and unravel its pathomechanisms. Their integration into clinical practice and pathological assessment presents a prominent strategy for early assessment of VaD. Current treatments mainly target symptoms rather than slowing development and progression of VaD. This review will summarize recent findings about classification, epidemiology, risk factors, pathophysiology, biomarkers, and predictive and therapeutic strategies of VaD, in order to promote better clinical outcomes and enhanced quality of life for affected individuals.},
}

@article {pmid41575555,
year = {2026},
author = {Yu, S and Ye, Z and Zhao, W and Yu, X and Qiu, Y and Lin, K and Lu, T and Ge, L and Sun, J and Hua, R},
title = {Genetic evidence on chemical communication between gut microbiota and neurological and psychiatric disorders: a Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1759-1773},
pmid = {41575555},
issn = {1433-8491},
support = {2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; YN2018ZD04and2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; },
abstract = {BACKGROUND: Accumulating evidence from clinical trials and preclinical studies revealed the importance of the microbiota-gut-brain axis (MGBA) in neurological and psychiatric disorders (NPDs). MGBA remains a blueprint for extended explorations. METHODS: We examine the bidirectional association between 5 NPDs (late-onset Alzheimer’s disease (AD), migraine, autism spectrum disorder (ASD), all anxiety disorder, depression) and gut microbiota (GM) via microbial-derived metabolites, neurotransmitter, and precursors including total branched-chain amino acids (BCAA), isoleucine, leucine, valine, acetate, tryptophan, kynurenine, glutamate, tyrosine, serotonin using two step Mendelian randomization. Five methods were performed, including inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. The robustness of results was supported by Cochran’s Q test, the MR-Egger regression, the MR pleiotropy residual sum and outlier, and the leave-one-out method. RESULTS: After false discovery rate correction, we found elevated isoleucine in plasma as a risk factor for AD and elevated tyrosine in plasma as a risk factor for anxiety. Conversely, AD has genetically effect on a lower level of total BCAA, isoleucine, leucine, valine, glutamate, and tyrosine in plasma. We also found that Clostridia, Clostridiales, Sutterella, and Ruminococcus torques group were positively correlated with isoleucine. Elevated Sutterella abundance was found strongly positively correlated with ASD. Desulfovibrionales and Desulfovibrionaceae were found strongly positively correlated with AD. Pathways of Clostridia/Clostridiales/Ruminococcus torques group/Sutterella- isoleucine- AD were established with mediating percentages ranging from − 54.265% to 132.908%. CONCLUSION: Our study elucidates how chemical signalling bridges communication between GM and NPDs, paving avenues for microbiota-based treatment.},
}

@article {pmid41603981,
year = {2026},
author = {Raswanthiya, SP and Fernandes, OP and Mathew, MP and Balgote, PJ and Sivaraman, J},
title = {Decoding BDNF in neurodevelopmental, neurodegenerative, and neurological disorders: mechanisms and therapeutic perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {330},
pmid = {41603981},
issn = {1573-4978},
abstract = {Brain-Derived Neurotrophic Factor (BDNF) is an essential neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis, critical for normal brain function as well as the pathology of neurological and psychiatric disorders. It primarily functions by activating TrkB receptors, which subsequently modulate intracellular signalling pathways such as PI3K-Akt, Ras-MAPK, and PLC-γ1. The expression of BDNF is precisely controlled by genetic, epigenetic, and transcriptional mechanisms, with environmental and activity-dependent factors providing further modulation. However, it is worth noting that BDNF dysregulation has been linked to major diseases such as depression, schizophrenia, autism spectrum disorder, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and depression, with growing evidence supporting its use as a biomarker for disease monitoring and treatment. This review provides a comprehensive overview of BDNF synthesis, regulation, and signalling mechanisms, highlighting its context-dependent roles in both health and disease. It also examines the role of BDNF in cerebellar development, specifically its effects on granule cells, Purkinje cells, and interneurons govern neuronal survival, migration, and synaptic refinement, and its disruption may predispose to neuropsychiatric vulnerability. While BDNF modulation correlates with clinical outcomes, it remains unclear whether BDNF upregulation directly contributes to therapeutic efficacy or is merely an associated response. BDNF shows promise as a diagnostic biomarker and therapeutic target, merging mechanistic and clinical insights, but requires further research for full potential in precision medicine.},
}

@article {pmid41636819,
year = {2026},
author = {Fu, H and Feng, J and Zhang, X and Tian, L and Sun, S and Bo, H and He, C and Wang, X},
title = {Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.},
journal = {Radiation and environmental biophysics},
volume = {65},
number = {1},
pages = {257-269},
pmid = {41636819},
issn = {1432-2099},
support = {NO.HYZHXM02004//State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center/ ; xcxjh20230610//Foundation of the Graduate Innovation Center, Nanjing University of Aeronautics and Astronautics/ ; },
abstract = {Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.},
}

@article {pmid41670842,
year = {2026},
author = {Majumder, D},
title = {Immune cell dynamics in neurological disorders: from inflammation to microgliopathy and Neuron-Glia crosstalk.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {378},
pmid = {41670842},
issn = {1573-4978},
abstract = {The immune system is a complex network of cells and molecules that preserves homeostasis and provides defence against pathogens. Within the central nervous system (CNS), immune cells perform distinct yet integrated roles, balancing neuronal survival with inflammatory responses. Neuroinflammation is a hallmark of several neurological disorders, where immune activation may become maladaptive and drive neurodegeneration. Microglia, the resident macrophage-like immune cells of the brain, represent a unique interface between immune and neural function. They regulate synaptic pruning, release trophic factors, and respond to injury; however, their chronic or patchy activation leads to microgliopathy, an emerging pathological state underpinning diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke. This review traces the evolution of immune involvement from peripheral to central contexts, examines microglial signalling mechanisms in health and disease, and highlights how dysregulated neuron–microglia communication contributes to disease pathology. This review also explores biomarkers, signalling cascades such as NF-κB, MAPK, JAK/STAT, and calcium-mediated pathways, and discuss future perspectives on targeting microglial states for therapeutic intervention.},
}

@article {pmid41677822,
year = {2026},
author = {Choi, S and Choi, Y and Cheon, DY and Lim, JS and Han, KD and Lee, M},
title = {Association between unhealthy lifestyles and young-onset dementia: a nationwide cohort study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41677822},
issn = {1433-8491},
support = {RS-2023-00223501//National Research Foundation of Korea/ ; },
abstract = {OBJECTIVES: The link between clusters of unhealthy lifestyle behaviors and the risk of young-onset dementia remains unclear. This study aimed to assess the impact of multiple unhealthy lifestyle behaviors on the risk of developing young-onset dementia, including all-cause dementia, Alzheimer’s disease, and vascular dementia. METHODS: We analyzed nationwide Korean National Health Insurance Service data from individuals aged 40–60 years who underwent health screening in 2009 and were followed until 2018 or age 65. The Unhealthy Lifestyle Behavior Score (ULBS) was derived from smoking, heavy drinking, and non-regular exercise (physical inactivity). Outcomes included all-cause young-onset dementia, Alzheimer’s disease, and vascular dementia. RESULTS: The study included 1,979,509 patients (average age 49.05 ± 5.96, 51.27% male), with distribution across ULBS categories as follows: 14.5% ULBS 0, 62.3% ULBS 1, 19.5% ULBS 2, and 3.7% ULBS 3. After adjusting for multiple variables, patients with ULBS 1, 2, and 3 showed a significantly increased risk of all-cause young-onset dementia compared to those with ULBS 0 in a dose-response relationship. (Adjusted hazard ratio [95% CI]: 1.147 [1.077–1.221], 1.486 [1.376–1.604], and 1.909 [1.704–2.138], respectively). INTERPRETATION: The accumulation of unhealthy lifestyle behaviors is significantly linked to a higher risk of all-cause young-onset dementia. These findings underscore the importance of promoting healthy lifestyle choices to mitigate the risk of developing young-onset dementia.},
}

@article {pmid41691358,
year = {2026},
author = {Scott, HM and Price, L and Ogden, M and Bharadia, T and Burke, P and Horne, R and Harding-Bell, A and Tonkin, A and Thomson, A},
title = {A rapid evaluation of the reporting and publishing practices of patient and public involvement and engagement in health research within a UK university institute.},
journal = {Research involvement and engagement},
volume = {12},
number = {1},
pages = {},
pmid = {41691358},
issn = {2056-7529},
abstract = {BACKGROUND: Patient and Public Involvement and Engagement is important to ensure research addresses the issues that matter most to patients and the public. However, reporting and publishing of these activities is variable and inconsistent. This rapid review aimed to assess how effectively, consistently, and transparently Patient and Public Involvement and Engagement is reported on in papers published by authors affiliated with a heath research institute at a UK Russell Group university. METHODS: A rapid review of all papers published by institute-affiliated authors (1st August 2021 to 31st December 2024) identified using PubMed. We also consulted with a group of patient co-authors to understand their experiences of being a Patient and Public Involvement and Engagement co-author in collaboration with researchers from the same institute. RESULTS: We retained and reviewed 523 papers for inclusion of Patient and Public Involvement and Engagement. There was significant variation in the reporting across the papers included. Overall, 21% of papers had reference to Patient and Public Involvement and Engagement activity in the main body of the paper, and 17% of papers included Patient and Public Involvement and Engagement in the acknowledgements. In terms of co-authorship, 5% of papers included an author with an affiliation to a charity/non-governmental organisation that represented Patient and Public Involvement and Engagement -related interested, e.g. Alzheimer’s Society, Caribbean and African Health Network and 1% of papers included a patient/lived-experience author. A total of 97% of papers were published open access but only 10% of articles included in this review had a plain English or lay summary. Only one paper included a published GRIPP2 form. The Patient and Public Involvement and Engagement group reviewed and contextualised our findings, supporting analysis and development of seven key recommendations to improve comprehensive, consistent, and transparent reporting of Patient and Public Involvement and Engagement in health research at an institute level. CONCLUSIONS: This work demonstrates the challenges that Patient and Public Involvement and Engagement faces and the importance of institutions reflecting on the practices of their academics, and the structures they put in place to encourage good and equitable practices of working with patents and the public.},
}

@article {pmid41708961,
year = {2026},
author = {Tahmasebi, F and Safarian, A and Asl, ER and Vahidinia, Z and Barati, S},
title = {The effect of astrocyte depletion and repopulation approaches in pathological condition of CNS.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41708961},
issn = {2240-2993},
abstract = {Astrocytes a highly diverse and functionally important class of glial cells in the central nervous system (CNS), are central to maintaining homeostasis, modulating synaptic activity, and supporting neuronal health. These cells exhibit remarkable heterogeneity, with distinct subtypes such as protoplasmic and fibrous astrocytes, each playing specialized roles in CNS physiology. Under pathological conditions, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis (MS), astrocytes undergo reactive transformations, and adopt either neurotoxic (A1) or neuroprotective (A2) phenotypes. While A1-reactive astrocytes contribute to synaptic dysfunction and exacerbate neuroinflammation, A2-reactive astrocytes promote tissue repair and neuronal survival. Studies using astrocyte depletion models show that their absence disrupts extracellular matrix stability, compromises blood-brain barrier (BBB) integrity, and enhances neuroinflammatory responses, underscoring their dual role in disease progression. Pharmacological strategies such as L-AAA or ganciclovir-mediated depletion highlight the therapeutic potential of modulating astrocyte activity to influence disease outcomes. By unraveling the complexity of astrocyte diversity and its dynamic responses in health and disease, researchers can uncover novel therapeutic targets for a wide range of CNS disorders.},
}

@article {pmid41817635,
year = {2026},
author = {Luo, Z and Zhong, Y and Zhao, C and Ouyang, C and Ren, J and Peng, H},
title = {The correlation between olfactory bulb volume and T&T odor threshold: a systematic review and meta-analysis.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41817635},
issn = {1931-7565},
support = {2023A1515010268//Natural Science Foundation of Guangdong Province/ ; },
abstract = {This meta-analysis aims to quantitatively assess the correlation between olfactory bulb (OB) volume measured by magnetic resonance imaging (MRI) and the T＆T olfactometer identification threshold, with subgroup analyses conducted in patients with neurodegenerative disorders and healthy individuals. We searched PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine Disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases for relevant studies. The procedure was under the guidance of the Preferred Systematic Reviews and Meta-Analyses Reporting Items (PRISMA) checklist. English or Chinese cross-sectional studies concerned with OB volume and olfactory function published before January 31, 2025, were searched in the data sources mentioned above. After study selection, data extraction, and the assessment of study quality, this meta-analysis was performed independently performed by two reviewers. Correlation coefficients were pooled using Fisher’s z transformation. Random- or fixed-effects models were applied according to heterogeneity. Subgroup analyses were conducted for neurodegenerative disorder patients and healthy controls. Fifteen studies concerning 1289 subjects were qualified for the study, including 824 patients who suffered from olfactory deficiency and 465 healthy individuals. Fourteen studies were of high quality, and one study was of medium quality. An overall correlation between OB volume and T＆T olfactory test score (r=-0.64, P= 0.01) was detected. Further subgroup analysis showed significant correlations among cognitive syndrome patients (mild cognitive impairment (MCI) and Alzheimer’s disease (AD)) (r=-0.84,P=0.82), Parkinson’s disease patients (PD) (r=-0.70,P=0.01), healthy subjects (r=-0.61,P=0.97). According to meta-regression analysis, age was not a source of heterogeneity. The result supported a significant correlation between OB volume and T＆T odor identification threshold. OB volume measurement may be a potential alternative for the T＆T odor identification test, especially in neurodegenerative individuals.},
}

@article {pmid41832594,
year = {2026},
author = {Gasparre, D and Habich, A and Mulet-Pons, L and Yanez-Perez, R and Westman, E and Barroso, J and Vaque-Alcázar, L and Bartres-Faz, D and Taurisano, P and Ferreira, D and , },
title = {The cognitive connectome of men and women: a study on sex differences across three cohorts.},
journal = {Biology of sex differences},
volume = {17},
number = {1},
pages = {},
pmid = {41832594},
issn = {2042-6410},
abstract = {BACKGROUND: Cognitive processes are essential for efficient daily functioning. Demographic factors such as age and education influence cognitive performance. However, the impact of sex on cognition is less understood and previous research has reported inconsistent findings. We investigated sex differences in cognitively unimpaired adults in three cohorts, using two complimentary approaches: a univariate approach to compare direct performance across cognitive domains and the multivariate approach of graph theory to compare global and nodal features as well as the modular organization of cognitive connectomes. METHODS: We included 4,259 cognitively unimpaired participants (334 from the GENIC cohort, 3,703 from the National Alzheimer’s Coordinating Center [NACC], and 222 from the Alzheimer’s Disease Neuroimaging Initiative [ADNI]). Cognitive variables were corrected for age and education, and cognitive connectomes were constructed using Spearman correlation coefficients. Sex differences in cognitive performance were examined through ANCOVAs as well as global and nodal network measures. RESULTS: Univariate analyses showed significant sex differences in three out of five cognitive domains across cohorts, mainly of small effect sizes. Graph theory analyses revealed minimal sex differences in cognitive module organization and no significant differences on global network measures, except for a higher modularity observed in women compared to men in the NACC. In contrast, nodal analyses revealed sex differences in several network measures. CONCLUSIONS: Sex differences in cognition seem to be of small effect size and limited to specific cognitive domains or cognitive variables, while the overall organization and global features of cognitive connectomes were largely comparable between men and women. Future studies should clarify whether men and women may rely on slightly different cognitive strategies to approach cognitive tasks without overt differences in cognitive ability.},
}

@article {pmid41863721,
year = {2026},
author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK},
title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863721},
issn = {1573-7365},
abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.},
}

@article {pmid41894075,
year = {2026},
author = {Kuwar, OK and Tejpal, S and Sharma, V and Sharma, A and Rao, A and Attri, M and Pallavi, and Dhingra, MS},
title = {Therapeutic potential of sulforaphane in neurodegenerative diseases: mechanistic Insights into Nrf2, NF-κB, TrkB, SIRT1, MAPK, and JAK/STAT signalling pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {41894075},
issn = {1573-4978},
abstract = {Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are chronic and progressive disorders distinguished by neuronal dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. Due to the multifactorial nature of these disorders, current pharmacotherapies provide limited symptomatic relief without altering disease progression. Sulforaphane, a naturally occurring isothiocyanate abundant in cruciferous vegetables like broccoli, has emerged as a potent neuroprotective compound owing to its pleiotropic effects on key cellular signalling pathways. This review provides a thorough overview of the mechanistic insights underlying SFN’s neuroprotective potential, with a focus on the modulation of key signalling pathways such as Nrf2/ARE, NFĸB, BDNF/TrkB, SIRT1, MAPK, and JAK/STAT. Through the activation of antioxidant defenses and suppression of inflammatory cascades, SFN effectively mitigates neuronal damage and supports cellular homeostasis. Preclinical studies consistently demonstrate SFN’s ability to attenuate oxidative stress, inhibit apoptosis, preserve mitochondrial function, and improve neurobehavioral outcomes. While limited clinical evidence supports its safety and bioactivity, further investigations are needed to establish its therapeutic utility in human populations. Overall, SFN represents a promising natural compound with significant potential for the prevention and management of neurodegenerative diseases through multi-targeted pathway modulation.},
}

@article {pmid41920376,
year = {2026},
author = {Hussain, MA and Naheed, S and Saeed, K and Karim, A and Ahmad, F and Qaisar, R and Alkahtani, SA},
title = {Can Difficulty Standing from a Chair Signal Early Risk of Chronic Illness? Insights from a Multi-Wave European Cohort.},
journal = {Calcified tissue international},
volume = {117},
number = {1},
pages = {},
pmid = {41920376},
issn = {1432-0827},
support = {ORF2026 - 277//Deanship of Scientific Research, King Saud University/ ; },
abstract = {BACKGROUND: Difficulty rising from a chair may indicate early functional decline and vulnerability to adverse health outcomes. While widely used in geriatric assessments, its role in predicting diverse health domains using large-scale longitudinal data remains underexplored. METHODS: We analysed 52,541 adults aged ≥ 50 years from the Survey of Health, Ageing and Retirement in Europe (SHARE), Waves 5–9 (2013–2022). Chair-rise difficulty was assessed at baseline using a single self-reported item: “Getting up from a chair after sitting for long periods.” Responses were dichotomized (0 = no difficulty, 1 = difficulty). Incident outcomes included musculoskeletal, cardiometabolic, cardiovascular, neurological, and psychosocial conditions, as well as low handgrip strength (HGS) and low quality of life (QoL). Logistic regression models estimated odds ratios (OR) adjusted for baseline comorbidity, BMI, age, sex, and country. RESULTS: At baseline, 18.6% reported chair-rise difficulty. Adjusted models showed higher odds of low QoL (OR 1.46, 95% CI 1.28–1.64), elevated depressive symptoms (OR 1.27, 1.12–1.43), and osteoarthritis (OR 1.25, 1.12–1.38). Associations with HGS and rheumatoid arthritis were small and imprecise. Cardiometabolic and vascular outcomes were attenuated or inversely associated after adjustment (e.g., hypertension: OR 0.47; diabetes: OR 0.64). Alzheimer’s disease and stroke showed no clear association. CONCLUSION: Self-reported chair-rise difficulty is a simple, scalable indicator of psychosocial burden and musculoskeletal morbidity in older adults. Its feasibility for extensive surveys supports its use in population-level screening, although associations with cardiometabolic outcomes require cautious interpretation.},
}

@article {pmid41940962,
year = {2026},
author = {Buchinger, D and Aleksic, T and Brücke, C and Berger-Sieczkowski, E and Nakuz, T and Traub-Weidinger, T and Milenkovic, I},
title = {Longitudinal serum uric acid levels are not associated with dopamine transporter binding in progressive supranuclear palsy.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41940962},
issn = {1435-1463},
abstract = {Progressive supranuclear palsy (PSP) causes rapid motor decline and severe dopaminergic dysfunction. While uric acid (UA) may act as a neuroprotective antioxidant in some neurodegenerative disorders (like Parkinson’s disease), its role in PSP remains unclear. This study evaluated the relationship between serum UA levels, measured cross-sectionally and longitudinally, and striatal dopamine transporter binding in PSP. A total of 33 PSP patients with repeated pre-[123I]FP-CIT SPECT UA measurements, along with 30 healthy control individuals and 30 patients with Alzheimer’s disease (AD), were retrospectively analyzed. Group and sex effects were analyzed with t tests and ANOVA. Effects of mean UA and longitudinal UA trajectories on FP-CIT SPECT binding in PSP were modeled using linear mixed-effects models and regressed against binding in four regions (caudate and putamen), separated into more-affected and less-affected side for both sexes. A Bayesian two-stage measurement-error model provided sensitivity analysis. UA was significantly lower in PSP (4.98 mg/dl) and AD (4.69 mg/dl) compared to healthy controls (5.71 mg/dL; p = 0.001). Sex had a significant effect on UA (F(1, 89) = 9.38, p = 0.003, partial η2 = 0.10), however, this effect was significant only in PSP (p< 0.001). Within PSP, UA–[123I]FP-CIT SPECT correlations were weak and nonsignificant, and neither UA intercept nor slope predicted [123I]FP-CIT SPECT binding (all p > 0.7). Bayesian estimates corroborated the absence of a credible relationship. In the present cohort, serum UA is reduced in PSP, primarily in females, but neither mean levels nor longitudinal changes are related to striatal [123I]FP-CIT SPECT binding, suggesting no clear association with dopaminergic degeneration in PSP, without precluding a potential role of uric acid at other disease stages.},
}

@article {pmid41945111,
year = {2026},
author = {Lai, Z and Zhang, B and Fu, Z and Li, R and Qian, Y and Zhang, Y and Xu, P and Du, Y},
title = {Research advances on Cordyceps sinensis and its components in relation to omics biomarkers for the neurological disorders.},
journal = {Die Naturwissenschaften},
volume = {113},
number = {3},
pages = {},
pmid = {41945111},
issn = {1432-1904},
support = {2026ZL0010//Zhejiang Traditional Chinese Medicine Science and Technology Program of China/ ; 82202605//National Natural Science Foundation of China/ ; 2023, DU YAOQIANG//Zhejiang Provincial Special Support Program for Cultivation of High-Level Innovative Health Talents of China/ ; },
abstract = {Cordyceps is a traditional medicinal fungus belonging to the species Ophiocordyceps sinensis. It grows in the alpine ecological zone of the Tibetan Plateau and exhibits dual characteristics of both insects and fungi. The primary species include Cordyceps sinensis and Cordyceps militaris. Rich in bioactive components such as cordycepin, polysaccharides, adenosine, and peptides, cordyceps demonstrates broad applications in immune regulation, anti-tumor activity, anti-inflammatory, and neuroprotection. Cordyceps sinensis and its components show great therapeutic potential in neurological diseases such as epilepsy, Alzheimer’s disease and Parkinson’s disease through multi-level and multi-target actions However, current research faces challenges including unclear mechanisms of action and insufficient clinical translation. In this review, we analyze the molecular mechanisms underlying cordyceps’ neuroprotective effects, including the regulating of apoptosis, improvement of mitochondrial function, and promoting of nerve repair. Utilizing network pharmacology, we explore the multi-targeted actions of cordyceps and predict the key pathways. Further we summarize the research progress in the integrated multi-omics analyses (genomics, transcriptomics, proteomics and metabolomics), to reveal the synergistic roles of cordyceps components in treating neurological disorders and identify potential molecular biomarkers. Additionally, we highlight the findings from preclinical experiments and animal models on cordyceps-based drugs, discussing their advantages and challenges for clinical application. Future studies should prioritize systematic exploration of standardized drug development, advanced multi-omics integration, and rigorous clinical trials. This will provide a more robust scientific foundation and practical guidance for the treatment of neurological diseases with cordyceps.},
}

@article {pmid41945254,
year = {2026},
author = {Brahadeeswaran, S and Sreedhar, S and Ramesh, S and Tamizhselvi, R},
title = {Targeting ferroptosis mediated cell death: a novel strategy for mitigating acute pancreatitis.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {41945254},
issn = {1573-4978},
abstract = {Acute pancreatitis (AP) is a common and potentially fatal inflammatory disorder characterized by pancreatic tissue inflammation and necrosis. Though our understanding of its pathogenesis has advanced, effective therapeutic approaches remain elusive, with many potential strategies still unexplored. Ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, plays a crucial role in tissue damage and inflammation. It has been implicated in various disorders, including neurodegenerative diseases like Alzheimer and Parkinson, ischemia-reperfusion injury, cancer, and other metabolic diseases. In AP, ferroptosis exacerbates disease progression by promoting pancreatic inflammation and cellular damage, thereby worsening clinical outcomes. However, its role in AP remains insufficiently explored due to the complexity of its molecular mechanisms and the limited availability of targeted interventions. This comprehensive review summarizes the factors involved in ferroptosis, such as glutathione depletion, defective lipid peroxide detoxification, dysregulation of iron homeostasis, and discusses established and emerging biomarkers. Furthermore, we discuss the FDA approved drugs and other investigational compounds targeting ferroptosis, along with the role of pro-inflammatory mediators, lipid peroxidation products, glutathione peroxidase 4 (GPX4), and iron regulatory proteins. The influence of PAMPs and DAMPs on ferroptosis signaling along with the potential role of epigenetic regulation is also highlighted. Overall, this review provides an integrated perspective on the role of ferroptosis in AP and emphasizes its potential as a novel therapeutic approach to mitigate AP. The goal is to use these insights into clinical practice to reduce the burden of this difficult condition.},
}

@article {pmid41961418,
year = {2026},
author = {Priyadarshni, A and Sharma, R and Bora, KS and Dewangan, HK},
title = {Pharmacological insights into deoxyelephantopin: a multifunctional sesquiterpene with therapeutic promise in cancer and neurodegenerative disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {41961418},
issn = {1573-4978},
abstract = {Deoxyelephantopin (DET), a sesquiterpene lactone predominantly isolated from Elephantopus scaber, has garnered attention for its emerging multifaceted potential bioactivity in both oncology and neurobiology. This review synthesizes current preclinical evidence on the pharmacological actions of DET and elucidates the pharmacological spectrum of DET, highlighting its potent anticancer, anti-inflammatory, hepatoprotective, and neuroprotective activities. DET demonstrates broad-spectrum cytotoxicity across various cancer cell lines, including breast, colon, pancreatic, and osteosarcoma, inducing apoptosis via mitochondrial pathways, generating reactive oxygen species (ROS), and modulating cell cycle regulators. Mechanistically, inhibits key oncogenic and inflammatory signalling cascades such as the NF-κB, PI3K/AKT/mTOR, MAPK, and STAT3 cascades, consequently inhibiting tumour proliferation, metastasis, and resistance to apoptosis. In preclinical models of neurodegeneration, DET exhibits pronounced neuroprotective effects against LPS-induced degeneration and associated cognitive decline. DET attenuates neuroinflammatory responses by diminishing pro-inflammatory mediators such as (iNOS, COX-2, TNF-α, IL-6) and increases anti-inflammatory cytokines (IL-4, IL-10) as well as maintains synaptic integrity with the upregulation of synaptic markers (PSD-95, SYP). Furthermore, DET mitigates neuronal apoptosis by inhibiting key apoptotic proteins (PARP-1, caspase 3), underscoring its preclinical potential for conditions like Alzheimer’s (AD) and Parkinson’s (PD) diseases. The review also discusses the translational potential of DET, emphasizing the need for dose optimization, clinical evaluation, and the exploration of synergistic therapies and analogue developments to overcome pharmacokinetic limitations. Collectively, the evidence positions DET as a versatile bioactive molecule with significant prospects for the development of novel therapeutics targeting various neurodegenerative diseases, warranting further investigation in clinical interventions. Nevertheless, no clinical data are available, and all existing evidence is based on in vitro and animal research. Rigorous pharmacokinetic, toxicological, and preclinical studies are needed before classifying deoxyelephantopin as a viable therapeutic agent.},
}

@article {pmid41964100,
year = {2026},
author = {Trigo-Alonso, P and Luengo, E and Fernández-Mendivíl, C and Viqueira, L and García-Magro, N and Del Sastre, E and Bernal, JA and Negredo, P and López, MG},
title = {Timing of microglial ablation determines protection from tau-mediated neurodegeneration and cognitive decline.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02291-1},
pmid = {41964100},
issn = {2051-5960},
support = {FPU16/03239//Ministerio de Ciencia, innovacion y universidades/ ; FPU20/03747//Ministerio de Ciencia, innovacion y universidades/ ; FPU18/00630//Ministerio de Ciencia, innovacion y universidades/ ; PID2023-151105OB-I00//Ministerio de Ciencia, innovacion y universidades/ ; PID2021-125039NB-I00//Ministerio de Ciencia, innovacion y universidades/ ; PDC2022-133809-I00 and PID2021-125986OB//Ministerio de Ciencia, innovacion y universidades/ ; P2022/BMD-7230//Comunidad de Madrid/ ; },
abstract = {Tauopathies comprise a diverse group of neurodegenerative diseases characterized by intracellular aggregation of the microtubule-associated protein tau, neuroinflammation, and neuronal loss. Since tau pathology shows the strongest correlation with cognitive decline in Alzheimer’s disease, understanding how microglia contribute to tau-mediated neurodegeneration remains a critical question. Here, we validated a tauopathy mouse model that progressively recapitulates key pathological features of tauopathy. Bilateral hippocampal injection of AAV-hTauP301L (AAV-hTau) resulted in widespread tau accumulation, early and sustained gliosis, complement component 1q (C1q) deposition, progressive reduction of hippocampal layer thickness and cognitive deficits. Notably, we observed marked activation of Cluster of Differentiation 68 (CD68+) microglia and the emergence of Complement 3 (C3+) reactive astrocytes, which developed in parallel over time. To dissect the role of microglia in tau-driven pathology, we depleted them at different stages using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. Microglial ablation conferred significant neuroprotection, with early depletion effectively mitigating cognitive decline and structural changes in hippocampal layers supporting an important role for microglial activation in tauopathy progression.Neuroprotection may result from decreased levels of insoluble p-tau oligomers, partial blockade of C3+ astrocyte induction and attenuation of microglial reactivity. Overall, our results support the potential of microglia-directed interventions as a promising therapeutic avenue for mitigating disease progression in tauopathies.},
}

@article {pmid41995815,
year = {2026},
author = {Pham, W and Jarema, A and Rim, D and Chen, Z and Khlif, M and Macefield, V and Henderson, L and Brodtmann, A},
title = {A comprehensive framework for automated segmentation of perivascular spaces in brain MRI with the nnU-Net.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {41995815},
issn = {1432-1920},
abstract = {BACKGROUND: Enlargement of perivascular spaces (PVS) is common in cerebral small vessel disease, Alzheimer’s disease, and Parkinson’s disease, reflecting impaired clearance pathways. While MRI provides a means to quantify perivascular spaces, manual annotation remains time-consuming and labour-intensive. Thus, there is a need for accurate automated MRI-based PVS segmentation methods. AIM: To optimise the nnU-Net, a deep-learning framework, for PVS segmentation. METHODS: 30 T1-weighted (T1w) MRI images acquired on three different scanners were used. PVS in the white matter (WM) and basal ganglia (BG) were manually labelled via a sparse annotation strategy and used to optimise the nnU-Net for T1w PVS segmentation. The same pipeline was applied to T2-weighted (T2w) images. Additionally, we trained T1w+FLAIR and T2w+FLAIR models to simultaneously segment PVS and white matter hyperintensities (WMH). Performance was assessed with 5-fold cross validation using the Dice similarity coefficient (DSC). RESULTS: A voxel-spacing agnostic model (mean DSC = 64.3 ± 3.3%) outperformed models that resampled images to a common resolution (DSC = 40.5–55%). Training on PVS segmentations derived from preprocessed T1w images substantially improved performance (DSC = 78.3 ± 1.7%). The T2w model performed best overall (DSC = 84.7 ± 1.3%), especially for WM-PVS (DSC = 90.4 ± 0.9%) compared to BG-PVS (DSC = 79.1 ± 2%). Multimodal models achieved DSCs of 75.6 ± 3.4% (T1w+FLAIR) and 77.5 ± 2.7% (T2w+FLAIR). CONCLUSIONS: Our deep learning models provide a robust framework for automated PVS quantification across MRI modalities.},
}

@article {pmid42010038,
year = {2026},
author = {Nakatsuji, M and Shibano, M and Fujimori, K},
title = {Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42010038},
issn = {1573-6903},
support = {25ak0101219h0202//Japan Agency for Medical Research and Development/ ; },
abstract = {Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.},
}

@article {pmid42045964,
year = {2026},
author = {Jha, V and Kalia, LV},
title = {LRRK2 and GBA1 in Lewy body diseases: neuropathological subtypes at opposite ends of a spectrum?.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42045964},
issn = {1750-1326},
abstract = {Lewy body diseases (LBDs), including Parkinson’s disease (PD), are defined by the presence of pathological intraneuronal α-synuclein aggregates but exhibit considerable heterogeneity in clinical course, neuropathology, and underlying mechanisms. This review summarizes neuropathological findings in PD associated with pathogenic variants in GBA1 and LRRK2 – the two most common genetic risk factors for PD – and highlights how these genetic forms represent neuropathological subtypes at opposite ends of a spectrum. GBA1-associated PD typically shows widespread Lewy pathology with cortical involvement and relatively limited Alzheimer-type co-pathology, while LRRK2-associated PD may occur with or without Lewy bodies and displays variability in tau and TDP-43 aggregates. We also examine how these genetic forms may serve as models for subtypes within idiopathic PD, including the potential existence of Lewy body-negative idiopathic PD. We propose a conceptual framework in which idiopathic PD encompasses GBA1-like and LRRK2-like subtypes, as well as intermediate forms with mixed pathologies. This perspective supports a shift toward biomarker-informed, mechanism-based classification of PD, beyond genetic labels alone, that may ultimately enable broader application of targeted therapeutic strategies.},
}

@article {pmid42050692,
year = {2026},
author = {Rahbek, MT and Kildegaard, H and Hallas, J and Ernst, MT and Lund, LC},
title = {Acetylcholinesterase inhibitors and the risk of delirium - a Danish nationwide register-based cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02060-1},
pmid = {42050692},
issn = {1758-9193},
abstract = {BACKGROUND: Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. METHODS: Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. CONCLUSIONS: Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.},
}

@article {pmid42076797,
year = {2026},
author = {Martineau, A and Conant, M and Myers Barnett, K and Norman, M and Lanza, E and Snowball, E and Forget, MF and Bruneau, MA and Couture, V and Nguyen, QD and Ducharme, S and Desmarais, P},
title = {Barriers to Clinical Care in Frontotemporal Dementia and Related Disorders: A Cross-Sectional Survey of Patients and Caregivers' Journey in the Canadian Healthcare System.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-13},
doi = {10.1017/cjn.2026.10609},
pmid = {42076797},
issn = {0317-1671},
abstract = {BACKGROUND: Frontotemporal dementia (FTD) and related disorders are major causes of young-onset dementia (YOD), yet caregivers often face delayed diagnosis and high distress. Data on the Canadian caregiving experience in FTD remain scarce. This study aimed to describe caregivers' profiles and experiences navigating diagnosis and care and to identify factors associated with diagnostic delay and caregiver burden.

METHODS: We conducted an online survey (June 2023-May 2024) of adults providing care to individuals with FTD. The survey captured sociodemographic characteristics, diagnostic journey, healthcare access and caregiver burden (Zarit Burden Interview, ZBI). Neuropsychiatric symptoms (NPS) were assessed using the Neuropsychiatric Inventory. Descriptive and multivariable analyses examined factors associated with delayed diagnosis and burden.

RESULTS: Ninety-seven caregivers participated (82.5% women; mean age 61.4 ± 13.1 years). Care recipients (58.8% men; mean age 72.9 ± 9.7 years) most commonly had behavioural-variant FTD (57.7%). Mean time to diagnosis was 3.1 ± 4.5 years and was longer for YOD, those without family history and those initially misdiagnosed. Nearly half were initially misdiagnosed as psychiatric disorders or Alzheimer. Women caregivers reported significantly longer diagnostic delays (+20 months, p = 0.005). Most caregivers reported substantial burden (mean ZBI = 23.1 ± 8.3) and severe distress related to NPS, especially disinhibition and irritability, which independently predicted higher burden.

CONCLUSION: Canadian FTD caregivers face prolonged diagnostic journeys, high neuropsychiatric-related distress and substantial unmet needs. Findings highlight gaps in awareness, access to specialized care and systematic assessment of caregiver burden, underscoring urgent priorities for improving diagnostic pathways and support services.},
}

@article {pmid42284682,
year = {2026},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Doré, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106329},
doi = {10.1016/j.ebiom.2026.106329},
pmid = {42284682},
issn = {2352-3964},
abstract = {BACKGROUND: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10[-5]). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).},
}

@article {pmid42285026,
year = {2026},
author = {Bayram, E},
title = {Time to pay attention to sleep for Alzheimer's disease in women.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100624},
doi = {10.1016/j.tjpad.2026.100624},
pmid = {42285026},
issn = {2426-0266},
}

@article {pmid42285404,
year = {2026},
author = {Xu, N and Xing, Y and Li, A and Liu, S and Gao, J and Liu, X and Xie, W and Guo, N and Chen, Y and Sun, X and Wu, J and Gong, W and Wang, D and Tang, Y and Liu, H},
title = {Personalized high-dose accelerated intermittent theta-burst stimulation improves cognitive function in mild Alzheimer's disease: A randomized sham-controlled trial.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103142},
doi = {10.1016/j.brs.2026.103142},
pmid = {42285404},
issn = {1876-4754},
}

@article {pmid42285406,
year = {2026},
author = {Mendoza-Camacho, DM and Espinoza-Gutiérrez, HA and Viveros-Paredes, JM and Flores-Soto, ME and Tejeda-Martínez, AR},
title = {Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.011},
pmid = {42285406},
issn = {1873-7544},
abstract = {Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid 2-Arachidonoylglycerol (2-AG) while simultaneously contributing to the generation of arachidonic acid and pro-inflammatory eicosanoids. Pharmacological or genetic inhibition of MAGL increases 2-AG levels and concurrently reduces the biosynthesis of pro-inflammatory lipid mediators, thereby modulating microglial activation, astrocytic responses, and neuronal excitotoxicity. Preclinical studies in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis consistently demonstrate that MAGL blockade attenuates neuroinflammation, preserves synaptic and neuronal integrity, improves motor and cognitive function, and, in some cases, delays disease progression. Although clinical evidence remains limited, the available data position MAGL as a metabolic convergence point between inflammation and neurodegeneration, suggesting that its modulation may represent a therapeutic strategy with disease-modifying potential.},
}

@article {pmid42285552,
year = {2026},
author = {},
title = {Correction: First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer's disease: the Dominantly Inherited Alzheimer's Network Study.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {97},
number = {7},
pages = {e2},
doi = {10.1136/jnnp-2022-329843corr1},
pmid = {42285552},
issn = {1468-330X},
}

@article {pmid42285553,
year = {2026},
author = {},
title = {Correction: How well do plasma Alzheimer's disease biomarkers reflect the CSF amyloid status?.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {97},
number = {7},
pages = {e1},
doi = {10.1136/jnnp-2024-334122corr1},
pmid = {42285553},
issn = {1468-330X},
}