@article {pmid42962668,
year = {2026},
author = {Santiago, JA and Rascol, O and Foltynie, T and Meissner, WG and Potashkin, JA and Gutierrez-Silva, JC and Shahrestani, MN and Wu, Y and Rundek, T and Haq, IU},
title = {Metabolic endotyping for mechanism-informed Alzheimer's and Parkinson's disease trials.},
journal = {Med (New York, N.Y.)},
volume = {},
number = {},
pages = {101336},
doi = {10.1016/j.medj.2026.101336},
pmid = {42962668},
issn = {2666-6340},
abstract = {Metabolically targeted therapies for Alzheimer's disease and Parkinson's disease have yielded mixed results despite convergent evidence implicating three interconnected axes of metabolic dysfunction: insulin signaling, cellular bioenergetics, and lipid-lysosomal biology. We argue that this pattern partly reflects a trial-design problem: therapeutics such as glucagon-like peptide 1 receptor agonists, terazosin, and stearoyl-CoA desaturase inhibitors generally have been tested in biologically unselected populations, with endpoints often distal to the targeted mechanism. We propose as a testable hypothesis that a metabolic endotype-a measurable, biomarker-supported pattern of metabolic dysfunction-spans subsets of both diseases and that failure to enrich for this endotype could dilute therapeutic signals in all-comer trials. We outline a modular four-tier framework integrating prodromal risk, metabolic vulnerability, pathway-specific confirmation, and mechanistic deep phenotyping to make Alzheimer's and Parkinson's disease trials more interpretable and therapeutically informative.},
}

@article {pmid42962966,
year = {2026},
author = {Santerre, M and Shcherbik, N and Sawaya, BE},
title = {The metabolic-brain axis: GLP-1 signaling, insulin resistance, and obesity pharmacotherapy in neurodegeneration.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156810},
doi = {10.1016/j.metabol.2026.156810},
pmid = {42962966},
issn = {1532-8600},
abstract = {The intersection of metabolic disease and neurodegeneration represents one of the most consequential frontiers in translational neuroscience. Converging epidemiological, mechanistic, and pharmacological evidence supports a bidirectional metabolic-brain axis in which systemic insulin resistance, obesity, and chronic metabolic inflammation are associated with and may contribute to alterations in neuronal survival, synaptic plasticity, and neuroimmune homeostasis. GLP-1 receptor agonists, originally developed for glycemic control and weight management, have therefore been investigated as potential disease-modifying therapies across Alzheimer's disease, Parkinson's disease, and related neurodegenerative conditions through mechanisms including neuronal PKA activation, microglial NLRP3 suppression, mitochondrial biogenesis, and restoration of AQP4 perivascular localization that may contribute to glymphatic waste clearance. Direct human evidence for these CNS mechanisms remains limited or absent, with current support derived primarily from preclinical models and indirect human data, as detailed in Table 1, warranting dedicated investigation in the context of GLP-1 receptor agonism. Importantly, the two pivotal phase 3 programs designed to test this hypothesis in humans - EVOKE/EVOKE+ in early Alzheimer's disease and Exenatide-PD3 in Parkinson's disease - have both now reported, and neither demonstrated a statistically significant benefit on its primary clinical endpoint, despite favorable biomarker and epidemiological signals preceding these results. This review synthesizes current knowledge on brain insulin signaling, GLP-1 neurobiology, obesity-driven neuroinflammation, and the translational evidence for metabolic therapeutics in neurodegeneration, and uses the dissociation between mechanistic plausibility, epidemiological association, and null confirmatory trial results to identify critical knowledge gaps and translational barriers related to CNS target engagement, optimal dosing, and disease-modifying efficacy of GLP-1 receptor agonists. The review is organized into four major themes: brain insulin signaling, central GLP-1 biology, obesity-associated neuroinflammation, and the translational evidence supporting metabolic therapies for neurodegenerative disease.},
}

@article {pmid42963328,
year = {2026},
author = {Kim, D and Ho, BC and van Voorst, H and Liu, Y and Benzinger, TLS and Sha, S and Mormino, E and Henderson, VW and Zaharchuk, G},
title = {Deep learning-based prediction of regional brain Tau PET burden from MRI.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71911},
pmid = {42963328},
issn = {1552-5279},
support = {P30AG066515/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Magnetic Resonance Imaging/methods ; *tau Proteins/metabolism ; *Deep Learning ; *Brain/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; Male ; Aged ; Predictive Learning Models ; Prediction Algorithms ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Regional tau is strongly associated with Alzheimer's disease (AD) symptoms, but tau positron emission tomography (PET) is not routinely available, limiting early risk stratification.

METHODS: We trained a deep learning model to predict regional tau PET standardized uptake value ratios (SUVRs) from magnetic resonance imaging (MRI) with and without basic demographics using public cohorts (Alzheimer's Disease Neuroimaging Initiative [ADNI], Open Access Series of Imaging Studies 3 [OASIS3-tau], Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study [A4], Harvard Aging Brain Study [HABS]). Mean absolute error (MAE), Pearson r, area-under-the-receiver-operating-curve (AUC), and comparison with cognitive testing were assessed in external test sets (SCAN, Stanford University).

RESULTS: The model achieved an MAE of 0.14 (95% confidence interval [CI]: 0.12-0.16) and r = 0.72 for an early uptake region (Braak I-IV), and an MAE of 0.14 (95% CI: 0.12-0.17) and r = 0.71 for a late uptake region (Braak V-VI). AUCs for binary tau positivity in these regions were 0.87 (95% CI: 0.83-0.90) and 0.88 (95% CI: 0.84-0.91), respectively.

DISCUSSION: Predicting regional tau burden from magnetic resonance imaging (MRI) is feasible and may enable scalable tau-informed clinical AD care.},
}

Humans
*Positron-Emission Tomography/methods
*Magnetic Resonance Imaging/methods
*tau Proteins/metabolism
*Deep Learning
*Brain/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Female
Male
Aged
Predictive Learning Models
Prediction Algorithms
Aged, 80 and over

@article {pmid42963333,
year = {2026},
author = {Tariot, PN and Dickson, SP and Dwyer, J and Granda, C and Hughes, L and Karlawish, J and Linz, N and Nair, KV and Paulsen, R and Pawson, D and Perneczky, R and Schindler, SE and Scholler, E and Taylor, J and Tiede, B and Vradenburg, G},
title = {Expert perspectives on the design and communication of endpoints in Alzheimer's disease clinical trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71951},
pmid = {42963333},
issn = {1552-5279},
support = {//Bristol Myers Squibb/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Clinical Trials as Topic ; *Endpoint Determination ; *Communication ; *Research Design ; },
abstract = {Disease-targeted therapies (DTTs) for Alzheimer's disease (AD) represent a major advance, yet challenges remain on how best to interpret and communicate their benefits. As clinical development increasingly targets the earliest stages of AD (before symptoms emerge and early symptomatic AD), there is a need for novel, complementary endpoints and improved communication of treatment benefits. The Global CEO Initiative on Alzheimer's Disease convened a multi-stakeholder working group to develop recommendations for improving the design and communication of endpoints in AD clinical trials. In the near term, communication can be improved by contextualizing treatment effects at the individual level, including framing benefits in terms of responder analyses and "time saved" over defined timeframes. In parallel, continued development of complementary endpoints is needed to enable more sensitive, scalable, and patient-centered measurements aligned with early intervention. These recommendations aim to support stakeholders in evaluating and communicating the meaningful benefits of current and emerging therapies.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
*Clinical Trials as Topic
*Endpoint Determination
*Communication
*Research Design

@article {pmid42963335,
year = {2026},
author = {Moscoso Rial, A and Leuzy, A and Raket, LL and Villemagne, VL and Klein, G and Tonietto, M and Olafson, E and Smith, R and Schwarz, CG and Baker, S and Saad, ZS and Bullich, S and Lopresti, B and Sanabria Bohorquez, S and Domingues Kolinger, G and Lutz, O and Boada, M and Betthauser, TJ and Charil, A and Collins, EC and Collins, JA and Gunn, RN and Higuchi, M and Hostetler, E and Hutchison, RM and Iaccarino, L and Insel, PS and Irizarry, MC and Jack, CR and Jagust, WJ and Johnson, KA and Johnson, SC and Tissot, C and Vállez García, D and Salvadó, G and Stephenson, D and Marquié, M and Mathotaarachchi, S and Mintun, MA and Ossenkoppele, R and Huang, Q and Mao, X and Gnörich, J and Pappas, I and Petersen, RC and Chiotis, K and Rabinovici, GD and Rosa-Neto, P and Stephens, AW and Whittington, A and Carrillo, MC and Pontecorvo, MJ and Budd Haeberlein, S and Dunn, B and Kolb, HC and Tatton, N and Karten, Y and Brendel, M and O'Bryant, S and Xie, F and Rowe, CC and Hansson, O and Doré, V and , and , },
title = {Tau positron emission tomography harmonization using the CenTauR approach: General conversion equations, relevant cut-points, and external validation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71886},
pmid = {42963335},
issn = {1552-5279},
support = {//Food and Drug Administration (FDA) of the Department of Health and Human Services (HHS)/ ; U19 AG024904/NH/NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; },
mesh = {*Positron-Emission Tomography/methods/standards ; Humans ; *tau Proteins/metabolism ; Radiopharmaceuticals ; *Brain/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Reproducibility of Results ; },
abstract = {INTRODUCTION: Tau positron emission tomography (PET) tracers differ in kinetics, binding properties, and quantification pipelines, complicating cross-study comparisons. The CenTauR approach provides a unified framework for harmonizing tau PET quantification across tracers.

METHODS: We defined a tracer-agnostic "Standard Method" using Statistical Parametric Mapping 12, standardized regions of interest, and harmonized acquisition parameters. Using data from five tau tracers-[[18]F]flortaucipir, [[18]F]MK-6240, [[18]F]PI-2620, [[18]F]RO948, and [[18]F]GTP1-we applied the Joint Propagation Model to derive linear equations converting regional standardized uptake value ratios into the tracer-independent CenTauR scale. Validation included independent cross-sectional, longitudinal, and test-retest datasets across multiple cohorts.

RESULTS: The CenTauR scale yielded highly consistent regional values across tracers, with strong cross-tracer agreement and robust performance in external validation cohorts. We also expressed clinically relevant cut-points and staging boundaries on the CenTauR scale.

DISCUSSION: The CenTauR approach enables harmonized, tracer-independent quantification of tau PET, supporting reproducibility across studies and improving interpretation in clinical research and multicenter trials.},
}

*Positron-Emission Tomography/methods/standards
Humans
*tau Proteins/metabolism
Radiopharmaceuticals
*Brain/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Reproducibility of Results

@article {pmid42963336,
year = {2026},
author = {Pyun, JM and Park, YH and Shade, LMP and Fardo, DW and Kim, S and Nho, K and , },
title = {Polygenic risk scores for LATE-neuropathologic change: Implications for clinical utility.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71824},
pmid = {42963336},
issn = {1552-5279},
support = {AACSFD-24-1310485/ALZ/Alzheimer's Association/United States ; P30AG010133/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; R01AG081951//NIH/ ; R01LM012535/LM/NLM NIH HHS/United States ; U01AG072177/AG/NIA NIH HHS/United States ; U19AG074879/AG/NIA NIH HHS/United States ; //National Research Foundation of Korea/ ; RS-2024-00461936)//Korean government (Ministry of Science and ICT/ ; },
mesh = {Humans ; Genetic Risk Score ; Female ; Positron-Emission Tomography ; Male ; Aged ; Executive Function ; Aged, 80 and over ; *Alzheimer Disease/pathology/genetics/diagnostic imaging ; Disease Progression ; *TDP-43 Proteinopathies/pathology/genetics/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Cognitive Dysfunction/pathology/genetics ; Neuropsychological Tests ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Limbic-predominant age-related TDP-43 encephalopathy (LATE) exhibits clinical features resembling Alzheimer's disease (AD) and frequently occurs as a co-pathology, yet there are fewer biomarkers for LATE relative to AD.

METHODS: We calculated polygenic risk scores for LATE-neuropathologic change (LATE-PRS) and performed association analysis with neuropathology (N = 99) and longitudinal cognitive change rates (N = 538) in Alzheimer's Disease Neuroimaging Initiative participants aged ≥ 75 years, stratified by amyloid positron emission tomography (PET) positivity status.

RESULTS: LATE-PRS was significantly associated with pathologically confirmed LATE (odds ratio = 2.292, P = 0.002), independent of AD pathology. In cognitively impaired individuals, LATE-PRS was associated with faster executive function decline in PET-negative individuals (β = -0.002, P = 0.041), and faster memory (β = -0.002, P < 0.001) and executive function (β = -0.001, P = 0.035) decline in PET-positive individuals. In the overall sample, associations were significant only in the PET-negative individuals.

DISCUSSION: LATE-PRS may serve as a potential biomarker for LATE risk and cognitive progression.},
}

Humans
Genetic Risk Score
Female
Positron-Emission Tomography
Male
Aged
Executive Function
Aged, 80 and over
*Alzheimer Disease/pathology/genetics/diagnostic imaging
Disease Progression
*TDP-43 Proteinopathies/pathology/genetics/diagnostic imaging
*Brain/pathology/diagnostic imaging
Cognitive Dysfunction/pathology/genetics
Neuropsychological Tests
Longitudinal Studies

@article {pmid42963367,
year = {2026},
author = {Tian, J and Jia, K and Chen, Y and Wang, T and Guo, L and Swerdlow, RH and Du, H},
title = {Mitochondrial complex IV disruption is a detrimental pathology conferring ssusceptibility to alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42963367},
issn = {1476-5578},
support = {R01AG075108//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01AG059753//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P30 AG072973//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; P30 AG035982//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; A20201159S//BrightFocus Foundation (BrightFocus)/ ; A2022036S//BrightFocus Foundation (BrightFocus)/ ; },
abstract = {Mitochondrial complex IV (CIV) is an integral part of the mitochondrial electron transport chain (ETC) and plays a pivotal role in maintaining mitochondrial function. In contrast to the long-standing recognition of its dysfunction in Alzheimer's disease (AD), the exact role of CIV deficit in the pathogenesis of this neurodegenerative disorder remains poorly defined. In this study, by incorporating clinical resources, mouse- and human-based models of AD risk, and a genetic approach to bypass defective CIV via the ectopic expression of alternative oxidase (AOX), we examined whether CIV deficits are a pathogenic driver of or a beneficial adaptation to AD-associated pathologies. Our results showed a clinicopathological association between neuronal CIV dysfunction and pathological characteristics of AD. Further experiments linked defective CIV to the development of mitochondrial dysfunction and synaptic loss in the tested mouse- and human-based models of AD risk. In addition, a reciprocal relationship between CIV dysfunction and amyloid pathology was determined. Lastly, a proteome-wide association study (PWAS) using genetic data from large-scale AD cohorts identified that downregulation of COX11, a crucial CIV assembly factor, confers susceptibility to AD risk. Collectively, our findings suggest that CIV dysfunction is a detrimental pathology contributing to AD-associated mitochondrial and neuronal damage. The dual role of CIV dysfunction, both as a consequence of and a contributor to amyloid toxicity in AD pathogenesis, further justifies the therapeutic potential of strategies targeting CIV deficits to diversify the tools for prevention and treatment of this neurodegenerative disorder.},
}

@article {pmid42963752,
year = {2026},
author = {Yang, X and Lyu, J and Wang, J and Quan, Y},
title = {Disentangling global atrophy burden from local structural patterns reveals clinically relevant heterogeneity in mild cognitive impairment.},
journal = {BMC neuroscience},
volume = {27},
number = {1},
pages = {},
pmid = {42963752},
issn = {1471-2202},
mesh = {Humans ; *Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid ; Atrophy/pathology ; Female ; Male ; Magnetic Resonance Imaging ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; Aged ; *Brain/pathology/diagnostic imaging ; Gray Matter/pathology/diagnostic imaging ; Aged, 80 and over ; White Matter/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous prodromal stage of Alzheimer's disease (AD). Imaging-based subtyping may conflate global neurodegenerative burden with local anatomical variation, limiting biological interpretability. We aimed to separate global atrophy burden from local structural patterns and assess their clinical relevance in MCI.

METHODS: Baseline ADNI-1 data from 731 participants were analyzed, including 205 cognitively normal individuals, 351 with MCI, and 175 with AD. A global atrophy index (GAI) was defined as the z-standardized ratio of TIV-adjusted whole-brain cerebrospinal fluid volume to TIV-adjusted gray matter plus white matter volume. Candidate regions were screened in the full CN-MCI-AD sample. Within MCI, regional measures were residualized against age, sex, education, and GAI to derive local residual structural features. Principal component analysis and unsupervised clustering were applied to identify imaging-based subtypes. Clinical associations were assessed using multivariable regression, and nested models evaluated the incremental explanatory value of continuous residual features beyond subtype labels.

RESULTS: GAI showed a clear gradient across cognitively normal, MCI, and AD groups. After adjustment for GAI, two local residual structural patterns were identified within MCI: a thalamic-striatal lower-residual subtype and a frontal-paralimbic lower-residual subtype. Compared with the thalamic-striatal subtype, the frontal-paralimbic subtype showed greater cognitive impairment and poorer daily functioning, with higher ADAS-Cog13 and FAQ scores after covariate adjustment. Associations with neuropsychiatric symptoms were weak. Continuous PCA-derived residual features provided additional explanatory value for ADAS-Cog13 and FAQ beyond subtype labels.

CONCLUSIONS: MCI heterogeneity is not explained solely by global atrophy. Local residual structural patterns were associated with cognitive and functional differences, and continuous residual features captured additional clinical information beyond discrete subtype labels. Separating global atrophy burden from local anatomical organization may improve interpretation of imaging heterogeneity in prodromal AD.},
}

Humans
*Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid
Atrophy/pathology
Female
Male
Magnetic Resonance Imaging
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
Aged
*Brain/pathology/diagnostic imaging
Gray Matter/pathology/diagnostic imaging
Aged, 80 and over
White Matter/pathology/diagnostic imaging

@article {pmid42964017,
year = {2026},
author = {Jing, Y and Li, D and Chen, L and Li, S and Yuan, X},
title = {miR-615-3p targets SESN2 to inhibit neuronal mitophagy in an in vitro Alzheimer's disease model by regulating the AMPK/ULK1 axis.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1873619},
pmid = {42964017},
issn = {1662-5099},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-β accumulation, mitochondrial dysfunction, and neuronal injury. miR-615-3p is upregulated in AD, but its role in regulating mitophagy remains unclear.

METHODS: HT22 hippocampal neurons were treated with Aβ1-42 to establish an AD-like model. Gain-of-function and loss-of-function experiments were conducted to assess the roles of miR-615-3p and its target SESN2, which were identified through bioinformatics and dual-luciferase assays. Cell viability, apoptosis, oxidative stress, mitochondrial function, inflammatory responses, and mitophagy-related proteins were evaluated. The involvement of the AMPK/ULK1 pathway was also examined.

RESULTS: miR-615-3p overexpression significantly reduced cell viability and ATP levels while increasing apoptosis, Aβ accumulation, lactate dehydrogenase release, reactive oxygen species production, mitochondrial membrane potential loss, and inflammatory cytokine levels. Mitophagy markers, including LC3-II/LC3-I, Parkin, and PINK1, were elevated. Mechanistically, miR-615-3p downregulated SESN2 and inhibited AMPK/ULK1 phosphorylation. SESN2 overexpression reversed these effects, restoring mitochondrial function, reducing oxidative stress and inflammation, and improving cell survival.

CONCLUSION: miR-615-3p aggravates neuronal injury by targeting SESN2 and regulating mitophagy through the AMPK/ULK1 pathway, suggesting a potential therapeutic target for Alzheimer's disease.},
}

@article {pmid42964118,
year = {2026},
author = {Zhang, L and An, H and Ding, M and Yu, X and Yan, F and Gu, C and Li, X},
title = {Cross-sectional associations of Kidney deficiency, Phlegm-stasis, and Heat-toxin syndrome patterns with disease severity in Alzheimer's disease: an exploratory study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1763273},
pmid = {42964118},
issn = {1663-4365},
abstract = {BACKGROUND: Current Alzheimer's diagnostics lack integration with Traditional Chinese Medicine's syndrome differentiation framework, making it difficult to fully capture the clinical heterogeneity and multidimensional nature of the disease.

METHODS: This cross-sectional study analyzed 236 AD patients stratified by CDR into early-stage (n = 127), moderate (n = 66), and severe (n = 43) groups. Using the SHA-03-W1 diagnostic instrument and Tian Jinzhou Scale, patients were classified into three TCM syndrome patterns: Kidney essence deficiency (n = 87), Phlegm-stasis obstructing the orifices (n = 93), and Heat-toxin obstructing the collaterals (n = 56). Data collected included demographics, cognitive scores (MMSE, MoCA), activities of daily living (ADL), and plasma biomarkers (GFAP, NfL, p-tau181, p-tau217, Aβ42/40). Statistical analyses involved intergroup comparisons (Chi-square and Kruskal-Wallis tests), Spearman correlation analysis between dementia severity/TCM patterns and clinical measures, logistic regression to examine factors associated with disease severity, and exploratory ROC analysis to describe discriminatory performance within this development sample.

RESULTS: Across the three CDR-defined severity groups (n = 236), MMSE, MoCA, ADL and estimated symptom duration differed significantly (p < 0.05, q < 0.05). Dementia severity correlated strongly with MMSE (r = -0.779), MoCA (r = -0.785) and ADL (r = 0.742) (p < 0.001), and only weakly with estimated symptom duration (r = 0.384, p < 0.001). TCM syndrome distribution patterns differed across severity stages, with kidney essence deficiency being most prevalent in the early-stage group (48%), Phlegm-stasis in the moderate group (54.5%), and Heat-toxin in the severe group (60.5%). In multivariable multinomial logistic regression (reference: early-stage AD), MMSE and ADL scores were associated with AD severity (MMSE: moderate vs. early, OR = 0.844, 95% CI 0.774-0.921; severe vs. early, OR = 0.485, 95% CI 0.351-0.671; ADL: moderate vs. early, OR = 1.128, 95% CI 1.065-1.196; severe vs. early, OR = 1.280, 95% CI 1.150-1.425; all p < 0.001). Among TCM syndrome elements, Heat-toxin was associated with both moderate and severe AD (Moderate vs. Early-stage: OR = 1.177, 95% CI 1.046-1.324, p = 0.007; Severe vs. Early-stage: OR = 1.498, 95% CI 1.205-1.861, p < 0.001) and Phlegm-stasis with moderate AD only (OR = 1.198, 95% CI 1.079-1.329, p = 0.001). In an exploratory ROC analysis, single indicators showed modest discriminatory performance for Heat-toxin syndrome, with CDR (AUC = 0.709) > ADL (AUC = 0.690) > MMSE (AUC = 0.683), whereas AUCs for Kidney deficiency (≤0.633) and Phlegm-stasis (≤0.581) were close to chance. In a sensitivity analysis excluding participants with CDR 0.5 (n = 186), the cognitive, functional and Heat-toxin associations were essentially unchanged, but the Phlegm-stasis score was associated with both moderate and severe AD, with comparable effect sizes (Moderate vs. Early-stage: OR = 1.26, 95% CI 1.12-1.42, p < 0.001; Severe vs. Early-stage: OR = 1.25, 95% CI 1.02-1.54, p = 0.032), indicating that its restriction to moderate AD was not robust.

DISCUSSION: In this cross-sectional single-center sample, TCM syndrome distributions and scores differed across concurrent CDR-defined severity groups, with kidney essence deficiency predominating in early-stage AD (48.0%), Phlegm-stasis in moderate AD (54.5%), and Heat-toxin in severe AD (60.5%). Heat-toxin scores were associated with greater concurrent cognitive and functional impairment, whereas plasma biomarkers showed limited and inconsistent associations. These findings do not establish temporal syndrome transitions or validated diagnostic utility outside this development sample, but provide hypothesis-generating evidence for future prospective investigations.},
}

@article {pmid42964137,
year = {2026},
author = {Mole, SS and Dwivedi, PSR and Lobo, WL and Shastry, CS and Khanal, P},
title = {Trans-anethole attenuates streptozotocin-induced cognitive dysfunction by modulating oxidative stress and cholinergic activity.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1954658},
pmid = {42964137},
issn = {1663-9812},
abstract = {INTRODUCTION: Cognitive impairment is a neurological disorder defined as an inability to learn, think, judge, remember, and make decisions. The primary cause of chronic, age- related cognitive decline is Alzheimer's disease (AD), which is frequently studied as a representative model. The current therapies for AD provide only symptomatic relief, which necessitates the need for safer, multi-target treatments. Trans- anethole, the primary constituent of Illicium verum, Pimpinella anisum, and Foeniculum vulgare, is an aromatic molecule that possesses several pharmacological activities, including anti-inflammatory and antioxidant effects, which may have neuroprotective benefits.

METHODS: The current study integrated in silico, in vitro, and in vivo approaches to examine the neuroprotective potential of trans- anethole. In silico studies were carried out to find out the potential molecular targets and pathways associated with the effects of trans-anethole against AD- related cognitive dysfunction. Cytotoxicity, antioxidant activity, and cholinesterase inhibition were assessed in vitro on BV2 cells. Intracerebroventricular (ICV) administration of streptozotocin (STZ: 3 mg/kg) in rats induces an insulin-resistant brain state leading to progressive cognitive and memory impairment, a condition that closely relates to sporadic Alzheimer's disease. ICV-STZ-induced Wistar rats were used to assess the effect of trans- anethole on AD-related cognitive dysfunction through behavioral, biochemical, and histopathological assessments.

RESULTS: A total of 174 common targets were identified, enriching pathways including apoptosis, AGE-RAGE, TNF, and PI3K- Akt signaling. Stable interactions were observed in molecular docking and molecular dynamics simulations. Trans-anethole demonstrates moderate cholinesterase inhibition and antioxidant activity in BV2 cells. Comparing STZ- treated rats to disease control, trans-anethole at doses of 100 mg/kg and 400 mg/kg significantly reduced lipid peroxidation, restored antioxidant enzyme levels, and attenuated cholinergic dysfunction. Histopathological findings showed qualitative preservation of hippocampal neuronal morphology.

DISCUSSION: Overall, these findings suggest that trans-anethole may represent a potential neuroprotective preclinical candidate for further investigation in Alzheimer's disease-related cognitive dysfunction.},
}

@article {pmid42964287,
year = {2026},
author = {Wang, K and Goel, D and Shi, JM and Rodriguez, VJ and Brown, DS and Yoo, DW and Karkar, R and Saha, K},
title = {A Taxonomy of Mental Health and Technology Needs for Alzheimer's and Dementia Caregivers.},
journal = {Ageing international},
volume = {51},
number = {4},
pages = {47},
pmid = {42964287},
issn = {0163-5158},
abstract = {UNLABELLED: Family members caring for individuals with Alzheimer's disease and related dementias (AD/ADRD) provide the foundation of long-term care worldwide. In 2023, more than 11 million U.S. family and friends contributed 18 billion hours of unpaid care, often at the cost of their own physical and mental health. These informal caregivers-also referred as the "invisible second patients"-experience elevated rates of mental health problems. Yet research commonly reduces their complex psychosocial experiences to a single construct of caregiver burden, obscuring which specific needs are unmet or effectively supported. At the same time, digital and AI-enabled technologies are rapidly expanding, from smartphone apps and videoconferencing to sensor platforms and AI chatbots. However, the absence of shared frameworks across medicine, psychology, and technology research limits cumulative progress. This study introduces a Caregiver Mental Health and Technology Taxonomy that systematically links AD/ADRD caregiver needs with corresponding classes of technology-based interventions. Drawing from an interdisciplinary literature review and two qualitative studies with caregivers, the taxonomy identifies mismatches between caregiver priorities and existing technological support, highlights under-served domains such as relational strain and compassion fatigue, and proposes design directions for adaptive, responsive systems. The framework offers a shared vocabulary to guide clinicians, researchers, and technology designers in developing more person-centered and clinically grounded innovation in dementia care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12126-026-09686-4.},
}

@article {pmid42964420,
year = {2026},
author = {Terman, SA},
title = {A newly defined substage of late-stage Alzheimer's disease, the "Dementia Gap": Can sedation to unconsciousness to relieve patients' intolerable suffering be moral?.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261460085},
doi = {10.1177/25424823261460085},
pmid = {42964420},
issn = {2542-4823},
abstract = {Advanced Alzheimer's disease is a terminal illness causing more intense, prolonged suffering than clinicians generally recognize. At least 500,000 Americans are trapped in the "Dementia Gap", a previously unidentified substage of advanced dementia. Patients lack capacity to voluntarily stop eating and drinking but can still eat and drink independently, making "dementia-specific" living wills ineffective until further disease progression requires assistance with oral feeding and hydrating. Additionally, patients experience "Non-Observable Suffering": inner emotional angst, inexpressible physical pain, and bi-directional suffering shared with loved ones. A dangerous non sequitur fallacy can lead casual observers to extrapolate peaceful inner states from withdrawn external behavior: "She's not suffering; she's just sitting there." To effectively relieve intolerable suffering, this article introduces "Moderate Anesthesia"-palliative sedation to unconsciousness modified to be clearly distinguishable from euthanasia. Cases demonstrate moral justification grounded in Sulmasy's "Reinvented Rule of Double Effect," "Parsimonious Direct Sedation," or the Principle of Proportionality. Two Dementia Gap patients the author treated are compared with two advanced cancer patients. Two withdrawn patients "awakened" through skillful interviewing, exemplifying this ethical warning: diligent efforts to detect and relieve non-observable suffering should precede implementing treatments of last resort. The article presents the "Three-Source Concordance" protocol using an illustrated patient decision aid and polling Patient Decision Committee members' substituted judgments to confirm the clinical appropriateness of implementing POLSTs that patients completed during advance care planning. A 42% cumulative lifetime dementia risk means many of us may reach the Dementia Gap. Launching the ARISE movement-Advocate by Recognizing and Investigating Suffering's (hidden) Existence-and convening expert panels to develop practice guidelines are moral imperatives.},
}

@article {pmid42964515,
year = {2026},
author = {Iulita, MF and Kolachalama, VB and Brugada-Ramentol, V and Harrison, J and Griffin, N and Benavides, GS and Vera-Campuzano, E and Minguillon, C and Alcolea, D and Mackintosh, L and Ward, L and Merino, AT and Balasa, M and Ishida, S and Rivera, OG and Calvet, MS and Robertson, J and Doecke, J and Mas, CP and Fallone, S and Charvat, M and Tarnanas, I and Jones, M and Streel, E},
title = {A multimodal digital NeuroMarker platform with composite and domain-level validity for identification of mild cognitive impairment: a cross-sectional study.},
journal = {EClinicalMedicine},
volume = {101},
number = {},
pages = {104266},
doi = {10.1016/j.eclinm.2026.104266},
pmid = {42964515},
issn = {2589-5370},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a clinically heterogeneous syndrome that can represent an early manifestation of neurodegenerative disease. Diagnosis relies on assessments that are difficult to scale, leaving many individuals unidentified.

METHODS: In this cross-sectional study conducted in the United States, Australia, and Spain between May 2022 and October 2024, 638 adults aged ≥ 50 years were classified as cognitively unimpaired (CU; n = 441) or MCI (n = 197) using Petersen/NIA-AA criteria. Participants completed a self-administered, tablet-based assessment (Altoida NeuroMarker Platform) integrating motor, speech, and augmented reality tasks. An XGBoost classifier was trained to distinguish CU from MCI. Diagnostic performance, test-retest reliability, and convergent validity were evaluated.

FINDINGS: Median assessment time was 13.8 min. Participants reported comfort with digital technology (67%), willingness to engage in cognitive screening (90%), and positive usability. Altoida's NeuroMarker differentiated MCI with ROC-AUC 0.90, 95% CI 0.88-0.92 and comparable performance in an independent cohort (ROC-AUC 0.87, 95% CI 0.80-0.93; n = 75). Cognitive composite and domain scores were lower in MCI than in CU. Classifier agreement across repeated assessments was κ = 0.60, and reliability of composite and domain scores was moderate-to-good (ICC 0.55-0.80). The composite score correlated with the Mini-Mental State Examination (MMSE) (r s = 0.40, p < 0.001) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Index (r s = 0.58, p < 0.001). The platform also showed convergent validity of cognitive domains (|r s| = 0.27-0.50, p < 0.001).

INTERPRETATION: A brief, self-administered multimodal assessment identified clinically adjudicated MCI and demonstrated convergent validity, test-retest reliability, and consistent performance in an independent cohort. Prospective studies should evaluate its implementation in real-world workflows.

FUNDING: Alzheimer's Drug Discovery Foundation; Altoida Inc.},
}

@article {pmid42964735,
year = {2026},
author = {Ghiasvand, K and Meftahi, GH},
title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102850},
doi = {10.1016/j.bbrep.2026.102850},
pmid = {42964735},
issn = {2405-5808},
abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.},
}

@article {pmid42964793,
year = {2026},
author = {Šišić, N and Barakovic, M and Edde, M and Théberge, A and Beaudoin, AM and Dumbia, M and Lapointe, E and Descoteaux, M and Magon, S and Gobbi, S},
title = {Agreement and longitudinal repeatability of established brain volumetry pipelines across healthy controls, multiple sclerosis, and Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1917471},
doi = {10.3389/fnins.2026.1917471},
pmid = {42964793},
issn = {1662-4548},
abstract = {INTRODUCTION: Brain volume estimates are increasingly used as longitudinal endpoints in neuroimaging studies and clinical trials, but outputs from different segmentation pipelines may not be interchangeable. In this study, we performed a version-specific comparison of six established brain segmentation pipelines across healthy controls (HC; n = 20), people with multiple sclerosis (MS; n = 19), and people with Alzheimer's disease (AD; n = 50).

METHODS: FreeSurfer v6, FreeSurfer v7.2, SAMSEG, FastSurfer v1, SIENAX/SIENA-XL, and CAT12 were evaluated. The primary aims were to quantify systematic offsets and inter-pipeline agreement in normalized baseline volume estimates, assess within-pipeline repeatability and longitudinal change-from-baseline concordance, and determine whether longitudinal processing reduced variability relative to cross-sectional processing. Gray matter, white matter, hippocampus, and thalamus were selected and normalized to intracranial volume. Agreement was assessed using intraclass correlation coefficients, while longitudinal change was evaluated using mixed-effects models and repeatability metrics.

RESULTS: Baseline volume estimates differed significantly across pipelines in 11 of 12 cohort-by-tissue comparisons (FDR-adjusted p < 0.001), with the largest pipeline-dependent offsets observed for grey matter, hippocampus, and thalamus. Inter-pipeline agreement was generally strong for white matter and lower for gray matter and subcortical structures (hippocampus and thalamus), particularly in pathological cohorts. Change-from-baseline models showed no significant Pipeline × Timepoint interactions after FDR correction, indicating broadly parallel longitudinal trajectories across pipelines after baseline normalization. However, significant pipeline main effects persisted in selected tissues, especially in AD and subcortical regions, indicating residual differences in the magnitude of estimated change. Longitudinal processing reduced within-subject variability in selected settings, particularly for FreeSurfer-derived hippocampal and thalamic estimates, but did not uniformly improve stability across all pipelines or tissues.

DISCUSSION: Together, these findings show that systematic offset, absolute agreement, longitudinal change magnitude, and short-interval repeatability represent distinct properties of volumetric pipelines and vary by tissue, cohort, and processing mode. Longitudinal processing reduced variability but not uniformly, highlighting pipeline- and tissue-dependent differences relevant to the interpretation of longitudinal volumetric measurements.},
}

@article {pmid42964797,
year = {2026},
author = {Gaggi, NL and Hurwitz, B and Bernal, J and O'Brien, C and Ren-Fielding, C and Lofton, H and Chen, J and Saperstein, A and Lee, SH and Chang, YJ and Yates, KF and Fieremans, E and Osorio, R and Convit, A},
title = {Brain and Cardiometabolic Effects of Major Weight Loss in People With Obesity: Preliminary Cohort Findings.},
journal = {Obesity science & practice},
volume = {12},
number = {6},
pages = {e70191},
doi = {10.1002/osp4.70191},
pmid = {42964797},
issn = {2055-2238},
abstract = {OBJECTIVE: Given the overlap between obesity-related metabolic and vascular abnormalities and Alzheimer's disease (AD) risk factors, it is critical to determine whether weight loss improves brain and cardiovascular health. This study examined whether ≥ 40% excess-weight loss is associated with improvements in cardiometabolic risk, brain structure, and cognition.

METHODS: The study was a longitudinal study of individuals with obesity undergoing metabolic and bariatric surgery or medical/behavioral weight-loss treatment. Participants were classified at follow-up as weight-loss (WL; ≥ 40% excess-weight loss) or non-weight-loss (nWL; < 40%). All completed medical evaluations, structural MRI, and cognitive testing at baseline and 1 year.

RESULTS: At 1 year, the WL group exhibited improvements in BMI, HbA1C, inflammatory, metabolic, and lipid profiles. MRI-based volumetrics revealed increases in subcortical gray-matter volume and preservation of AD-vulnerable regions. Cognitive performance remained unchanged.

CONCLUSIONS: Achieving ≥ 40% excess-weight loss was associated with improvements in metabolic health and brain structure, including favorable subcortical volume increases. These findings underscore the potential of sustained weight reduction to mitigate risks linked to metabolic syndromes and neurodegeneration. Longer-term follow-up is warranted to determine whether continued metabolic improvements lead to detectable cognitive gains and additional brain-health benefits beyond 1 year.},
}

@article {pmid42964963,
year = {2026},
author = {Zhang, C and Liu, X and Fan, J and Li, W and Shi, J and Tian, M},
title = {Cerebellar Topological Alterations Across the Alzheimer's Disease Continuum.},
journal = {Psychiatry and clinical psychopharmacology},
volume = {36},
number = {4},
pages = {361-372},
doi = {10.65801/pcp.3523},
pmid = {42964963},
issn = {2475-0581},
abstract = {Background: Alzheimer's disease (AD) is characterized as a network disconnection syndrome. Despite evidence implicating the cerebellum in cognitive network integration, its associated electrophysiological network topology dynamics across the AD continuum remain unexplored. Methods: We enrolled 34 healthy controls (HC), 40 patients with mild cognitive impairment (MCI), and 30 AD patients in this study. Cortical and cerebellar signals were recorded with a whole-brain EEG cap, and weighted functional connectivity networks were constructed using the phase-locking value (PLV). Graph theory was used to analyze network topological metrics across the AD continuum, focusing on cerebellar nodes. Topological metrics were correlated with neuropsychological scores, and network-based statistics (NBS) identified differential connectivity patterns among groups. Results: Network changes were most prominent in the theta band, with additional alterations in the delta band. Both MCI and AD groups showed reduced small-world metrics, although small-world organization remained present. These groups also showed increased nodal centrality in the frontal, occipital and cerebellar regions (at CB1, CB2 and CBZ in MCI but only at CBZ in AD) but decreased in the central and temporal regions. NBS analysis identified selective theta-band reorganization of cerebello-cortical connectivity. An inverted U-shaped relationship was found between cerebellar nodal centrality and neuropsychological scale scores. Conclusions: The cerebellar theta rhythm may be a key pattern involved in cognitive processing, and the topological changes of the cortical-cerebellar network may represent candidate electrophysiological network markers across different AD stages. These markers may reflect stage-related differences in cerebellar function, shifting from compensation in MCI to decompensation in AD.},
}

@article {pmid42964993,
year = {2026},
author = {Blivet, G and Bertrand, C and Brauge, D and Delrieu, J and Touchon, J},
title = {Photobiomodulation as a regulator of neuroinflammation: mechanistic insights and therapeutic potential in brain disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1902491},
doi = {10.3389/fneur.2026.1902491},
pmid = {42964993},
issn = {1664-2295},
mesh = {Humans ; *Low-Level Light Therapy/methods ; *Neuroinflammatory Diseases/radiotherapy/metabolism ; Animals ; *Brain Diseases/radiotherapy/therapy/metabolism ; },
abstract = {Brain disorders, including neurodegenerative, neuropsychiatric, and cerebrovascular diseases, represent a growing global health challenge contributing to disability and mortality worldwide. Although these conditions differ in etiology and clinical presentation, accumulating evidence identifies neuroinflammation as a shared pathological mechanism. Involving microglial activation, astrocytic reactivity, cytokine dysregulation, oxidative stress, mitochondrial dysfunction, and blood-brain barrier disruption, it contributes to synaptic dysfunction, neuronal loss, and disease progression, yet therapeutic strategies targeting these processes remain limited. Photobiomodulation (PBM), the therapeutic application of low-intensity red to near-infrared light, has emerged as a neurotechnology capable of modulating biological pathways relevant to neuroinflammation. Preclinical studies suggest that PBM may influence mitochondrial activity through cytochrome c oxidase-mediated mechanisms, enhancing cellular metabolism while regulating reactive oxygen species, inflammatory signaling pathways, and tissue homeostasis. Through these effects, PBM may attenuate neuroinflammatory responses, regulate glial activation, and support neuroprotective processes across multiple neurological models. This narrative review examines evidence supporting neuroinflammation as a common denominator across major brain disorders and explores the biological rationale for PBM as a therapeutic strategy. It summarizes the cellular and molecular basis of PBM, its effects on neuroinflammatory pathways, and preclinical and clinical findings across brain disease models. Preclinical findings consistently support a multi-target anti-inflammatory effect, whereas clinical investigation remains at an early stage, with encouraging results in Alzheimer's disease and multiple sclerosis but mainly negative data on primary outcomes in Parkinson's disease and major depressive disorder. Further research is needed to optimize treatment parameters, clarify mechanisms of action, and determine clinical efficacy across disease contexts.},
}

Humans
*Low-Level Light Therapy/methods
*Neuroinflammatory Diseases/radiotherapy/metabolism
Animals
*Brain Diseases/radiotherapy/therapy/metabolism

@article {pmid42965095,
year = {2026},
author = {Cao, M and Leng, L and Liu, P and Fan, Z and Peng, G},
title = {Rapidly Progressive Alzheimer's Disease: Candidate Mechanisms and Diagnostic Challenges.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {638910},
doi = {10.2147/CIA.S638910},
pmid = {42965095},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/diagnosis/pathology ; Biomarkers/blood ; Disease Progression ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD) usually follows a slowly progressive course, but some patients experience unusually rapid cognitive and functional decline. This clinical phenotype, commonly termed rapidly progressive Alzheimer's disease (rpAD), has no consensus definition; its status as a distinct biological entity remains unresolved, and its reported frequency depends strongly on operational criteria and referral settings. To synthesize current evidence, we conducted targeted literature searches (up to August 31, 2026) of clinical, neuropathological, and biomarker studies. This narrative review extends earlier overviews by integrating newer genetic, tau-seeding, and blood-biomarker findings with conflicting clinical evidence, while distinguishing candidate mechanisms from established diagnostic tools. Selected autopsy and biomarker studies suggest differences in amyloid-β and tau conformations, synaptic and mitochondrial proteins, neuroinflammatory responses, and concomitant pathologies; however, most data are associative, derive from small or selected cohorts, and do not establish rpAD as a discrete disease subtype. In practice, evaluation should confirm AD pathology while promptly excluding treatable causes and rapidly progressive mimics, particularly Creutzfeldt-Jakob disease (CJD), using established tools such as cerebrospinal fluid biomarkers, MRI, and PrP RT-QuIC. Cerebrospinal fluid, molecular imaging, structural MRI, and emerging blood biomarkers can provide supportive evidence, but no biomarker profile has been prospectively validated as an rpAD-specific diagnostic rule. Harmonized definitions and prospective, biomarker-stratified multicenter validation are required before candidate mechanisms or biomarkers can guide rpAD-specific interventions.},
}

Humans
*Alzheimer Disease/diagnosis/pathology
Biomarkers/blood
Disease Progression
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Magnetic Resonance Imaging

@article {pmid42965512,
year = {2025},
author = {Calderón-Garcidueñas, L and Cejudo-Ruiz, FR and Torres-Jardón, R},
title = {The olfactory bulb, prefrontal and anterior cingulate cortex are early pediatric targets for anthropogenic magnetic nanoparticles and their motion behavior under electromagnetic fields.},
journal = {Gaceta medica de Mexico},
volume = {162},
number = {2},
pages = {213-222},
doi = {10.24875/GMM.M26001158},
pmid = {42965512},
issn = {0016-3813},
mesh = {Humans ; *Electromagnetic Fields/adverse effects ; *Prefrontal Cortex/pathology ; *Olfactory Bulb/pathology ; Child ; *Gyrus Cinguli/pathology/drug effects ; Mexico ; *Magnetite Nanoparticles ; Male ; Female ; Microscopy, Electron, Transmission ; Spectrometry, X-Ray Emission ; Particulate Matter ; },
abstract = {BACKGROUND: Alzheimer's, Parkinson's, and fronto-temporal lobar degeneration neuropathology hallmarks are present in young urbanites exposed to fine particulate matter (PM2.5), ultrafine PM (UFPM), and nanoparticles (NPs). Metals associated with deteriorated automobile catalysts, diesel motor emissions, brake-pads dust, and electronic waste, including rare earth elements, are entering children's brains. Cognition deficits and brain structural and volumetric changes by magnetic resonance are documented in Metropolitan Mexico City (MMC) children.

OBJECTIVES: The objectives of the study are to identify ferromagnetic materials and their motion behavior upon exposure to magnetic fields 25-1,000 mT AC in 48 brain samples including olfactory bulbs, anterior cingulate, and prefrontal cortex.

MATERIAL AND METHODS: Using magnetophoresis, we identified small displacements and significant magnetic vector direction variations in magnetic particles. Transmission electron microscopy and energy-dispersive X-ray spectrometry identified the location and composition of the ferrimagnetic NPs.

RESULTS: MMC brain samples from 12 children 8.5 ± 7.6 years and 16 adults 39.2 ± 19.6 year showed ferrimagnetic NPs with magnetic motion behavior possessing organelle and soluble protein risk for neural damage, olfactory deficits, and neuropsychiatric burden, common early neurodegenerative manifestations.

CONCLUSION: Critical brain areas are damaged in early pediatric ages and neurodegeneration is in progress in MMC young urbanites at high risk of poor academic performance. Environmental MMC UFPM/NPs controls are needed.},
}

Humans
*Electromagnetic Fields/adverse effects
*Prefrontal Cortex/pathology
*Olfactory Bulb/pathology
Child
*Gyrus Cinguli/pathology/drug effects
Mexico
*Magnetite Nanoparticles
Male
Female
Microscopy, Electron, Transmission
Spectrometry, X-Ray Emission
Particulate Matter

@article {pmid42965578,
year = {2026},
author = {Kumar, A and He, Y and Kim, S and Hsu, FC and Meade, CS and Kiraly, DD and Strowd, R and Lesser, GJ and Deep, G},
title = {Longitudinal plasma protein profiling in glioblastoma patients using NULISAseq reveals treatment-associated changes across radiation and chemotherapy.},
journal = {Journal of neuro-oncology},
volume = {180},
number = {2},
pages = {},
pmid = {42965578},
issn = {1573-7373},
mesh = {Humans ; *Glioblastoma/blood/therapy/radiotherapy/pathology/drug therapy ; *Brain Neoplasms/blood/therapy/radiotherapy/drug therapy/pathology ; Female ; *Temozolomide/therapeutic use ; Male ; *Proteomics/methods ; *Biomarkers, Tumor/blood ; Longitudinal Studies ; Middle Aged ; Antineoplastic Agents, Alkylating/therapeutic use ; Chemoradiotherapy ; Aged ; Adult ; },
abstract = {PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumor with poor outcomes despite surgery, radiotherapy (RT), and temozolomide (TMZ). Monitoring relies on imaging, which is confounded by pseudoprogression and provides limited molecular insight. Circulating biomarkers may offer a minimally invasive approach to track disease and treatment effects.

METHODS: We performed targeted longitudinal proteomic profiling of plasma from post-surgery GBM patients (n = 11) at baseline (pre-radiotherapy (RT)), after RT with concomitant TMZ, and after adjuvant TMZ, alongside healthy controls (n = 15), using the NULISAseq CNS panel covering 131 proteins related to neurodegeneration, neuroinflammation, and vascular health. Differential expressions were assessed using volcano plots, hierarchical clustering, paired statistical comparisons and longitudinal trends analysis.

RESULTS: At baseline, GBM plasma showed elevated markers of neuroaxonal and glial injury, extracellular matrix regulators, and inflammatory signaling compared to controls. Several established neurodegeneration and Alzheimer's disease- related biomarkers were also higher in GBM plasma versus controls. Following radiotherapy and concomitant TMZ, cytokines including IL10, IL5, and IL33 increased, indicating systemic immune activation, while BDNF showed a modest decline. Adjuvant TMZ treatment attenuated radiotherapy-induced cytokine elevations and reduced neuronal injury markers, suggesting therapy-driven reduction of inflammatory and neurodegenerative signals. Longitudinal analysis confirmed dynamic shifts in specific proteins across baseline, radiotherapy, and TMZ phases.

CONCLUSION: High-sensitivity plasma proteomics suggested therapy-induced changes in CNS-specific and immune markers in GBM, highlighting candidate biomarkers that can be further developed for real-time monitoring of treatment response. These findings suggest candidate circulating markers that may complement imaging for monitoring disease biology and therapeutic response, and warrant validation in larger cohorts.},
}

Humans
*Glioblastoma/blood/therapy/radiotherapy/pathology/drug therapy
*Brain Neoplasms/blood/therapy/radiotherapy/drug therapy/pathology
Female
*Temozolomide/therapeutic use
Male
*Proteomics/methods
*Biomarkers, Tumor/blood
Longitudinal Studies
Middle Aged
Antineoplastic Agents, Alkylating/therapeutic use
Chemoradiotherapy
Aged
Adult

@article {pmid42965647,
year = {2026},
author = {Van Skike, CE and DeRosa, N and Galvan, V and Hussong, SA},
title = {Correction to: Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11357-026-02609-w},
pmid = {42965647},
issn = {2509-2723},
}

@article {pmid42965704,
year = {2026},
author = {Labonte, J and Miner, AE and Groh, JR and Montoliu-Gaya, L and Tripodis, Y and Aparicio, HJ and Turk, KW and Budson, AE and Farrer, L and Goldstein, LE and Qiu, WQ and Mez, J and McKee, AC and Zetterberg, H and Stein, TD and Gobom, J and Ashton, NJ and Alosco, ML},
title = {Leveraging immunoprecipitation mass spectrometry and neuropathology to identify the clinical value of different blood tau species in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42965704},
issn = {1432-1459},
support = {P30AG072978/AG/NIA NIH HHS/United States ; 1UL1TR001430//BU-CTSI/ ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; AF-1032107//Alherimerfonden/ ; 22HLT07//European Partnership on Meterology/ ; 2025-373//Stiftelsen för Gamla Tjänarinnor/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/pathology ; Female ; Male ; Cross-Sectional Studies ; Biomarkers/blood ; Mass Spectrometry/methods ; Aged ; Immunoprecipitation ; Phosphorylation ; Aged, 80 and over ; *Brain/pathology ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Advances in plasma-based assays have allowed for the study of several tau and p-tau epitopes. P-tau217 has emerged as one of the most robust markers of Alzheimer's disease (AD) pathology. Despite their strong diagnostic performance, plasma tau biomarkers require further validation to clarify their clinical utility.

OBJECTIVE: To investigate the associations between a panel of phosphorylated and non-phosphorylated tau species measured in antemortem plasma and clinical features of autopsy-confirmed AD.

METHODS: Cross-sectional data from 123 participants from the BU ADRC who had antemortem blood draws and brain donation following death. Participants completed neuropsychological testing during life as part of their National Alzheimer's Coordinating Center-Uniform Data Set (NACC UDS) evaluation. AD neuropathology was diagnosed using NIA-Reagan criteria. Time interval between testing at last visit and autopsy ranged from 0 to 12 years, mean = 5.54 years. Raw neuropsychological test scores were used for analysis. Sample size ranged from 65 to 91 across the tests. Plasma samples were analyzed using immunoprecipitation mass spectrometry (IP-MS) for phosphorylated tau species (p-tau-181, 199, 202, 205, 217, 231) and non-phosphorylated tau (195-209, 212-221) peptides. Two ratios were analyzed, p-tau217/tau212-221 and p-tau205/tau195-209.

RESULTS: 123 participants took part in this study, 55 (44.7%) female, and 6 (4.9%) Black/African American. The mean (SD) age at blood draw was 78.17 (8.55). The strongest association between plasma biomarkers with neuropsychological test outcomes was observed with the ratio p-tau217/tau212-221 (b = - 0.564-0.404, plow-high = 0.00-0.18), followed by p-tau217 (b = - 0.478-0.377, plow-high = 0.00-0.28), both significantly correlating with six of the eight neuropsychological measures (p < 0.05). Followed by the ratio p-tau205/tau195-209 (b = - 0.513-0.356, plow-high = 0.00-0.55), p-tau205 (b = - 0.365-0.226, plow-high = 0.00-0.44), then p-tau231 (b = - 0.319-0.237, plow-high = 0.02-0.62). Fewer significant relationships and weaker effect sizes were observed among the other biomarkers. The effect sizes of the ratio p-tau217/tau212-221, followed closely by p-tau217 on neuropsychological test outcomes, were observed to be the most similar to the effect sizes of autopsy-confirmed AD (b = - 0.564-0.393).

CONCLUSIONS: Plasma p-tau217 and p-tau ratios were comparable to autopsy-confirmed AD in predicting clinical outcomes of AD. This study highlights the promise and potential utility of plasma biomarkers for symptom monitoring.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/pathology
Female
Male
Cross-Sectional Studies
Biomarkers/blood
Mass Spectrometry/methods
Aged
Immunoprecipitation
Phosphorylation
Aged, 80 and over
*Brain/pathology
Neuropsychological Tests

@article {pmid42965717,
year = {2026},
author = {Kaur, A and Goel, RK},
title = {Revealing Pharmacological Target for Comorbid Epilepsy in Alzheimer's Disease: Neurochemical Insights from STZ Mice.},
journal = {Neurochemical research},
volume = {51},
number = {6},
pages = {},
pmid = {42965717},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/metabolism/chemically induced/drug therapy/complications ; *Epilepsy/metabolism/drug therapy/chemically induced ; Streptozocin/toxicity ; Mice ; Male ; Oxidative Stress/drug effects/physiology ; Maze Learning/drug effects ; Acetylcholinesterase/metabolism ; Brain/metabolism/drug effects ; Kindling, Neurologic/drug effects ; Pentylenetetrazole ; },
abstract = {Despite growing evidences of shared neurochemical alterations linked to comorbid epilepsy in AD, effective unified therapeutic strategies remain lacking. Thus, the present investigation was designed to identify shared neurochemical changes associated with lowered convulsive threshold in STZ (streptozotocin) model of AD-type dementia to pharmacologically address this comorbidity. Swiss albino mice were injected STZ (3 mg/kg, ICV) to induce AD-like pathology. On day 22nd, STZ mice were divided into two groups: one group served as AD control (STZ) and another group (STZ + PTZ) received PTZ (35 mg/kg) kindling to assess the reduced epileptogenesis threshold while naïve served as negative control. One more group was involved as epileptic control (PTZ). All groups underwent behavioral assessment using elevated plus maze, novel object recognition test and radial arm maze. Mice were euthanized on day 48th to collect the brain samples. The brain homogenate was used to assess redox status (GSH, TBARS and ROS), acetylcholinesterase (AChE) activity, amyloid and tau protein expression, histological alterations for specific disease pathology. As well as for neurochemical analysis to assess the shared neurochemical targets associated with comorbid epilepsy in AD. STZ mice were subjected to PTZ kindling exhibited significant greater seizure severity. The kindled status achieved by the sixth injection of PTZ, indicating reduced epileptogenic threshold. Behavioural results indicated significant cognitive impairment in STZ + PTZ treated mice compared with naive mice in EPM, NORT and RAM test. Significantly increased oxidative stress and cholinergic dysfunctions observed in STZ + PTZ mice. Neurochemical analysis revealed augmented excitatory neurotransmitter levels, along with declined glycine, GABA, taurine and arginine in STZ + PTZ mice. Moreover, reduced levels of monoamines and their metabolites reflect cognitive deficits in STZ and STZ + PTZ mice. This increased susceptibility to seizures was accompanied by significantly increased oxidative stress and excitatory neurotransmission in STZ + PTZ mice. Collectively, these observations suggest that AD related neurodegeneration may predispose to epileptogenesis further aggravate neurochemical changes. Our findings suggest that taurine, arginine and monoamines may serve as a shared neurochemical target for comorbid epilepsy in AD-type dementia.},
}

Animals
*Alzheimer Disease/metabolism/chemically induced/drug therapy/complications
*Epilepsy/metabolism/drug therapy/chemically induced
Streptozocin/toxicity
Mice
Male
Oxidative Stress/drug effects/physiology
Maze Learning/drug effects
Acetylcholinesterase/metabolism
Brain/metabolism/drug effects
Kindling, Neurologic/drug effects
Pentylenetetrazole

@article {pmid42965728,
year = {2026},
author = {Watkinson, B and Bast, T and Williams, S and Bourgade, K and Garcia-Rates, S and Hasan, S and Greenfield, S},
title = {Intracerebral Administration of a Novel, Bioactive Peptide Induces a Biochemical Profile in Rat Brain Reminiscent of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {6},
pages = {},
pmid = {42965728},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/metabolism/chemically induced/pathology ; Male ; *Brain/drug effects/metabolism/pathology ; Rats ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Peptides/administration & dosage ; Injections, Intraventricular ; Acetylcholinesterase/metabolism ; *Peptide Fragments/administration & dosage ; },
abstract = {Alzheimer's disease (AD) presents a great unmet clinical need, but the much needed replication of the characteristic neuropathology in animal models has had limited success. Here, we provide in vivo evidence that T30, a bioactive peptide posited to drive AD, can induce in the rat brain a biochemical profile resembling AD pathology. Bilateral microinfusions of T30 into the medial septum/vertical diagonal band were administered twice a week for three weeks in rats. Although there was no effect on locomotor activity, novel object recognition and watermaze delayed-matching-to-place performance, T30 infusion reduced weight growth in the rats. Post mortem immunohistochemistry showed that T30 increased the AD biomarkers amyloid beta and phosphorylated tau in the cortex, hippocampus, and midbrain. Significant neuronal loss, indicated by reduced NeuN[+] staining, was observed in brain tissue pooled from neocortex, hippocampus and midbrain. Further analysis showed a strong correlation between the 14mer T14, the active component of T30, and levels of its parent molecule acetylcholinesterase. However, this correlation only applied to protein levels, not enzymatic activity, suggesting independence from cholinergic transmission. Together, these findings support a non-cholinergic, peptide-driven mechanism by which T30 contributes to Alzheimer's-like neurodegeneration.},
}

Animals
*Alzheimer Disease/metabolism/chemically induced/pathology
Male
*Brain/drug effects/metabolism/pathology
Rats
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Peptides/administration & dosage
Injections, Intraventricular
Acetylcholinesterase/metabolism
*Peptide Fragments/administration & dosage

@article {pmid42965774,
year = {2026},
author = {Takahashi, R and Ikegami, S and Iseki, C and Nakajima, M and Oishi, K and Ishii, K},
title = {Anatomical VOI-based assessment of the three DESH components in probable idiopathic normal pressure hydrocephalus.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42965774},
issn = {1867-108X},
abstract = {PURPOSE: To evaluate whether anatomical volume-of-interest (VOI) thresholds derived from a SINPHONI-2 reference cohort could provide standardized component-wise quantification of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in a separate clinical cohort.

MATERIALS AND METHODS: Thresholds were derived from 61 SINPHONI-2 cases using a prespecified mildest-case rule and applied without re-optimization to 33 participants with probable idiopathic normal pressure hydrocephalus (iNPH), 26 with Alzheimer disease, 18 with progressive supranuclear palsy, and 20 normal controls. DESH metric-S summed binary positivity for ventriculomegaly, Sylvian fissure enlargement, and tight high-convexity and medial sulci; DESH metric-I was defined as (Sylvian fissure volume + lateral ventricular volume)/high-convexity and medial sulcal volume. Evans index and callosal angle were evaluated as conventional imaging measures.

RESULTS: For iNPH versus pooled non-iNPH, DESH metric-S had an area under the curve (AUC) of 0.958 (95% CI, 0.921-0.990), sensitivity of 97.0% (84.7-99.5%), and specificity of 92.2% (83.0-96.6%). DESH metric-I had an AUC of 0.995 (95% CI, 0.983-1.000), sensitivity of 100.0% (89.6-100.0%), and specificity of 93.8% (85.0-97.5%).

CONCLUSION: Anatomical VOI-based measures provided standardized component-wise quantification of DESH morphology. DESH metric-S retained the status of each component, whereas DESH metric-I provided a continuous summary. Because DESH contributed to probable-iNPH classification, the observed discrimination reflects concordance with a DESH-supported classification rather than independent diagnostic accuracy for iNPH. External validation, including cohorts spanning incomplete/non-DESH morphology and treatment-response outcomes, is required before clinical or prognostic use.},
}

@article {pmid42966047,
year = {2026},
author = {Devi, B and Jangid, K and Temgire, P and Kumar, N and Thareja, S and Kumar, P and Kumar, V},
title = {Computationally driven design and validation of piperazine-bridged phthalimide derivatives as multifunctional agents against Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 3},
pages = {119417},
doi = {10.1016/j.ejmech.2026.119417},
pmid = {42966047},
issn = {1768-3254},
abstract = {A multi-target-directed ligand (MTDL) strategy has been proposed as an effective approach for treating complex multifactorial neurological disorders like Alzheimer's Disease. A 3D-QSAR pharmacophore model of piperazine derivatives against AChE was developed and validated (R[2] = 0.99 and Q[2] = 0.91). The best pharmacophore hypothesis model (AHR_1) was used to screen an in-house generated library of 188 phthalimide-piperazine derivatives, followed by structure-based virtual screening against the targeted enzymes. The docking scores of the identified eleven hit molecules were found to be better than the standard inhibitors, and MD simulations confirmed the stability of the compound-target complexes. As a proof of concept, the top hits were synthesized in the laboratory and evaluated for their inhibitory potential. Compound VPT-2 displayed IC50 values of 0.897 μM against AChE and 0.519 μM against MAO-B, while VPT-5 showed IC50 values of 3.45 μM against AChE and 1.074 μM against MAO-B, respectively. VPT-2 and VPT-5 inhibited Aβ1-42 self-aggregation significantly by 43.27 % and 43.28 %, respectively at a concentration of 20 μM, after 48 h. Additionally, an MTT assay using SH-SY5Y cells confirmed the safety of both the lead compounds up to 20 μM. Both compounds exhibited neuroprotective effects against 6-OHDA-induced neurotoxicity and significantly reduced intracellular ROS levels by 80-90 % at 5 μM. Thus, in this drug design strategy, CADD is integrated with in vitro experimental validation for the identification of phthalimide-piperazine derivatives as promising multi-target drug candidates for the treatment of Alzheimer's disease.},
}

@article {pmid42966163,
year = {2026},
author = {Gao, C and Shi, R and Jiang, X and Chai, H and He, X},
title = {Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126237},
doi = {10.1016/j.jns.2026.126237},
pmid = {42966163},
issn = {1878-5883},
abstract = {Neurodegenerative diseases (NDDs) are increasingly understood as multifactorial disorders characterized by intertwined pathological processes, in which metabolic dysfunction may act as a critical and potentially disease-amplifying contributor to the proteinopathy-driven pathological cascade. Despite growing recognition that microglial and astrocytic metabolism governs central nervous system tissue damage-repair homeostasis, intercellular metabolic crosstalk between glia and neurons remains insufficiently synthesized across major NDDs. This review delineates how core metabolic pathways, including glycolysis, mitochondrial respiration, lipid processing, and amino acid transport, shape glial reactivity in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We highlight glial metabolic reprogramming, a proposed theoretical framework arising from severe glial metabolic dysregulation. Within this framework, persistent pathological stress may drive reactive glia to sequester local energy substrates in excess, which is hypothesized to trigger bioenergetic failure in neighboring neurons. Broad-spectrum anti-inflammatory agents show poor clinical performance because they only block cytokine outputs rather than reverse glial metabolic exhaustion. Therapeutic efforts should therefore shift toward restoring glial metabolic flexibility. Cell-type-specific metabolic reprogramming, instead of pan-metabolic suppression, may circumvent systemic adverse effects. Precision strategies targeting such intercellular metabolic imbalance could provide promising cell-resolved metabolic avenues to retard NDD progression.},
}

@article {pmid42966413,
year = {2026},
author = {Li, C and Zhang, M and Xia, H and Zhi, X and Wang, N and Guo, J and Wang, K and Wang, L and Wang, X and Zhang, W},
title = {Reduced BNIP1 impairs autophagosome-lysosome fusion in hippocampal neurons and contributes to Alzheimer's disease pathology.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112186},
doi = {10.1016/j.brainresbull.2026.112186},
pmid = {42966413},
issn = {1873-2747},
abstract = {BNIP1 (BCL2‑interacting protein 1) belongs to the soluble N‑ethylmaleimide‑sensitive factor attachment protein receptor (SNARE) family. Statistical screening based on the Gene Expression Omnibus (GEO) dataset GSE48350 reveals reduced BNIP1 expression in patients with Alzheimer's disease (AD), suggesting that BNIP1 is a potentially key regulatory protein for investigating AD pathogenesis. In this study, we detected BNIP1 protein levels in APP/PS1 transgenic mice and APP‑overexpressing HT22 hippocampal neuronal cells, screened key interacting proteins of BNIP1 via mass spectrometry, and further performed gain‑ and loss‑of‑function assays using overexpression plasmids and small interfering RNA (siRNA) to verify the protein function of BNIP1. Our findings indicate that, in these experimental models, reduced BNIP1 expression contributes to AD‑related pathological alterations by impairing autophagosome‑lysosome fusion. Restoration of BNIP1 expression enhances Rab5b‑mediated Rab7 recruitment and consequently ameliorates autophagosome‑lysosome fusion. This study suggests that reduced BNIP1 expression is involved in AD‑related pathological alterations.NIP1 (BCL2-interacting protein 1) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family. Statistical screening based on the Gene Expression Omnibus (GEO) dataset GSE48350 reveals reduced BNIP1 expression in Alzheimer's disease (AD) patients, which renders BNIP1 a potentially key regulatory protein for investigating AD pathogenesis. In this study, we detected BNIP1 protein levels in APP/PS1 transgenic mice and APP-overexpressing HT22 hippocampal neuronal cells. Mass-spectrometry analysis was performed to screen key interacting proteins of BNIP1. Gain- and loss-of-function experiments were further conducted using overexpression plasmids and small interfering RNAs (siRNAs) to verify the protein function of BNIP1. Our findings indicate that decreased BNIP1 may act as an important contributing factor mediating AD-associated autophagosome-lysosome fusion defects in these experimental models. Restoration of BNIP1 expression enhances Rab5b-mediated Rab7 recruitment and consequently ameliorates aberrant autophagosome-lysosome fusion. This study suggests that BNIP1 serves as a potentially key regulatory protein for mechanistic research into Alzheimer's disease.},
}

@article {pmid42966482,
year = {2026},
author = {Li, J and Wang, Y and Liu, Y and Ji, Y and Lu, P and Yang, W and Zhang, S},
title = {Nanomedicine for Alzheimer's Disease: A Stage-Matched Framework Integrating Pathological Network Modulation, Blood-Brain Barrier Delivery, and Clinical Translation.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109709},
doi = {10.1016/j.phrs.2026.109709},
pmid = {42966482},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) remains one of the most difficult neurodegenerative disorders to treat. Therapeutic failure is driven mainly by two barriers: the multifactorial pathological network of AD and the limited access of most therapeutics to the brain imposed by the blood-brain barrier (BBB). Conventional symptomatic drugs and emerging antibody-based therapies provide clinical benefit, but they do not fully address the interacting processes involving amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic impairment. In this review, we discuss nanomedicine as an integrated platform for AD intervention. We summarize the major pathological nodes that provide targets for nanomedicine-based therapy and discuss BBB structure and transport mechanisms. We then compare polymeric, inorganic, carbon-based, lipid-based, protein-based, nucleic acid-based, and biomimetic platforms in terms of delivery function, intrinsic bioactivity, pathological modulation, and translational risk. Assisted brain-delivery strategies are also discussed, including focused ultrasound-mediated BBB modulation and intranasal nose-to-brain delivery. We then review clinical-stage AD nanomedicine candidates and summarize the key barriers to their translation. This review integrates stage-dependent pathology, BBB transport, and nanoplatform properties. It proposes a stage-matched framework for preclinical, mild symptomatic, and moderate-severe AD. At each stage, the framework matches active pathological nodes with feasible BBB transport strategies, carrier features, and administration routes. It may guide the development of mechanistically defined, reproducible, and clinically testable nanomedicines.},
}

@article {pmid42966483,
year = {2026},
author = {Liu, D and Li, P and Gao, Q and Liu, B and Li, W and Liu, X},
title = {SIRT1 Signaling in Alzheimer's Disease: Regulation of Mitochondrial Biogenesis and Therapeutic Implications.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109713},
doi = {10.1016/j.phrs.2026.109713},
pmid = {42966483},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is one of the leading causes of dementia worldwide. Its pathological features include Aβ deposition, Tau hyperphosphorylation, and impaired neuronal energy metabolism, accompanied by persistent oxidative stress. As a nicotinamide adenine dinucleotide (NAD[+])-dependent deacetylase, sirtuin 1 (SIRT1) is a central regulator of mitochondrial biogenesis. This review systematically examines the emerging roles of SIRT1 in regulating these pathological processes in AD, with a particular focus on its regulation of mitochondrial biogenesis. It also delineates the complex regulatory mechanisms governing SIRT1, including NAD[+]-metabolism-dependent regulation, protein interaction-dependent regulation, post-translational modifications such as ISGylation and nitrosylation, and non-coding RNA-mediated post-transcriptional regulation. In addition, the coordinated influence of upstream activators and downstream effectors is discussed. Impairment of SIRT1-mediated mitochondrial biogenesis may exacerbate neuronal energy deficits and oxidative stress in AD, thereby increasing susceptibility to neurodegeneration. This review further elucidates the molecular mechanisms underlying the SIRT1-mitochondrial biogenesis axis. By integrating upstream activating signals with downstream effectors, SIRT1 creates a permissive regulatory environment for peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-driven, mitochondrial transcription factor A (TFAM)-mediated mitochondrial biogenesis, thereby facilitating quality-controlled renewal of the mitochondrial network. In addition, this review discusses the potential value of dynamic biomarker monitoring following therapeutic targeting of the SIRT1 pathway and summarizes current challenges and future intervention strategies. Targeting SIRT1-mediated mitochondrial biogenesis may provide a promising avenue for the development of novel therapeutic strategies for AD.},
}

@article {pmid37703428,
year = {2024},
author = {Hirata, K and Matsuoka, K and Tagai, K and Endo, H and Tatebe, H and Ono, M and Kokubo, N and Oyama, A and Shinotoh, H and Takahata, K and Obata, T and Dehghani, M and Near, J and Kawamura, K and Zhang, MR and Shimada, H and Yokota, T and Tokuda, T and Higuchi, M and Takado, Y},
title = {Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {95},
number = {1},
pages = {104-115},
doi = {10.1002/ana.26797},
pmid = {37703428},
issn = {1531-8249},
support = {JP22dk0207063//Japan Agency for Medical Research and Development/ ; JP19dm0207072//Japan Agency for Medical Research and Development/ ; JP22dk0207055//Japan Agency for Medical Research and Development/ ; JP21zf0127004//Japan Agency for Medical Research and Development/ ; JP19H01041//Japan Society for the Promotion of Science/ ; JP21K18268//Japan Society for the Promotion of Science/ ; },
abstract = {OBJECTIVE: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD.

METHODS: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [[11]C]PiB and [[18]F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography.

RESULTS: Myo-inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05).

INTERPRETATION: We found high myo-inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2024;95:104-115.},
}

@article {pmid37787094,
year = {2024},
author = {Sadlon, A and Takousis, P and Ankli, B and Alexopoulos, P and Perneczky, R and , },
title = {Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function.},
journal = {Annals of neurology},
volume = {95},
number = {1},
pages = {195-206},
pmid = {37787094},
issn = {1531-8249},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Debate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative.

METHODS: Participants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid β1-42, phosphorylated tau 181 (ptau181), total tau (t-tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes.

RESULTS: The study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non-Alzheimer pathophysiology and chronic pain showed increased CSF levels of t-tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid-positive and neurodegeneration-negative chronic pain patients showed higher memory function cross-sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group.

INTERPRETATION: Our study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2024;95:195-206.},
}

@article {pmid42957394,
year = {2026},
author = {Veziroglu, E and Nikpanah, M and Farhadi, F and Kalbi, D and Hensley, C and McConathy, J},
title = {PET for Evaluation of Neurologic Diseases: Part one: Neurodegenerative Diseases.},
journal = {Radiologic clinics of North America},
volume = {64},
number = {6},
pages = {1023-1037},
doi = {10.1016/j.rcl.2026.07.008},
pmid = {42957394},
issn = {1557-8275},
mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; *Positron-Emission Tomography/methods ; Radiopharmaceuticals ; Fluorodeoxyglucose F18 ; Brain/diagnostic imaging ; },
abstract = {This review of PET for evaluation of neurological diseases is divided into two parts; part one examines the clinical use of positron emission tomography (PET) in neurodegenerative diseases. FDG-PET can identify characteristic patterns of cerebral metabolism and help distinguish among neurodegenerative disorders. Amyloid and tau PET have expanding diagnostic and theranostic roles in Alzheimer's disease, including assessment of disease-specific pathology and treatment eligibility. FDOPA-PET evaluates presynaptic dopamine synthesis and supports assessment of Parkinson's disease and other parkinsonian syndromes. Combined with structural imaging and clinical evaluation, PET can improve diagnostic confidence, refine prognosis, and inform treatment decisions.},
}

Humans
*Neurodegenerative Diseases/diagnostic imaging
*Positron-Emission Tomography/methods
Radiopharmaceuticals
Fluorodeoxyglucose F18
Brain/diagnostic imaging

@article {pmid42957517,
year = {2026},
author = {Li, J and Lin, T and Long, Z and Lin, J and Gao, F and Shen, Y},
title = {Endothelial BACE1 impairs insulin signaling to drive cerebral small vessel disease and stroke.},
journal = {Science bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.scib.2026.10.030},
pmid = {42957517},
issn = {2095-9281},
abstract = {Cerebral small vessel disease (CSVD) is a major cause of stroke and dementia, yet its molecular etiology remains incompletely understood, and no disease-modifying therapies are currently available. Here, we identify a non-canonical pathogenic mechanism linking β-secretase 1 (BACE1), a therapeutic target for Alzheimer's disease, to vascular insulin resistance. BACE1 was upregulated in the cerebral endothelium of patients with hypertensive arteriopathy and cerebral amyloid angiopathy. The upregulated endothelial BACE1 cleaved the β-subunit of insulin receptor (INSR), disrupting the INSR-Akt-endothelial nitric oxide synthase (eNOS) signaling axis required for vascular homeostasis. This disruption occurred early in disease progression in a relevant rodent model of CSVD, the stroke-prone spontaneously hypertensive rat fed a high-salt diet. Treatment with the clinical BACE1 inhibitor elenbecestat (E2609) restored endothelial function, ameliorated cerebrovascular pathology, and significantly reduced stroke incidence. INSR blockade abolished these protective effects, supporting an INSR-dependent mechanism. These findings identify an intersection between neurodegenerative and metabolic pathways in the vasculature and suggest that BACE1 inhibitors, previously abandoned in Alzheimer's disease treatment, may have therapeutic potential for stroke prevention and CSVD therapy.},
}

@article {pmid42957617,
year = {2026},
author = {Abdolmaleki, M and Gaynor, LS and Liu, D and Hohman, TJ and Gifford, KA and Zetterberg, H and Jefferson, AL and Bolton, CJ},
title = {Improving the Diagnostic Accuracy of Plasma Alzheimer's Disease Biomarkers With Objective and Subjective Cognitive Screening.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70565},
pmid = {42957617},
issn = {2328-9503},
support = {AACSF-24-1294323/ALZ/Alzheimer's Association/United States ; IIRG-08-88733/ALZ/Alzheimer's Association/United States ; F32-AG076276/AG/NIA NIH HHS/United States ; K23-AG084850/AG/NIA NIH HHS/United States ; K24-AG046373/AG/NIA NIH HHS/United States ; P20-AG068082/AG/NIA NIH HHS/United States ; R01-AG034962/AG/NIA NIH HHS/United States ; R01-AG056534/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Blood-based biomarkers are increasingly used to identify Alzheimer's disease (AD) pathology and may play an important role in early disease screening and participant selection for clinical trials. However, their performance across stages of cognitive impairment remains unclear. This study examined whether plasma biomarkers differ in their ability to predict amyloid pathology by performance on cognitive screening measures.

METHODS: Participants were older adults from the community-based Vanderbilt Memory and Aging Project (N = 154; mean age = 72 ± 6 years; 37% MCI). Plasma phosphorylated tau (p-tau)231 and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa technology. Amyloid positivity was defined by cerebrospinal fluid β-amyloid 42/40 ratio < 0.072. Objective cognitive impairment was defined as ≤ 26 on the Montreal Cognitive Assessment; cognitive complaints were assessed by a single-item self-report. Logistic regression and stratified ROC analyses evaluated associations between biomarkers and amyloid status, with area under the ROC curve (AUC) values compared using DeLong's test.

RESULTS: Forty-seven percent of participants were amyloid positive. Higher plasma p-tau231 was associated with increased odds of amyloid positivity (OR = 1.18, p < 0.001; AUC = 0.73). Discriminative accuracy was significantly higher among individuals without subjective cognitive concerns (AUC = 0.85) than among those individuals with concerns (AUC = 0.67; p = 0.02). Plasma GFAP was also associated with amyloid positivity (OR = 1.01, p < 0.001; AUC = 0.75) and showed greater accuracy among participants with objective cognitive impairment (AUC = 0.82) compared to unimpaired individuals (AUC = 0.63; p = 0.03).

CONCLUSIONS: Plasma p-tau231 and GFAP were associated with amyloid pathology, but their diagnostic accuracy varied by cognitive screening results, highlighting the value of integrating brief cognitive assessments when interpreting blood-based biomarkers.},
}

@article {pmid42957639,
year = {2026},
author = {Lista, S and Emanuele, E and Cuperlovic-Culf, M and Mahdi, A and Singh, V and López-Ortiz, S and Khoramipour, K and Merino-País, M and Minoretti, P and Cisale, GY and Heslegrave, A and Imbimbo, C and Sancesario, GM and Bendlin, BB and Imbimbo, BP and Zetterberg, H and Santos-Lozano, A},
title = {Artificial intelligence applications in microbiota-gut-brain axis research: Implications for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500124},
doi = {10.1177/13872877261500124},
pmid = {42957639},
issn = {1875-8908},
abstract = {Alterations in the gut microbiota (GM) are increasingly implicated in Alzheimer's disease (AD) pathogenesis through the microbiota-gut-brain axis (MGBA), influencing neuroinflammation, amyloid-β deposition, and tau aggregation. The inherent complexity of microbiota data necessitates artificial intelligence (AI) and machine learning (ML) to identify novel biomarkers and therapeutic targets. In this narrative review, we examined AI applications in AD-related GM research, including metataxonomic and metagenomic approaches. AI methods facilitate microbial signature identification and enterotype characterization associated with AD progression, enable multi-omics integration clarifying molecular pathways linking GM dysbiosis to neurodegeneration, support predictive modeling for early AD detection, and inform personalized MGBA-targeted interventions. Employed techniques include classical ML (e.g., random forests) for taxonomic classification, deep learning (e.g., neural networks) for complex pattern recognition, and explainable AI for identifying key bacterial taxa and metabolic functions. Significant challenges persist regarding methodological standardization, larger longitudinal cohorts, and ethical considerations in clinical applications. Future priorities include developing interpretable models, integrating longitudinal multi-omics data to establish causality, and validating AI-derived insights for precision AD prevention and treatment. AI uniquely enables high-dimensional, non-linear analyses that advance understanding of microbiome-brain interactions, though clinical translation requires rigorous validation and interdisciplinary collaboration.},
}

@article {pmid42957774,
year = {2026},
author = {O'Leary, K},
title = {A small-molecule TREM2 agonist for Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/d41591-026-00055-x},
pmid = {42957774},
issn = {1546-170X},
}

@article {pmid42957838,
year = {2026},
author = {Abaresh, S and Ivantsova, E and Parmar, MS},
title = {Glymphatic Dysfunction as a Multisystem Pathway Linking Systemic Health Conditions to Alzheimer's Disease: Mechanisms, Risk Factors, and Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42957838},
issn = {1559-1182},
mesh = {Humans ; *Glymphatic System/pathology/metabolism/physiopathology ; *Alzheimer Disease/therapy/physiopathology/metabolism/pathology ; Animals ; Risk Factors ; *Health ; },
abstract = {The glymphatic system is a glia-associated perivascular pathway involved in cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and the transport and clearance of neurotoxic metabolites, including amyloid-β (Aβ) and tau, from the central nervous system. Growing evidence suggests that alterations in glymphatic and perivascular clearance are associated with Alzheimer's disease (AD) pathology and may contribute to the accumulation of neurotoxic proteins and neurodegeneration. This review examines the role of the glymphatic system in AD and explores how aging, sleep disturbances, hypertension, ischemic heart disease, high-fat diet, diabetes, and gut microbiome dysbiosis impair glymphatic transport. A recurring mechanism across experimental models is the loss of perivascular AQP4 polarization, while vascular, metabolic, and inflammatory conditions may converge on related perivascular and neurovascular processes that impair CSF-ISF exchange and solute handling. Neuroimaging studies using markers such as DTI-ALPS, perivascular space burden, and free-water measurements provide evidence of alterations in glymphatic-related and perivascular processes in AD and demonstrate associations with amyloid deposition, neurodegeneration, and cognitive decline. Furthermore, glymphatic dysfunction may interact with neuroinflammation and tau pathology, creating a self-reinforcing cycle that accelerates disease progression. Emerging therapeutic strategies, including continuous theta-burst stimulation, positive airway pressure therapy for obstructive sleep apnea, pharmacological enhancement of AQP4 function, and nutritional interventions, have shown potential in experimental and early translational studies to influence glymphatic-related processes and may mitigate AD-related pathology. Collectively, current findings suggest that glymphatic and perivascular clearance pathways may represent an important link between systemic health conditions and AD. Because related pathways are implicated across multiple systemic conditions, interventions targeting glymphatic and perivascular dysfunction may have broader relevance to brain health, but their clinical effects remain to be established.},
}

Humans
*Glymphatic System/pathology/metabolism/physiopathology
*Alzheimer Disease/therapy/physiopathology/metabolism/pathology
Animals
Risk Factors
*Health

@article {pmid42957873,
year = {2026},
author = {Carron, C and Noë, S and Vanderlinden, G and Koole, M and Schramm, G and Van Laere, K},
title = {Effects of motion and white matter hyperintensities on reference region based [18]F-SynVesT-1 PET quantification in Alzheimer's disease and healthy volunteers.},
journal = {EJNMMI research},
volume = {16},
number = {1},
pages = {},
pmid = {42957873},
issn = {2191-219X},
support = {SAO-FRA 2021/0004//Internationale Stichting Alzheimer Onderzoek/ ; 1292326N//Fonds Wetenschappelijk Onderzoek/ ; C24M/22/031//KU Leuven/ ; },
abstract = {BACKGROUND: [18]F-SynVesT-1 is a PET tracer targeting synaptic vesicle protein 2A, a surrogate marker of synaptic density. Simplified quantification using pseudo-reference regions such as the centrum semiovale (CSO) or whole cerebellum (CER) has previously been validated in healthy volunteers and Alzheimer's disease. This study assessed how motion correction and white-matter hyperintensities (WMH) affect [18]F-SynVesT-1 quantification. We reconstructed [18]F-SynVesT-1 images for 40 healthy volunteers and 31 patients with Alzheimer's disease 60-90 minutes post-injection with 3 motion handling methods: no motion correction; 5 minute frame-based post-reconstruction coregistration and averaging, and a high-temporal-resolution data-driven motion correction applied during reconstruction. WMH were segmented from T2-FLAIR images and excluded from the CSO to generate lesion-corrected CSO regions. A region-based voxelwise partial volume correction was applied. SUV and SUVRCSO/CER were compared across motion- and lesion-handling methods and the effects on group differentiation were explored.

RESULTS: Data-driven motion correction during reconstruction improved visual image sharpness and increased SUV in high-binding cortical regions (median +0.3-1.0%, p≤0.001) while reducing SUV in the low-binding CSO (median -0.5%, p=0.001). Coregistering and averaging of frames only increased contrast when there was severe motion. The cerebellum was one of the least affected regions by motion correction (median SUV +0.4% with PETDDLM, p<0.001). WMH affected CSO SUV only when ≥25% of the region contained lesions and never affected the cerebellar SUV. SUVRCSO yielded better group differentiation than SUVRCER after accounting for motion and WMH. Individual patients' z-scores differed significantly in both directions depending on the use of SUVRCSO or SUVRCER (e.g. mean absolute difference of 1.00± 0.82 in the precuneus).

CONCLUSION: Data-driven motion correction during reconstruction reduced the impact of head movements and attenuation mismatches, improving image contrast and quantitative accuracy. SUVRCER was less sensitive to motion and WMH than SUVRCSO, indicating greater robustness. When motion and WMH effects were controlled, SUVRCSO provided slightly better group differentiation than SUVRCER. These findings suggest that CSO may be preferred for group comparisons in well-controlled datasets, while the cerebellum represents a more robust reference region in the presence of motion or substantial WMH burden. The study was registered on ClinicalTrials.gov (NCT05384353), first posted on 20 May 2022.},
}

@article {pmid42957970,
year = {2026},
author = {Mendes, AJ and Boccalini, C and Ribaldi, F and Pievani, M and Peretti, D and Garibotto, V and Chincarini, A and Frisoni, GB and , },
title = {APOE ε4 gene dose drives a canonical and predictable topography of amyloid deposition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71935},
pmid = {42957970},
issn = {1552-5279},
support = {//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI (Department of Defense)/ ; //National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering/ ; //AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research/ ; 320030_185028/SNSF_/Swiss National Science Foundation/Switzerland ; 320030_182772/SNSF_/Swiss National Science Foundation/Switzerland ; 20030_169876/SNSF_/Swiss National Science Foundation/Switzerland ; 320030_220269/SNSF_/Swiss National Science Foundation/Switzerland ; //Association Suisse pour la Recherche sur la Maladie d'Alzheimer, Fondation Segré, Ivan Pictet, Race Against Dementia Foundation, Fondation Child Care, Fondation Edmond J Safra, Fondation Minkoff, Fondazione Agusta, McCall Macbain Foundation, VELUX Foundation, Schmidheiny Foundation/ ; Ricerca Corrente 2025-2027//Italian Ministry of Health/ ; },
mesh = {Humans ; *Apolipoprotein E4/genetics ; Female ; Positron-Emission Tomography ; Male ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism ; Aged ; *Brain/diagnostic imaging/metabolism/pathology ; *Gene Dosage ; Heterozygote ; *Amyloid/metabolism ; *Amyloid beta-Peptides/metabolism ; Genotype ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Apolipoprotein E ε4 (APOE ε4) carriership is associated with higher amyloid burden in Alzheimer's disease (AD), but whether it constrains the spatial predictability of amyloid deposition at the individual level remains unknown.

METHODS: We analyzed voxel-wise amyloid positron emission tomography data from 781 amyloid-positive individuals across two independent cohorts (Alzheimer's Disease Neuroimaging Initiative and Geneva Memory Center), spanning the full clinical continuum. Individual topographic similarity to canonical AD amyloid maps and within-group spatial homogeneity were assessed via voxel-wise correlations and linear regression adjusted for age, sex, and global amyloid burden.

RESULTS: APOE ε4 carriers exhibited amyloid distributions more aligned with canonical AD topographies than non-carriers (p < 0.001), with a clear gene-dose effect on within-group spatial homogeneity: Homozygotes showed the highest inter-subject consistency, followed by heterozygotes and non-carriers. Effects were robust across tracers, clinical stages, and cohorts.

DISCUSSION: APOE ε4 gene dose constrains the spatial predictability of amyloid accumulation, informing genotype-stratified approaches in anti-amyloid trials.},
}

Humans
*Apolipoprotein E4/genetics
Female
Positron-Emission Tomography
Male
*Alzheimer Disease/genetics/diagnostic imaging/metabolism
Aged
*Brain/diagnostic imaging/metabolism/pathology
*Gene Dosage
Heterozygote
*Amyloid/metabolism
*Amyloid beta-Peptides/metabolism
Genotype
Aged, 80 and over

@article {pmid42957973,
year = {2026},
author = {Liu, J and Xiao, BW and Mai, X and Wang, YC and Fei, Y and Wang, Y and Hou, SX},
title = {ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71926},
pmid = {42957973},
issn = {1552-5279},
support = {82450108//National Natural Science Foundation of China/ ; 32370739//National Natural Science Foundation of China/ ; 32271510//National Natural Science Foundation of China/ ; 2023YFA1800202//National Key R&D Program of China/ ; 2024YFA1306000//National Key R&D Program of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism ; Humans ; Ubiquitination ; *Ubiquitin Thiolesterase/metabolism/genetics ; Mice ; Disease Models, Animal ; Drosophila ; *Drosophila Proteins/metabolism/genetics ; Phosphorylation ; *Tauopathies/metabolism/pathology ; },
abstract = {INTRODUCTION: Hyperphosphorylated Tau accumulation drives neurodegeneration in Alzheimer's disease (AD), but mechanisms linking impaired Tau ubiquitination to disease progression remain incompletely defined.

METHODS: We integrated Drosophila RNAi screening, human AD datasets, cellular assays, and mouse tauopathy models to evaluate arrestin domain-containing 4 (ARRDC4) in Tau pathology. ARRDC4-dependent regulation of Tau ubiquitination was examined using proteomics, proximity labeling, co-immunoprecipitation, BiFC, domain mapping, genetic suppression, and small-molecule interference.

RESULTS: ARRDC4 was upregulated in AD-relevant human and animal datasets and correlated with Tau burden. ARRDC4 overexpression promoted Tau phosphorylation, self-association, seeded aggregation, secretion, and inflammatory activation. Mechanistically, ARRDC4 brought Tau and USP14 into proximity, suppressing Tau ubiquitination. Genetic ARRDC4 deficiency or pharmacological disruption of the ARRDC4-USP14 interface restored Tau ubiquitination and ameliorated Tau pathology, neuroinflammation, neuronal injury, and behavioral deficits across cellular, Drosophila, and mouse models.

DISCUSSION: ARRDC4 is a regulator of Tau proteostasis and a potential therapeutic target for Tau-associated AD pathology.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism
Humans
Ubiquitination
*Ubiquitin Thiolesterase/metabolism/genetics
Mice
Disease Models, Animal
Drosophila
*Drosophila Proteins/metabolism/genetics
Phosphorylation
*Tauopathies/metabolism/pathology

@article {pmid42957985,
year = {2026},
author = {Hu, P and Zhang, M and Wei, X and Xiao, S and Li, B and Liu, K and Su, G and Han, B and Shi, X and Wei, C and Sun, J and Zhang, Z and Han, Z and Shen, L},
title = {Total salvianolic acids protect APP/PS1 mice from Alzheimer's disease by attenuating neuroinflammation through hippocampal lipid regulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498369},
doi = {10.1177/13872877261498369},
pmid = {42957985},
issn = {1875-8908},
abstract = {BackgroundTotal salvianolic acids (TSA) have been shown to exert neuroprotective effects in cognition-associated behavioral tests in APP/PS1 mice in our previous research; however, research on TSA-mediated modulation of hippocampal lipid metabolism remains limited.ObjectiveThis study elucidated the therapeutic mechanisms underlying prophylactic TSA administration by integrating lipidomic profiling and demonstrating TSA-induced neuroprotection through suppression of hippocampal neuroinflammation in APP/PS1 mice.MethodsTen 3.5-month-old APP/PS1 mice and ten age-matched wild-type mice received intraperitoneal saline injections as the disease model and healthy control groups. Another twenty APP/PS1 mice were allocated to two TSA treatment groups (30 mg/kg/day and 60 mg/kg/day). After fifteen weeks of intervention, memory performance was assessed using the Y-maze test. Hippocampal Aβ, IBA1, and GFAP protein expression levels were quantified by western blotting. Targeted UHPLC-MS/MS was used for quantitative detection of hippocampal lipid biomarkers.ResultsThe 60 mg/kg TSA group exhibited improved memory in Y-maze tests, with elevated spontaneous alternation rate (p < 0.05) and arm entries (p < 0.01). The latency to enter the novel arm was significantly reduced at both doses of TSA (p < 0.01). TSA at 60 mg/kg reduced hippocampal inflammation markers IBA1 (p < 0.05), GFAP (p < 0.05), and Aβ (p < 0.01) in APP/PS1 mice. Lipids revealed significant changes in 41 lipid species after TSA treatment. TSA suppressed the levels of glycerides, sterol lipids, and free fatty acids while increasing glycolipids including monogalactosyldiacylglycerols. TSA also regulated sphingomyelins by reducing acyl chain-modified PCs and increasing phosphatidylserines.ConclusionsThis study reveals TSA's preventive potential against Alzheimer's disease by modulating inflammation-associated lipid metabolism in APP/PS1 mice.},
}

@article {pmid42958309,
year = {2026},
author = {Kurz, C and Leonhardt, S and Hufnagel, A and Wizemann, S and Deutelmoser, H and Menzel, P and Perneczky, R},
title = {A prospective observational study measuring the stability of plasma pTau181 using the Elecsys Phospho-Tau (181P) plasma immunoassay for early detection of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42958309},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood ; Immunoassay/methods ; Male ; Female ; Biomarkers/blood ; Aged ; Prospective Studies ; Early Diagnosis ; Phosphorylation ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Plasma tau phosphorylated at threonine 181 (pTau181) is a key blood-based biomarker that correlates with the burden of amyloid-beta (Aβ) pathology in Alzheimer's disease (AD). The Elecsys[®] Phospho-Tau (181P) Plasma (pT181p) immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) is intended for use as an aid in the early detection of Aβ pathology in adults ≥ 55 years presenting with complaints of cognitive decline and is Conformité Européenne-marked and approved for clinical use by the US FDA. Here, we evaluated the stability of plasma pTau181 measured using the pT181p immunoassay under different pre-analytical and storage conditions in samples from an intended-use population.

METHODS: Whole blood samples from individuals presenting at LMU Hospital with symptom severity ranging from subjective cognitive decline to moderate AD dementia were collected in three different tubes for plasma preparation (Li-Heparin, K2-EDTA, and K3-EDTA). These were transported under cooled (never frozen) conditions to the measurement site and processed within 6 h of collection. Plasma samples were stored at different temperatures for varying durations, and impact on plasma pTau181 recoveries was assessed.

RESULTS: Out-of-specification results not meeting pre-defined acceptance criteria observed in an initial cohort (n = 14), were found to be the result of buffy coat/erythrocyte contamination. Pre-analytical procedures were modified to prevent contamination during post-centrifugation plasma transfer. In samples from a separate cohort (n = 10), no instabilities were observed and acceptance criteria were met. After considering safety margins, analyte stability for all sample types was determined to be 2 days at 25 °C, 7 days at 4 °C, 12 weeks at -20 °C, and 16 weeks at -80°C; stability was also observed after one freeze/thaw cycle.

CONCLUSIONS: pT181p immunoassay measurements were stable and robust with respect to different sample handling procedures and storage conditions. These findings support implementation of the assay into routine, non-specialist healthcare settings to facilitate practical blood-based testing to rule out AD-related Aβ pathology.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood
Immunoassay/methods
Male
Female
Biomarkers/blood
Aged
Prospective Studies
Early Diagnosis
Phosphorylation
Middle Aged
Aged, 80 and over

@article {pmid42958401,
year = {2026},
author = {Cao, S and Chen, Y and Li, J and Li, Z and Liu, D and Zhong, L and Dong, X and Dai, J and Yin, H},
title = {Target-area dosimetry-guided photobiomodulation improves pathology and cognitive function in APPswe/PS1dE9 mice.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42958401},
issn = {1479-5876},
support = {2023-I2M-2-008//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; 2023YFB3609103//National Key Research and Development Program of China/ ; 62175261//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Low-Level Light Therapy ; *Cognition/radiation effects ; Monte Carlo Method ; Mice, Transgenic ; *Radiometry ; Alzheimer Disease/physiopathology/pathology/radiotherapy ; *Presenilin-1/metabolism ; Brain/pathology/radiation effects/physiopathology ; Mice ; Calibration ; Amyloid beta-Protein Precursor/metabolism ; },
abstract = {BACKGROUND: Photobiomodulation (PBM) has shown potential in Alzheimer's disease (AD) models, but substantial heterogeneity in irradiation parameters and the lack of intracerebral dose quantification have limited reproducibility and mechanistic interpretation. In transcranial PBM, surface power density does not reliably reflect energy delivery to brain targets due to wavelength-dependent tissue attenuation.

METHODS: We developed a target-area dosimetry- guided PBM framework by integrating Monte Carlo-based light transport modeling with inverse calibration for selected representative wavelength-target conditions. Based on these simulations, inverse calibration was performed for selected representative wavelength-target combinations, with 810 nm irradiation optimized for PFC-directed PBM and 1060 nm, 40 Hz pulsed irradiation optimized for HIPP-directed PBM. APPswe/PS1dE9 mice received region-oriented and comparative PBM treatments, followed by behavioral, pathological, and electrophysiological assessments.

RESULTS: Monte Carlo simulations revealed marked wavelength-dependent differences in intracerebral light distribution under identical surface irradiation. Inverse calibration supported the selection of region-specific irradiation parameters and highlighted the need to consider target-area light exposure rather than surface power alone. Among the tested irradiation conditions, PBM improved spatial learning and memory and modulated amyloid burden, neuroinflammatory responses, synaptic markers, and neural network activity. Among these treatments, combined hippocampal irradiation with 810 nm and 1060 nm light produced the most consistent overall responses, while 810 nm PFC irradiation also showed beneficial effects across several outcome measures.

CONCLUSIONS: These findings support target-area dosimetry as an important physical consideration for the design and interpretation of region-oriented PBM protocols in AD models. By integrating intracerebral light propagation modeling with biological evaluation, this study provides a methodological framework for improving PBM parameter selection and guiding future optimization of transcranial PBM interventions.},
}

Animals
*Low-Level Light Therapy
*Cognition/radiation effects
Monte Carlo Method
Mice, Transgenic
*Radiometry
Alzheimer Disease/physiopathology/pathology/radiotherapy
*Presenilin-1/metabolism
Brain/pathology/radiation effects/physiopathology
Mice
Calibration
Amyloid beta-Protein Precursor/metabolism

@article {pmid42958434,
year = {2026},
author = {Ma, L and Wang, Y and Goudey, B and Jin, L and Pan, Y},
title = {Neuropathological and vascular determinants of cerebral amyloid angiopathy risk: evidence from the NACC cohort.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42958434},
issn = {1758-9193},
support = {GNT2007912//National Health and Medical Research Council/ ; GNT2022203//NHMRC-AMED Dementia Collaborative Research Grant/ ; 23AARF-1020292//Alzheimer's Association USA/ ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/genetics/epidemiology ; Female ; Male ; *Brain/pathology ; Aged ; Cohort Studies ; Risk Factors ; *Alzheimer Disease/pathology/genetics/epidemiology ; Aged, 80 and over ; Frontotemporal Lobar Degeneration/pathology ; Lewy Bodies/pathology ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is strongly associated with Alzheimer's disease neuropathologic changes (ADNC), but its links with other brain pathologies remain unclear.

METHODS: We conducted a clinicopathological study of 3,267 participants from the National Alzheimer's Coordinating Center (NACC) cohort. Neuropathological evaluations included potential risk factors for CAA, such as ADNC, Lewy body pathology (LBP), frontotemporal lobar degeneration (FTLD), and other neuropathologies.

RESULTS: We found that ADNC and LBP were associated with increased odds of CAA, with the risk increasing according to ADNC severity and in cases of limbic/amygdala-predominant LBP. In contrast, FTLD, particularly the FTLD-TDP subtype, was inversely associated with CAA. Among other neuropathologies, CAA was positively associated with microinfarcts, arteriolosclerosis, white matter rarefaction, and hippocampus/cortical atrophy, but inversely associated with lobar atrophy and higher brain weight. In addition, APOE ε4 carriers with mixed ADNC, LBP, and FTLD exhibited the highest risk. Stronger associations between ADNC and CAA were observed in participants aged < 80 years and in males, whereas females demonstrated greater vulnerability to vascular- and atrophy-related correlates. Several neuropathology-CAA associations were also more pronounced among APOE ε4 carriers.

CONCLUSION: These findings highlight the interplay of neurodegenerative, vascular, sex, and APOE ε4 in CAA susceptibility, with implications for risk stratification.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/genetics/epidemiology
Female
Male
*Brain/pathology
Aged
Cohort Studies
Risk Factors
*Alzheimer Disease/pathology/genetics/epidemiology
Aged, 80 and over
Frontotemporal Lobar Degeneration/pathology
Lewy Bodies/pathology

@article {pmid42958467,
year = {2026},
author = {Dou, J and Zhu, Y and Du, Z and Zhang, G},
title = {LncRNA FBXL19-AS1 regulates the miR-650/ITGB3 axis to drive pathological progression in Alzheimer's Disease.},
journal = {Hereditas},
volume = {163},
number = {1},
pages = {},
pmid = {42958467},
issn = {1601-5223},
support = {Grant No. 2541ZF292//Baoding Science and Technology Program/ ; },
mesh = {Humans ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics/pathology ; *RNA, Long Noncoding/genetics ; Female ; *Integrin beta3/genetics ; Disease Progression ; Apoptosis ; Cell Proliferation ; Male ; Gene Expression Regulation ; Aged ; Amyloid beta-Peptides ; Cell Line, Tumor ; Cell Line ; DNA-Binding Proteins ; F-Box Proteins ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by complex and not yet fully understood pathological mechanisms. This study was designed to explore the molecular mechanisms of long non-coding RNA (lncRNA) FBXL19-AS1 in the pathological progression of AD.

METHODS: 110 AD patients and 110 healthy controls were recruited for this study. Relevant gene expression was measured using reverse transcription quantitative real-time PCR (RT-qPCR), and the diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis. AD cell models were established by treating SH-SY5Y and BV2 cells with amyloid β (Aβ)25-35. Cell proliferation was evaluated using the cell counting kit-8 (CCK-8) assay, cell apoptosis was analyzed by flow cytometry, and the secretion levels of inflammatory factors were determined via enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter assay was performed to confirm the direct regulatory interactions.

RESULTS: In AD patients, the FBXL19-AS1 and integrin subunit beta 3 (ITGB3) expression were significantly elevated, whereas microRNA-650 (miR-650) expression was markedly reduced. FBXL19-AS1 showed certain diagnostic potential for AD, and its expression was negatively correlated with Montreal Cognitive Assessment (MoCA) scores. Following treatment with Aβ25-35, SH-SY5Y cells exhibited reduced proliferative capacity and increased apoptosis, while BV2 cells showed elevated levels of inflammatory factors. Additionally, Aβ25-35 treatment led to upregulated expression of FBXL19-AS1 and ITGB3, along with downregulated expression of miR-650. Knockdown of FBXL19-AS1 effectively reversed these effects. However, inhibition of miR-650 partially attenuated the changes induced by FBXL19-AS1 knockdown. Furthermore, knockdown of FBXL19-AS1 markedly reduced ITGB3 expression, whereas concurrent inhibition of miR-650 partially reversed this downregulatory effect.

CONCLUSION: FBXL19-AS1 appears to interact with and modulate miR-650, thereby affecting ITGB3 expression and potentially participating in the pathological progression of AD.},
}

Humans
*MicroRNAs/genetics
*Alzheimer Disease/genetics/pathology
*RNA, Long Noncoding/genetics
Female
*Integrin beta3/genetics
Disease Progression
Apoptosis
Cell Proliferation
Male
Gene Expression Regulation
Aged
Amyloid beta-Peptides
Cell Line, Tumor
Cell Line
DNA-Binding Proteins
F-Box Proteins

@article {pmid42958586,
year = {2026},
author = {Lee, S and English, AC and Peloso, GM and Bis, JC and Boerwinkle, E and Choi, SH and Heard-Costa, NL and Lin, H and Xia, R and Seshadri, S and Destefano, AL and Fornage, M and Sedlazeck, FJ},
title = {The impact of structural variation on Alzheimer's disease in the Alzheimer's disease sequencing project.},
journal = {Genome biology},
volume = {27},
number = {1},
pages = {},
pmid = {42958586},
issn = {1474-760X},
support = {U01-AG058589/AG/NIA NIH HHS/United States ; U01-AG058589, U01-AG052409, P30-AG066546/AG/NIA NIH HHS/United States ; U01-AG058589, U01-AG068221/AG/NIA NIH HHS/United States ; U01-AG058589, U01-AG052409, U01-AG070112/AG/NIA NIH HHS/United States ; U01-AG068221/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; *Genomic Structural Variation ; Whole Genome Sequencing ; Linkage Disequilibrium ; },
abstract = {INTRODUCTION: Structural variants (SV), genomic alterations spanning more than 50 base pairs, can significantly impact gene expression and protein function. However, their contribution to Alzheimer's disease (AD) remains poorly understood. Leveraging a novel SV calling pipeline, we identified SVs with high accuracy in a diverse sample of the Alzheimer's Disease Sequencing Project (ADSP) and investigated the role of SVs in AD.

RESULTS: We analyze SVs in 16,841 individuals from ADSP whole genome sequencing data using BioGraph, a semi-assembly-based method that employs graph-based representation for accurate SV detection. We identify 456,644 high-quality SVs, 65% of which were novel. Of these, 272,728 SVs directly impact genes, including 86 AD-related genes. We perform association analyses within three ancestry groups, including 3,371 African (AFR), 6,327 European (EUR), and 2,126 Latin (LAT). We observe multiple deletions and insertions in moderate to high linkage disequilibrium with known AD loci, including TPCN1 and TMEM106B. In EUR, genome-wide association analysis identifies two significant low-frequency deletions associated with AD, located in introns of CCDC12 and CCDC88B, both encoding coiled-coil domain-containing proteins. Gene-based analyses further identify rare pathogenic SVs in several known AD genes, including PSEN1 in LAT and ABCA7 in AFR.

CONCLUSIONS: Using a novel graph-based SV calling pipeline, we identify high-quality SVs across a large and ancestrally diverse cohort. Our analyses reveal both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.},
}

*Alzheimer Disease/genetics
Humans
*Genomic Structural Variation
Whole Genome Sequencing
Linkage Disequilibrium

@article {pmid42958598,
year = {2026},
author = {Abd-ElRaouf, K and Murphy, DT and Cheong, LYT and Zeng, J and Lo, CH},
title = {The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42958598},
issn = {2047-9158},
support = {Start-up grant//Syracuse University/ ; 25AARG-1375299//Alzheimer's Association Research Grant/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Lysosomes/metabolism/pathology ; *Intrinsically Disordered Proteins/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD) are characterized by the accumulation of intrinsically disordered proteins (IDPs), including amyloid-β (Aβ), tau, and α-synuclein (αSyn). These proteins disrupt neuronal homeostasis through toxic aggregation, impaired proteostasis, and progressive neurodegeneration, in part via dysfunction of the autophagy-lysosomal pathway (ALP). A central feature of this impairment is defective vacuolar-type (H[+])-ATPase (V-ATPase) function, leading to lysosomal deacidification and reduced degradative capacity. Pathological IDP species converge on V-ATPase through direct interactions with its subunits or by perturbing its assembly, while also exerting protein-specific effects, including lysosomal membrane destabilization, impaired hydrolase activity, and disrupted endolysosomal trafficking. These combined mechanisms create a reciprocal relationship between lysosomal dysfunction and IDP accumulation, in which impaired lysosomal degradation further promotes the persistence and aggregation of pathological IDP species. This review synthesizes current insights into the molecular interplay between IDPs and lysosomal acidification across AD, FTD, and PD, and highlights how these processes contribute to disease progression. We further discuss emerging therapeutic strategies aimed at restoring lysosomal function. These findings underscore lysosomal dysfunction as a common feature of IDP-driven neurodegeneration and a potential therapeutic target across these disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Lysosomes/metabolism/pathology
*Intrinsically Disordered Proteins/metabolism
Animals
Autophagy/physiology

@article {pmid42958736,
year = {2026},
author = {Saltiel, N and Howard, E and Lee, AJ and Moody, JN and Hayes, JP and , },
title = {Traumatic brain injury history moderates age-related episodic memory change in older veterans: the DOD-ADNI longitudinal cohort study.},
journal = {Brain injury},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/02699052.2026.2752523},
pmid = {42958736},
issn = {1362-301X},
abstract = {BACKGROUND: Traumatic brain injury (TBI) has been associated with increased risk of dementia and cognitive decline, but its relationship with age-related cognitive trajectories remains unclear. This study examined associations between TBI history and age-related changes in cognitive function in aging military veterans.

METHODS: Data from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD-ADNI) repository were used to evaluate whether TBI history moderates the relationship between age and longitudinal change in domain-specific cognitive performance. To investigate these relationships, this study utilized data from neuropsychological assessments collected at baseline and 12-month timepoints from a sample consisting of 203 Vietnam War veterans, 99% of whom were male, aged 60-84 years, with varying TBI histories.

RESULTS: Results revealed that TBI history moderated the association between age and change in episodic memory. Older age was associated with greater memory decline among individuals with TBI. No interaction effects were observed for executive functions or language.

CONCLUSIONS: These findings suggest that TBI history is associated with differences in age-related episodic memory change and highlight the importance of considering TBI history in studies of cognitive aging. Considering the modest proportion of variance explained by the interaction and homogeneous veteran sample, additional research is warranted.},
}

@article {pmid42959066,
year = {2026},
author = {Lin, D and Luo, Y and Qiu, X and Ye, P and Chen, R and Xu, W and Zheng, R and Fu, X and Fan, K and Chen, D and Yang, B and Chen, L and Ou, Q and Liu, X},
title = {Serum neuron-derived extracellular vesicle mitochondrial DNA as a potential biomarker for mild cognitive impairment due to AD.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1924123},
pmid = {42959066},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents the initial clinical manifestation, eventually evolving into the distinctive features of Alzheimer's disease (AD), making its early identification crucial. Notably, mitochondrial dysfunction is an early characteristic of AD. Neuron-derived extracellular vesicles (NDEVs) can cross the blood-brain barrier, and their mitochondrial DNA (mtDNA) can reflect intracerebral lesions, showing considerable potential. In this study, we investigated the alterations in mtDNA within serum NDEVs and evaluated their potential as early diagnostic biomarkers for MCI due to AD.

METHODS: A total of 42 MCI patients, 49 AD patients, and 57 age-matched cognitively unimpaired (CU) controls were enrolled. Serum NDEVs were enriched and characterized, and their mtDNA levels were quantified by qPCR. ROC curve was used to analyze diagnostic performance, and the integration of multimodal biomarkers was explored.

RESULTS: Serum NDEVs mtDNA levels were decreased in patients with AD-MCI, and a significant positive correlation was observed between serum NDEVs mtDNA levels and MMSE scores in MCI patients (r = 0.4864, P = 0.0407), and a similar association was observed in the AD group (r = 0.3857, P = 0.0469). In terms of diagnostic performance, serum NDEV mtDNA demonstrated outstanding discrimination between CU controls and AD subjects, achieving an area under the curve (AUC) of 0.965 (95% CI: 0.933-0.997), with 97.92% sensitivity and 89.09% specificity. Moreover, it also demonstrated moderate efficacy in differentiating early MCI from AD (AUC = 0.736, 95% CI: 0.629-0.842; sensitivity = 72.92%, specificity = 66.67%). In exploratory analyses of clinical and metabolic factors, serum NDEV mtDNA levels were positively correlated with HCY in MCI patients, while in AD patients, NDEV mtDNA levels were elevated in those with diabetes and positively correlated with TG. Notably, integrating NDEV mtDNA with established biomarkers, including p-Tau 217, GFAP, and APOE ε4 carrier status, significantly improved the accuracy of MCI detection, highlighting its value in multimodal biomarker strategies.

CONCLUSION: Serum NDEVs mtDNA levels were significantly reduced in patients with MCI and AD, suggesting strong potential as an early diagnostic biomarker for MCI due to AD.},
}

@article {pmid42959148,
year = {2026},
author = {Subih, O and Al Mustafa, WA and AlOmem, TA and Alrasheed, AM and Altunaiji, MS and Alhasan, AAM and Alshehri, AIA and Alshahrani, BM and Alharbi, RJM and Alshatti, AM and Al Mutairi, ME and Alkhaldi, SM and Bifari, IN},
title = {The association between diabetic retinopathy and cognitive impairment in patients with diabetes mellitus: a systematic review and meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1881602},
pmid = {42959148},
issn = {1664-2392},
mesh = {Humans ; *Diabetic Retinopathy/complications/epidemiology ; *Cognitive Dysfunction/epidemiology/etiology ; *Diabetes Mellitus/epidemiology ; },
abstract = {BACKGROUND: Diabetic retinopathy (DR) is a recognized microvascular complication of diabetes in which neurovascular and neurodegenerative mechanisms may also contribute. This systematic review evaluated the association between DR and cognitive impairment or dementia, including Alzheimer's disease and vascular dementia, using evidence from cross-sectional and longitudinal observational studies.

METHODS: We searched for relevant articles up to December 2025 from PubMed, Scopus, Web of Science, and Cochrane Library. Two independent reviewers extracted data from the selected studies, including baseline information and outcomes. All quantitative syntheses were conducted using R version 4.4.1.

RESULTS: Fourteen studies with reported study populations totaling 2,871,847 participants were included. Seven studies contributed to the crude dichotomous synthesis, which did not demonstrate a statistically significant association between diabetic retinopathy and cognitive impairment or dementia (OR 1.07, 95% CI 0.94-1.23; p=0.310; I[2]=52.3%). Seven studies contributed adjusted longitudinal estimates for incident dementia; diabetic retinopathy was associated with a higher incidence of dementia (HR 1.55, 95% CI 1.19-2.02; p=0.001; I[2]=97.8%; 95% prediction interval 0.65-3.68). Evidence concerning Alzheimer's disease and vascular dementia remained inconsistent.

CONCLUSION: Longitudinal evidence suggests that diabetic retinopathy is associated with a higher incidence of dementia, although substantial heterogeneity and the observational evidence base limit confidence in the pooled estimate. Evidence concerning Alzheimer's disease and vascular dementia remains inconclusive.

https://doi.org/10.17605/OSF.IO/YS462, identifier YS462.},
}

Humans
*Diabetic Retinopathy/complications/epidemiology
*Cognitive Dysfunction/epidemiology/etiology
*Diabetes Mellitus/epidemiology

@article {pmid42959361,
year = {2026},
author = {Sarwar, MR and Godbee, K and Cross, AJ and Geethadevi, GM and Magin, P and Baker, AL and Bonevski, B and O'Reilly, SL and Varnfield, M and Jayasena, R and Ward, SA and Mahal, A and Versace, V and Simon Bell, J and Namara, KM and Anstey, KJ and Hernan, A and Thomas, D and Manias, E and Elliott, RA and Lee, CY and Tullipan, M and van den Bosch, D and Ferreira, C and Nguyen, N and Feyissa, TR and George, J},
title = {A multidomain, nurse-led, mobile health-supported intervention for dementia risk reduction in primary care (HAPPI MIND): a pragmatic, single-blind, two-arm, cluster randomised controlled trial.},
journal = {The Lancet regional health. Western Pacific},
volume = {75},
number = {},
pages = {102000},
pmid = {42959361},
issn = {2666-6065},
abstract = {BACKGROUND: Modifiable midlife risk factors contribute substantially to dementia, yet scalable preventive interventions in primary care are limited. We evaluated the effectiveness of a multidomain, nurse-led, mobile health (mHealth)-supported behavioural intervention (HAPPI MIND) among middle-aged adults.

METHODS: We conducted a cluster randomised controlled trial in adults aged 45-65 years with ≥2 modifiable dementia risk factors, from 31 Australian general practices (intervention = 13, control = 18). Clinics were randomised to the intervention or control group. Practice nurses collected socio-demographic and clinical data using validated tools. Participants completed the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI) dementia risk assessment, which assessed exposure to modifiable risks and protective factors for dementia. Intervention participants received five nurse-led motivational interviewing sessions over 12 months, an individualised action plan, and access to the mHealth application. Control participants received the ANU-ADRI report, an educational booklet on dementia risk reduction, and referral to their general practitioner as appropriate. Outcome assessors and data analysts were blinded. The primary outcome was the change in ANU-ADRI score from baseline to 12 months. Analyses followed intention-to-treat principles using linear mixed-effects models with multiple imputation for missing data. The trial was prospectively registered (ACTRN12621001168842); the intervention is complete, and this report presents the prespecified primary outcome at 12 months.

FINDINGS: Between February 2022 and April 2023, 403 participants (intervention = 201; control = 202) were enrolled (mean age 56.4 years [SD 5.7]; 63% female). At 12 months, the adjusted mean change in ANU-ADRI score was 0.791 (95% CI -0.895 to 2.478) in the intervention group and -0.807 (-2.339 to 0.725) in the control group, with an adjusted between-group mean difference of 1.598 (0.423-2.773; p = 0.0080), favouring the intervention. Results from per-protocol and complete-case analyses were consistent. Seven adverse events occurred, including two deaths (one in each group).

INTERPRETATION: A multidomain, nurse-led, mHealth-supported behavioural intervention produced modest but statistically significant improvements in estimated dementia risk profiles over 12 months among middle-aged adults in Australian primary care. Further implementation, processes, and economic evaluations are needed before broader adoption can be recommended.

FUNDING: Australian Government National Health and Medical Research Council, Boosting Dementia Research Grants (GNT1171851).},
}

@article {pmid42959393,
year = {2026},
author = {Bermudez, C and Pillai, JJ and Burkett, BJ and McDonald, JS and Johnson, DR and Wiste, HJ and Weigand, SD and Jack, CR and Vemuri, P and Petersen, RC and Graff-Radford, J and Ramanan, VK and Cogswell, PM},
title = {Differences in anti-amyloid therapy eligibility assessment based on use of the SWI versus GRE sequence.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70524},
pmid = {42959393},
issn = {2352-8729},
abstract = {INTRODUCTION: The number of microhemorrhages (mHs) increases risk of amyloid-related imaging abnormalities (ARIAs) in those undergoing anti-amyloid treatments for Alzheimer's disease. It is unclear whether using different magnetic resonance imaging (MRI) sequences to detect mH would alter treatment decisions.

METHODS: We retrospectively analyzed 55 adults (mean age 72.1 ± 7.1 years) evaluated for cognitive concerns who had MRI exams including both susceptibility-weighted imaging (SWI) and gradient echo (GRE) sequences. Three neuroradiologists independently identified and then reached consensus on mH detection. Participants were classified into mH burden categories (none, 1, 2-4, ≥ 5).

RESULTS: Readers identified 83 mHs (mean 1.51) on SWI versus 54 (mean 0.98) on GRE. Burden categories agreed in 34 (61.8%) participants, was higher on SWI in 17 (30.9%) participants, and higher on GRE in 4 (7.3%) participants.

CONCLUSIONS: Readers on average identified more mHs on SWI than GRE, altering risk categories. Prospective studies are needed to establish SWI-based safety thresholds for anti-amyloid therapies.},
}

@article {pmid42959452,
year = {2026},
author = {Acquarone, E and Gutierrez, SBG and Zhang, H and Morin, A and Maccecchini, M and Arancio, O},
title = {Combined administration of buntanetap and dulaglutide counteracts synaptic dysfunction and memory loss in an Alzheimer's disease mouse model.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70336},
pmid = {42959452},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) results from disruptions in proteostasis, metabolism, and neurotrophic signaling that impair synaptic plasticity and memory. Dulaglutide, a blood-brain barrier (BBB)-permeant glucagon-like peptide-1 (GLP-1) receptor agonist, enhances phosphoinositide 3-kinase (PI3K)/Akt and cAMP response element-binding protein (CREB) signaling, while buntanetap reduces translation of aggregation-prone proteins such as amyloid precursor protein (APP), tau, α-synuclein, and transactive response DNA-binding protein of 43 kDa. Although both compounds show cognitive benefits individually, their potential synergistic effects remain unexplored.

METHODS: APP/presenilin 1 (PS1) mice and wild-type (WT) littermates were treated with dulaglutide or buntanetap at high or subthreshold doses, alone or in combination, beginning at plaque deposition. Spatial memory was assessed through the 2-day radial arm water maze (RAWM), associative memory using contextual fear conditioning, and hippocampal Schaffer collateral-CA1 long-term potentiation (LTP) was evaluated as a measure of synaptic plasticity. Motor, sensory, motivational, and shock-sensitivity controls were included to rule out confounding non-cognitive effects. Meso Scale Discovery and Western blotting analyses were performed on frozen hippocampal tissue to assess amyloid beta (Aβ) and the postsynaptic density protein 95 (PSD95) marker levels.

RESULTS: High doses of either dulaglutide or buntanetap alone rescued deficits in spatial and contextual memory as well as LTP in APP/PS1 mice, whereas lower doses produced minimal or partial benefit. Concurrent administration of low, individually ineffective doses of buntanetap (1 mg/kg) and dulaglutide (0.1 mg/kg) fully rescued RAWM performance, restored contextual fear memory and CA1 LTP, reduced Aβ levels, and restored PSD95. The combination treatment did not alter behavior in WT mice across control behavioral tasks, confirming treatment specificity for AD-related deficits.

DISCUSSION: Our findings demonstrate a strong synergistic interaction between BBB-permeant dulaglutide and buntanetap at subthreshold doses, showing that combined enhancement of neurotrophic signaling and reduction of proteotoxic stress can rescue hippocampal dysfunction in early AD. This convergence between GLP-1 receptor-mediated pathways and inhibition of neurotoxic protein synthesis supports the clinical evaluation of GLP-1-based combination therapies with proteostatic modulators such as buntanetap.},
}

@article {pmid42959522,
year = {2026},
author = {Matta, C and Cheon, YH and Vágó, J and Mészár, Z and Kim, EH and Jiang, S and Balogh, A and Zana, M and Dinnyés, A and Jin, EJ},
title = {Engineered peroxisomes and patient-derived iPSC models as potential biomaterial platforms for precision neuroprotection in oxidative stress-driven central nervous system disorders.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103752},
pmid = {42959522},
issn = {2590-0064},
abstract = {Peroxisomes couple hydrogen peroxide metabolism to lipid homeostasis, making their functions relevant to neurological disease and to the design of intracellular catalytic biomaterials. However, the strength of disease-specific evidence and the functions reproduced by current materials vary substantially. This narrative review distinguishes modified biological peroxisomes from artificial and biomimetic platforms and evaluates how patient-derived induced pluripotent stem cell (iPSC) models could support their development. We examine membrane chemistry, substrate permeability, enzyme retention, catalytic activity, cell targeting, blood-brain barrier transport, three-dimensional tissue penetration, and intracellular fate. We separate the established causal role of peroxisomal defects in primary peroxisomal disorders from associative or unresolved findings in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Kleefstra syndrome is discussed as a hypothesis-generating neurodevelopmental model, without assuming a primary peroxisomal defect. Published artificial-organelle studies establish selected catalytic and delivery capabilities, but do not validate the integrated patient-specific CNS therapeutic strategy proposed here. We therefore outline a staged evaluation framework that combines materials characterization with mechanistic controls, differentiated neural cultures, multicellular models, animal pharmacology, safety, and manufacturing assessment. Comparison with conventional antioxidant carriers, plasmalogen supplementation, and PPAR agonists should determine whether compartmentalized catalysis offers a measurable advantage. We provide a platform classification, a disease-resolved evidence hierarchy, and a set of controls and measurable endpoints intended to make peroxisome-inspired constructs comparable across studies. Clinical development will require evidence of disease-relevant benefit beyond ROS reduction and an acceptable therapeutic window.},
}

@article {pmid42959676,
year = {2026},
author = {, },
title = {Retraction: MicroRNA Let-7f-5p Promotes Bone Marrow Mesenchymal Stem Cells Survival by Targeting Caspase-3 in Alzheimer Disease Model.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {2023227},
doi = {10.3389/fnins.2026.2023227},
pmid = {42959676},
issn = {1662-4548},
abstract = {[This retracts the article DOI: 10.3389/fnins.2018.00333.].},
}

@article {pmid42959922,
year = {2026},
author = {Prahutama, A and Suparti, and Utami, IT and Mudafiq, MH and Ceballos, RF},
title = {Conditional ordinal regression based on chain rule probability in Swin Transformer for improved ordinal image classification.},
journal = {MethodsX},
volume = {17},
number = {},
pages = {104200},
pmid = {42959922},
issn = {2215-0161},
abstract = {• Effective image analysis relies on robust feature extraction, a capability for which Swin Transformer is suited. However, ordinal image classification specifically requires capturing the ordered progression of labels. Conventional multiclass methods ignore the natural order of labels and treat them as independent categories, treating all misclassifications equally and leading to severe prediction errors. • To overcome this limitation, Swin Transformer with Conditional Ordinal Regression (CORN) is proposed to model the ordered progression of categories. This framework decomposes the ordinal task into a sequence of conditional binary classifications using chain rule probability. This enables the model to learn the dependency relation between categories and reduces the prediction errors. The proposed Swin+CORN framework is examined on three medical image datasets, namely RetinaMNIST, Alzheimer and Knee Osteoarthritis, and compared with standard Swin-based multiclass classification and Swin+CORAL as an alternative ordinal regression approach. • Swin+CORN achieves the best overall performance over all the three datasets. The proposed framework consistently outperforms both Swin+Multiclass and Swin+CORAL in terms of accuracy and prediction error. Experimental results show the efficiency of the hierarchical visual representation learning combined with CORN for the ordinal image categorisation task.},
}

@article {pmid42960058,
year = {2026},
author = {Bychkov, ML and Ochneva, AG and Ushakova, VM and Morozova, AY and Zorkina, YA and Abramova, OV and Kostyuk, GP and Kirpichnikov, MP and Paramonov, AS and Lyukmanova, EN},
title = {Dysregulation of Expression of Nicotinic Acetylcholine Receptors and Ly6/uPAR Proteins in the Cingulate Gyrus of the Cerebral Cortex of Patients with Alzheimer's Disease.},
journal = {Acta naturae},
volume = {18},
number = {3},
pages = {48-55},
pmid = {42960058},
issn = {2075-8251},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder associated with the dysfunction of nicotinic acetylcholine receptors (nAChRs). The function of nAChRs is normally regulated by endogenous ligands, such as acetylcholine and three-finger proteins belonging to the Ly6/uPAR family. However, information on the involvement of these proteins in the pathogenesis of AD is lacking. In this study, by using a bioinformatic analysis, we identified increased mRNA levels of Ly6/uPAR proteins (Lynx1, Lynx2, SLURP-1, Ly6G6E, etc.) in the entorhinal, temporal, and frontal cortex in AD patients with neurodegenerative symptoms, as well as an increase in the mRNA level of Ly6E in the hippocampus in patients with asymptomatic AD. Furthermore, in the cortex and cerebellum, we identified multidirectional changes in the mRNA expression of different nAChR subunits and regulators of inflammation (CD59, CD177, Lypd2, Lypd4, and Lypd8) and metabolism (GPIHBP and Ly6D), also belonging to the Ly6/uPAR protein family. By using immunostaining and Western blotting, we confirmed increased protein levels of Lynx1, Lynx2, and the β2 nAChR subunit in the cingulate gyrus adjacent to the entorhinal cortex in patients with AD, as well as decreased protein levels of the α4 and α7 nAChR subunits. These findings point to complex dysregulation of the cholinergic system in the AD brain at the expression levels both of the individual nAChR subtypes and its natural modulators belonging to the Ly6/uPAR family.},
}

@article {pmid42960243,
year = {2026},
author = {Zhang, BY and Wallman-Jones, A and Salminen, LE and Oyen, E and Leguizamon, M and Axelrod, J and Molinare, CP and Noriega-Makarskyy, DT and Williams, JT and Han, SD},
title = {Age-dependent gray matter correlates of perceived financial exploitation vulnerability in cognitively unimpaired older adults.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100173},
pmid = {42960243},
issn = {2589-9589},
abstract = {Financial exploitation vulnerability in aging is a growing public health concern, yet its neural correlates remain poorly understood. Although psychosocial and cognitive factors confer risk, emerging evidence suggests that regional differences in brain structure may also contribute to vulnerability before overt cognitive impairment. In this study, 128 cognitively unimpaired older adults (ages 51 to 87 years, 76% female) completed structural magnetic resonance imaging and the Perceived Financial Vulnerability Scale, a self-report measure of financial exploitation risk. We examined age-stratified associations between perceived financial exploitation vulnerability and gray matter volume in relatively younger (n = 67) and older (n = 61) participants. Whole-brain voxel-based morphometry analyses revealed that higher perceived financial exploitation vulnerability was associated with lower gray matter volume in the right amygdala/anterior hippocampus (max t = 4.55, pFWE = 0.029) and left precuneus (max t = 5.40, pFWE = 0.031) among older participants, but not younger participants. In post hoc exploratory analyses modeling age as a continuous variable across the full sample, the age × perceived financial exploitation vulnerability interaction was significant for gray matter volume in the left precuneus and was observed at a trend level in the right amygdala/anterior hippocampus, with more negative associations at older ages. These cross-sectional findings identify regional gray matter correlates of perceived financial exploitation vulnerability that may vary across later adulthood.},
}

@article {pmid42960253,
year = {2026},
author = {Greenlee, MA and Amniouel, S and Rivera, I and Suh, J and Martinez, NJ and Simeonov, A and Head, E and Tycko, R and Zheng, W and Fleming, BD and Zhang, Q},
title = {A fibril-selective single-domain antibody targets pathogenic amyloid-β assemblies and protects human neurons.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117946},
pmid = {42960253},
issn = {2589-0042},
abstract = {Alzheimer disease is characterized by extracellular amyloid-β deposition that contributes to neuronal dysfunction and degeneration. Although anti-amyloid-β antibodies reduce plaque burden, their use requires monitoring for amyloid-related imaging abnormalities. Here, phage display against immobilized Aβ40 fibrils representing a patient-relevant polymorph identified J8, a fibril-selective, Fc-free single-domain antibody. J8 bound fibrils with high apparent affinity, showed no detectable binding to monomeric Aβ40, decorated fibril surfaces, and recognized plaque-associated amyloid in Alzheimer disease brain tissue. During concurrent fibril exposure, J8 reduced apoptotic signaling in human induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids. Single-nucleus profiling of pooled organoids identified fibril-associated stress programs and opposite-direction expression patterns in the FibJ8 condition; fibril-associated changes showed the strongest directional concordance with advanced disease pathology. These findings identify J8 as a fibril-selective candidate and support organoid-based evaluation of anti-amyloid reagents as a fit-for-purpose preclinical tool.},
}

@article {pmid42960311,
year = {2026},
author = {Lehrer, S},
title = {ERBB4 Perturbation Supports a Developmental Cytoskeletal Reactivation Hypothesis in Alzheimer's Disease.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e117166},
pmid = {42960311},
issn = {2168-8184},
abstract = {BACKGROUND: Aberrant reactivation of developmental cytoskeletal programs may contribute to Alzheimer's disease (AD). We tested whether a prespecified Arp2/3-RAC1-MYH10-KIF5C module is regulated by Erb-B2 receptor tyrosine kinase 4 (ERBB4) in an AD-model neuronal state, providing a perturbational test of the hypothesis that aberrant re-engagement of developmental cytoskeletal machinery contributes to AD.

METHODS:  We performed a secondary analysis of publicly available single-nucleus RNA-sequencing data from ERBB4 perturbation experiments using pseudobulk analysis with the primary conservative excitatory-neuron classifier. A prespecified 10-gene module comprising Actr2, Actr3, Arpc1a, Arpc2, Arpc3, Arpc4, Arpc5, Rac1, Myh10, and Kif5c was tested using CAMERA and expression-matched permutation analyses.

RESULTS: ERBB4 disruption in 5 × FAD excitatory neurons downregulated all 10 module genes (CAMERA P = 0.0207). Arpc4, Arpc1a, and Kif5c remained significant after false-discovery-rate correction. Expression-matched permutation testing independently supported pathway downregulation (mean log-fold-change P = 0.0102; 10/10 genes down P = 0.0041; CAMERA permutation P = 0.0150). ERBB4 overexpression in wild-type neurons did not significantly alter the complete module, although Arpc5 was significantly induced, suggesting selective component responsiveness.

CONCLUSIONS: Independent perturbational data support ERBB4-dependent regulation of a prespecified Arp2/3-centered cytoskeletal program in AD excitatory neurons, with effects dependent on the disease context.},
}

@article {pmid42960521,
year = {2026},
author = {Roveta, F and Mendes, AJ and Garibotto, V and Boccalini, C and Lathuiliere, A and Rainero, I and Rubino, E and Zetterberg, H and Ashton, NJ and Ribaldi, F and Frisoni, GB and , },
title = {The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70558},
pmid = {42960521},
issn = {2328-9503},
support = {//State of Geneva/ ; //Private Foundation of Geneva University Hospitals/ ; //Association Suisse pour la Recherche sur la Maladie d'Alzheimer (A.P.R.A.)/ ; //Fondation Segré/ ; //Race Against Dementia Foundation/ ; //Fondation Child Care/ ; //Fondation Edmond J. Safra/ ; //Fondation Minkoff/ ; //Fondazione Agusta/ ; //McCall Macbain Foundation/ ; //Nicole et René Keller/ ; //Fondation AETAS/ ; AirAlzh-AGYR-2023//Associazione Italiana Ricerca Alzheimer Onlus/ ; //Italian Ministry of the University (MUR)/ ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; 320030_182772/SNSF_/Swiss National Science Foundation/Switzerland ; 32003B0_220269/SNSF_/Swiss National Science Foundation/Switzerland ; },
abstract = {OBJECTIVE: To clarify the relative contributions of amyloid and tau to synaptic dysfunction in Alzheimer's disease (AD).

METHODS: We included 109 cognitively unimpaired and impaired individuals from the Geneva Memory Center with available CSF synaptic biomarkers (neurogranin, SNAP-25, GAP-43). Participants were stratified according to amyloid (A) and tau (T) status, and group comparisons and correlations between synaptic and AD biomarkers were assessed. Multiple linear regression models evaluated the independent associations of amyloid and tau with synaptic markers: Model I (n = 109) included CSF Aβ42 and p-tau181, while Model II (n = 69) included amyloid PET centiloid and CSF p-tau181. Mediation analyses were performed to further investigate these relationships. Findings were replicated in the ADNI cohort (n = 787).

RESULTS: Synaptic biomarker levels were significantly higher in A+/T+ individuals compared with A-/T- and A+/T- groups (p < 0.001). CSF p-tau181 strongly correlated with synaptic markers. In Model I, GAP43 was positively associated with both CSF Aβ42 (β = 0.31, 95% CI 0.23-0.40) and p-tau181 (β = 0.94, 95% CI 0.84-1.04; p < 0.001). In Model II, lower amyloid PET centiloid (β = -0.31, 95% CI -0.46 to -0.16) and higher p-tau181 (β = 1.02, 95% CI 0.86-1.19) predicted increased GAP43 (p < 0.001), with the same pattern of associations observed for neurogranin and SNAP-25. The association between amyloid burden and synaptic biomarkers was largely indirect, statistically mediated by CSF p-tau181. Results were replicated in ADNI.

INTERPRETATION: Tau pathology showed strong associations with synaptic biomarkers, with a potential mediating role in the association between amyloid pathology and synaptic dysfunction. These findings support a central role of tau-related processes in synaptic dysfunction in AD.},
}

@article {pmid42960557,
year = {2026},
author = {Benitez, A and Hickey, R and Baker, N and Thorn, K and Watson, Z and Nunn, L and McRae-Clark, A},
title = {Sex Differences in Stress Reactivity and Dementia Risk: A Pilot Study of Older Adults With Problematic or Frequent Cannabis Use.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261502978},
doi = {10.1177/08919887261502978},
pmid = {42960557},
issn = {1552-5708},
abstract = {IntroductionWe conducted a pilot study of older cannabis users with problematic or frequent (i.e. ≥4/7 days/week) use as a preliminary test of the hypothesis that compared to men, women would demonstrate greater stress reactivity and dementia risk.Methods47 participants ages 50-75 (55.3% male, 68% with cannabis use disorder) completed the Trier Social Stress Test, neuropsychological testing, 3T brain MRI, and blood draw.ResultsMen demonstrated: greater salivary cortisol, systolic blood pressure, and craving post-stress induction; worse memory and executive function; greater risk of heart disease or stroke and white matter hyperintensity volumes. There were no sex differences in Alzheimer's disease plasma biomarkers.ConclusionsAmong non-treatment-seeking older adults with problematic or frequent cannabis use, men may have greater risk for dementia due to stress reactivity and vascular risk factors. Future work must replicate and verify this unexpected sex difference and the specificity of these effects to cannabis use.},
}

@article {pmid42960616,
year = {2026},
author = {Warren, JR and Grodsky, E and Muller, CL and Manly, JJ and Brickman, AM and Kim, S and Himmelstern, J and Demmer, RT},
title = {Periodontal disease, biomarkers of ADRD risk, and cognitive functioning.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70210},
pmid = {42960616},
issn = {1943-3670},
support = {U01AG058719/NH/NIH HHS/United States ; R03DE034500/NH/NIH HHS/United States ; SG-20717567/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Periodontitis is a hypothesized risk factor for cognitive impairment. Many prior studies lack information on biological markers of Alzheimer's disease and related dementias (ADRD) risk or genetic risk markers. We assessed the association between periodontitis, biological markers of ADRD risk, and cognitive test performance with robust adjustment for risk factors including high risk genotypes for ADRD.

METHODS: We use data from the United States High School and Beyond (HS&B:80) cohort study, a nationally representative sample of ∼26,830 people enrolled during high school in 1980 through midlife in 2021. Baseline data include information about educational contexts, opportunities, and outcomes; early life circumstances; and demographic group memberships. HS&B:80 data from 2021 include indicators of periodontal disease diagnosis history, blood biomarkers of ADRD risk, and multiple measures of cognitive functioning. We calculated false discovery rates (FDR) to account for multiple comparisons.

RESULTS: Our analyses included 13,950 HS&B:80 panelists (mean age 58 years), among whom 15.2% reported a history of periodontal disease. Periodontal disease was associated with lower general cognitive functioning and scores on some domain-specific cognitive tasks; it was also associated with increased levels of pTau-181 and C-reactive protein. We find no evidence of heterogeneity in associations by sex, race and ethnicity, or number of apolipoprotein E (APOE) ε4 alleles. Only working memory attained a FDR < 10% after multiple comparisons adjustment.

CONCLUSION: In this large, diverse, population-representative, community-dwelling sample, self-reported periodontal disease was cross-sectionally associated with cognitive functioning at age ∼60 and some biomarkers of ADRD risk although most associations were not significant after multiple comparisons corrections.

PLAIN LANGUAGE SUMMARY: Poor gum health has been suggested as a possible contributor to memory and thinking problems later in life, but many studies have not been able to account for important biological and genetic risk factors linked to Alzheimer's disease and related dementias. To better understand this relationship, we analyzed data from nearly 14,000 participants in a large, nationally representative U.S. study who were approaching age 60 in 2021. About 15% reported having been diagnosed with periodontal (gum) disease. People with a history of gum disease tended to perform slightly worse on measures of overall cognitive function and some specific thinking tasks. They also had modestly higher levels of blood markers associated with inflammation and increased risk of Alzheimer's disease and related dementias. These associations were similar across men and women, racial and ethnic groups, and people with different levels of genetic risk based on apolipoprotein E (APOE) status. While this study cannot determine whether gum disease causes cognitive decline, the findings suggest that poor periodontal health may be potentially linked to both cognitive performance and biological signs associated with dementia risk in midlife, highlighting the importance of future research that can better understand if these observations are causal or coincidental.},
}

@article {pmid42960972,
year = {2026},
author = {Vashist, A and Lakshmana, MK},
title = {Alzheimer's disease: targeted nanomedicine to mitigate neuroinflammation.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/17435889.2026.2754961},
pmid = {42960972},
issn = {1748-6963},
}

@article {pmid42961122,
year = {2026},
author = {Xiao, Y and Zhou, Z and Jin, M and Wang, C and Qian, X and Jia, F},
title = {Bidirectional transitions between subjective cognitive decline and normal cognition and risk of mild cognitive impairment: A multistate Markov model study in NACC UDS.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502867},
doi = {10.1177/13872877261502867},
pmid = {42961122},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) may be an early indicator of Alzheimer's disease but often reverts to normal cognition (NC), leaving its prognostic significance uncertain.ObjectiveTo quantify bidirectional transitions between SCD and NC and to evaluate the long-term risk of progression to mild cognitive impairment after reversion.MethodsUsing longitudinal data from the National Alzheimer's Coordinating Center Uniform Data Set, we fitted continuous-time multistate Markov models for NC, SCD, mild cognitive impairment (MCI), and dementia. Three cohorts were analyzed: baseline SCD, baseline NC, and post-SCD reversion. Transition intensities and 15-year state-occupancy probabilities were estimated, and covariate effects were assessed using nested multivariable models. Death was evaluated as a competing absorbing state in a sensitivity analysis.ResultsThe primary analysis included 4283 participants with baseline SCD, 11,709 with baseline NC, and 2099 in the post-SCD reversion cohort. In the baseline-SCD cohort, reversion to NC was substantially more frequent than progression to MCI (transition intensity ratio, 3.27; 95% CI, 3.05-3.50). However, the post-SCD reversion cohort showed a long-term cognitive risk profile similar to the baseline-SCD cohort and less favorable than the baseline-NC cohort. Older age, APOE ε4 carriage, informant-reported decline, and greater neuropsychiatric or functional impairment were associated with higher progression risk, whereas older age and depression were associated with lower reversion intensity.ConclusionsSCD is a dynamic cognitive state with substantial potential for reversion, but reversion to NC does not necessarily restore the long-term risk profile observed in individuals cognitively normal at baseline.},
}

@article {pmid42961128,
year = {2026},
author = {Kamihara, T and Kato, R and Morisaki, A and Kaneko, S and Omura, T and Shimizu, A},
title = {Deciphering the neuroprotective signaling of SGLT2 inhibitors in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502860},
doi = {10.1177/13872877261502860},
pmid = {42961128},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) currently lacks fundamental curative treatments. While epidemiological evidence increasingly links sodium-glucose cotransporter 2 (SGLT2) inhibitors to reduced AD risk, the underlying molecular mechanisms remain poorly understood.ObjectiveThis study aimed to elucidate the potential molecular pathways through which SGLT2 inhibitors intervene in AD pathophysiology using a bioinformatics approach.MethodsPotential targets for empagliflozin and dapagliflozin were predicted via SwissTargetPrediction. AD-related differentially expressed genes (DEGs) were identified from a human brain dataset (GSE125583) utilizing the GREIN platform. Common genes were analyzed for functional networks (GeneMANIA/STRING) and pathway enrichment (KEGG). Hub proteins were identified using Cytoscape centrality metrics, and organ-specific expression was verified through the RefEx database.ResultsFifty-seven genes were common to SGLT2 inhibitor targets and AD DEGs. Notably, the transporters SLC5A11 and SLC2A1 were significantly upregulated in AD brains and exhibited high brain-specific expression. Pathway analysis revealed significant involvement in the MAPK and FoxO signaling pathways, which regulate apoptosis, autophagy, and oxidative stress. Key hub proteins identified included ERBB2, HSP90AA1, DPP4, and SLC2A1. It is hypothesized that SGLT2 inhibitors exert neuroprotective effects by targeting these upregulated transporters, thereby suppressing MAPK signaling and activating the FoxO pathway.ConclusionsOur findings suggest that SGLT2 inhibitors may normalize MAPK/FoxO signaling and restore cellular homeostasis in the AD brain. This study provides a potential theoretical insight for the drug repositioning of antidiabetic agents and offers key indicators for the design of future clinical and basic research in AD therapy.},
}

@article {pmid42961134,
year = {2026},
author = {Dissard, M and Deheinzelin, L and Ouadghiri, S and Creusat, A and Rey, S and Delahouliere, L and Mathieu, E and Vallet, M and Brissard, A and Brunet, C and Derobert, I and Lacour, M and Zarea, A and Martinaud, O and Wallon, D and Morin, A},
title = {Draw me a zebra: Study of an item-drawing protocol to assess semantic memory in a memory clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502808},
doi = {10.1177/13872877261502808},
pmid = {42961134},
issn = {1875-8908},
abstract = {BackgroundSemantic memory is often impaired in neurodegenerative diseases such as Alzheimer's disease and frontotemporal lobar degeneration. Evaluating it requires cross-referencing the results of different tests in several modalities. However, most of the available tests only assess verbal production, which may be altered by conditions other than semantic deficits, making interpretation more difficult.ObjectiveTo evaluate the Item Drawing Test (IDT), a non-verbal semantic production task, and examine its reliability and preliminary discriminative ability for detecting semantic impairment in a memory clinic population.MethodsForty-one patients with suspected neurodegenerative disease were assessed using an algorithm combining two semantic memory tests from GREMOTs, the Pyramids and Palm Trees Test, and the IDT, which included 10 drawings for a total score of 49 points. Diagnostic performance was explored using receiver operating characteristic analysis. Inter-rater reliability and associations with global cognitive status (MMSE) were also examined.ResultsThe IDT distinguished 16 patients with semantic impairment (SI) from those without. The optimal threshold score was 42/49 (sensitivity = 88%, specificity = 81.3%; AUC = 0.839; 95% CI = 0.699-0.978). Inter-rater reliability was excellent (intraclass correlation coefficient = 0.972; 95% CI = 0.953-0.984). IDT score correlated moderately with MMSE (r = 0.53, p = 0.0004). In multivariable logistic regression including MMSE, global cognitive status remained significantly associated with SI (p = 0.008). Qualitative analysis of the IDT results provided detailed information about patients' semantic knowledge. Patients with SI produced semantic errors, semantic feature substitutions, and showed visuospatial errors or a tendency toward prototype.ConclusionsThe IDT enables a rapid detection of semantic impairment in patients at risk of neurodegenerative disease. This tool may be useful in clinical practice to limit the influence of verbal production in semantic assessment.},
}

@article {pmid42961136,
year = {2026},
author = {Chen, F and Hong, Y and Guan, H and Zhu, Y and Li, J and Fang, X and Ye, F},
title = {Unveiling the molecular bridge between hearing loss and dementia via plasma proteomic mapping.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502870},
doi = {10.1177/13872877261502870},
pmid = {42961136},
issn = {1875-8908},
abstract = {BackgroundHearing loss (HL) is a potentially modifiable risk factor for dementia, but the circulating molecular features shared by hearing impairment and dementia remain unclear.ObjectiveTo derive a plasma proteomic signature of hearing impairment and examine its association with incident all-cause dementia and its statistical contribution to the hearing-dementia association.MethodsWe analyzed 13,941 UK Biobank participants with plasma proteomics and speech-in-noise hearing assessments. A proteomic signature of hearing impairment was derived using elastic-net regression with 10-fold cross-validation. A proteomic signature was constructed and tested for associations with incident all-cause dementia using Cox models. Mediation, functional enrichment, and exploratory drug-signature enrichment analyses were also performed.ResultsElastic-net regression selected 64 proteins, and the composite signature correlated with hearing impairment (point-biserial r = 0.232). Compared with normal hearing, insufficient (HR = 1.338, 95% CI: 1.015-1.763) and poor hearing (HR = 2.021, 95% CI: 1.244-3.283) were associated with higher dementia risk after multivariable adjustment. The proteomic signature was associated with incident dementia (HR = 1.791, 95% CI: 1.312-2.445). Estimated proportions mediated were 22.99% (95% bootstrap CI: 4.87%-129.05%) and 14.61% (95% bootstrap CI: 2.21%-64.21%), respectively. Drug-signature enrichment yielded exploratory compound-protein signals.ConclusionsIn this prospective cohort, hearing impairment and a derived plasma proteomic signature were associated with incident all-cause dementia. These findings provide hypothesis-generating evidence for circulating molecular features shared by hearing impairment and dementia but require external validation and mechanistic investigation before causal or clinical interpretation.},
}

@article {pmid42961137,
year = {2026},
author = {Yao, MY and Guo, HH and Li, QY and Huang, LY and Tan, L and Wang, HF and , },
title = {Cerebrospinal fluid p62/SQSTM1 is associated with tau pathology, brain structural alterations, and cognitive impairment in adults without dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502791},
doi = {10.1177/13872877261502791},
pmid = {42961137},
issn = {1875-8908},
abstract = {BackgroundThe involvement of cerebrospinal fluid (CSF) Sequestosome-1 (SQSTM1, commonly known as p62), an autophagy-related scaffold protein, in Alzheimer's disease (AD) pathogenesis is not well established in human populations.ObjectiveTo investigate the associations of baseline CSF p62/SQSTM1 levels with cognitive function, AD biomarkers, brain structure, and incident dementia in non-demented individuals.MethodsWe included 557 dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative cohort. Multivariate regression and interaction analyses examined associations of CSF p62/SQSTM1 with cognition, AD biomarkers, and brain volumes and their modification by age, sex, APOE genotype, and diagnostic status. Kaplan-Meier and Cox analyses assessed dementia-free survival and incident dementia risk. Mediation analysis tested whether AD pathology and brain structure mediated the association between p62/SQSTM1 and cognition.ResultsElevated CSF p62/SQSTM1 levels correlated with poorer cognition, heightened tau pathology, increased sTREM2 and PGRN levels, and decreased whole-brain and fusiform gyrus volumes. Age modified p62/SQSTM1 associations with cognition and whole-brain volume. Subgroup analyses revealed that significant associations between p62/SQSTM1 and cognitive function (MMSE, MEM) were primarily observed in the middle-aged group. Longitudinal analyses further showed that participants in the highest quartile (Q4) exhibited an increased risk compared to the lowest (Q1) (HR = 1.78, 95% CI 1.16-2.73). Mediation analysis indicated that tau pathology and reduced brain volumes mediated the association between p62/SQSTM1 and cognition.ConclusionsHigher p62/SQSTM1 levels were associated with tau pathology and an elevated risk of AD. Tau-related pathological changes and brain structural alterations might be involved in the relationship between the p62/SQSTM1-related autophagy processes and cognition.},
}

@article {pmid42961255,
year = {2026},
author = {Silva, MMAF and Lopes, RF and Almeida, TG and Silva, AFD and Silva, VND and Leite, LKT and Serbim, AK},
title = {Health Literacy of caregivers of older adults with Alzheimer's disease: a qualitative study.},
journal = {Revista gaucha de enfermagem},
volume = {47},
number = {},
pages = {e20260018},
doi = {10.1590/1983-1447.2026.20260018.en},
pmid = {42961255},
issn = {1983-1447},
mesh = {Humans ; *Health Literacy ; *Caregivers/psychology ; *Alzheimer Disease/nursing ; Female ; Qualitative Research ; Aged ; Male ; Middle Aged ; },
abstract = {OBJECTIVE: to understand the health literacy skills experienced by family caregivers of older adults with Alzheimer's disease.

METHOD: qualitative, exploratory-descriptive study, conducted with 12 family caregivers of older adults with Alzheimer's disease, participants of a support group on social media, in the municipality of Arapiraca, Alagoas. Data collection occurred through semi-structured interviews about seeking, understanding, communicating, and assessing information about the disease. Data were analyzed using thematic analysis.

RESULTS: the caregivers' health literacy was built through autonomous search for information, use of digital sources, and difficulties in translating received guidelines into safe care practices. Communication of information occurred predominantly in family and community networks, while the evaluation of content reliability was found to be fragile.

FINAL CONSIDERATIONS: caregivers' health literacy goes beyond access to information and involves the ability to understand, communicate, and critically evaluate it in daily caregiving. The findings support the development of nurse-led educational interventions, the strengthening of digital health literacy, and the implementation of institutional actions to support family caregivers.},
}

Humans
*Health Literacy
*Caregivers/psychology
*Alzheimer Disease/nursing
Female
Qualitative Research
Aged
Male
Middle Aged

@article {pmid42961631,
year = {2026},
author = {Dong, S and Gao, K and Lin, W and Chen, W and Liu, H and Wang, Q and Yi, Z},
title = {Cost-Effectiveness Analysis of Disease-Modifying Therapies for Early Alzheimer's Disease in China.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42961631},
issn = {2193-8253},
support = {72674010//National Natural Science Foundation of China/ ; MBRC0012025062//Talent Development Plan for the Future in Medical-Engineering Integration of BRA-CDCHE and ZTA/ ; },
abstract = {INTRODUCTION: Lecanemab and donanemab are disease-modifying therapies for early Alzheimer's disease, but their long-term economic value in China remains uncertain. This study evaluated their long-term cost-effectiveness in China.

METHODS: A lifetime Markov model compared lecanemab plus standard of care (SoC), donanemab plus SoC, and SoC alone from the Chinese healthcare system and societal perspectives. Treatment cohorts were stratified by apolipoprotein E ε4 genotype. The model incorporated Chinese real-world costs, treatment-related adverse events, discontinuation, and post-discontinuation benefits. Outcomes included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses assessed parameter uncertainty, while scenario analyses examined drug prices, treatment populations, administration routes, and efficacy assumptions.

RESULTS: From the healthcare system perspective, ICERs (in United States dollars [USD]) for lecanemab plus SoC and donanemab plus SoC were USD 309,841.194/QALY and USD 232,793.705/QALY, respectively. Corresponding societal ICERs were USD 300,434.358/QALY and USD 212,256.111/QALY. All estimates exceeded the prespecified willingness-to-pay threshold. The ICER for lecanemab was driven mainly by treatment efficacy and drug price, whereas donanemab was most sensitive to the duration of residual treatment effect. Varying the treatment-eligible population had limited impact on the ICERs. From the healthcare system perspective, ICERs ranged from USD 304,889.902 to USD 310,071.658/QALY for lecanemab and USD 211,226.601 to USD 240,400.661/QALY for donanemab; the corresponding societal ranges were USD 293,467.938-312,810.263/QALY and USD 204,513.613-214,437.087/QALY. At assumed United States prices for subcutaneous lecanemab, intravenous administration had a slightly lower ICER from the healthcare system perspective (USD 309,841.194/QALY versus USD 317,811.454/QALY), whereas all-subcutaneous administration had a slightly lower societal ICER (USD 298,027.332/QALY versus USD 300,434.358/QALY).

CONCLUSION: Neither lecanemab nor donanemab was cost-effective at current Chinese prices. Patient selection had limited impact. The lower ICER for donanemab depended on the assumed residual treatment effect after discontinuation.},
}

@article {pmid42961657,
year = {2026},
author = {Rezapour, R and Jaberi-Asl, A and Vasheghani Farahani, A and Bahramirad, A and Farhadi, M and Jameie, SB},
title = {Resveratrol partially restores the expression of the clock genes Per1 and Bmal1 in the suprachiasmatic nucleus of scopolamine-induced Alzheimer's rat model.},
journal = {Experimental brain research},
volume = {244},
number = {12},
pages = {},
pmid = {42961657},
issn = {1432-1106},
mesh = {Animals ; *Resveratrol/pharmacology ; *Alzheimer Disease/metabolism/chemically induced/drug therapy/pathology ; Male ; *Period Circadian Proteins/metabolism/genetics/drug effects ; *ARNTL Transcription Factors/metabolism/drug effects/genetics ; Rats, Wistar ; Disease Models, Animal ; *Suprachiasmatic Nucleus/drug effects/metabolism ; Rats ; Scopolamine/toxicity ; *Antioxidants/pharmacology ; Stilbenes/pharmacology ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia and is associated with disruptions in biological rhythms regulated by clock genes within the suprachiasmatic nucleus (SCN). Altered expression of these genes may contribute to disease progression and symptom severity. Resveratrol (Res), a polyphenolic compound with antioxidant and neuroprotective properties, has been reported to alleviate AD-related impairments. This study aimed to examine the effects of Res on the expression of the clock genes Bmal1, Per1, and p53 in the SCN of a scopolamine-induced AD rat model. Thirty-six male Wistar rats were randomly assigned to four groups: control (Cont), AD, AD+ethanol (AD + Eth), and AD+Resveratrol (AD + Res). AD was induced by intraperitoneal injection of scopolamine, and histopathological confirmation was performed using Congo red staining. The mRNA expression levels of Bmal1, Per1, and p53 in the SCN were quantified by qRT-PCR, and neuronal density was assessed using Nissl staining. The expression of Bmal1 and Per1 was significantly decreased in the AD and the AD + Eth groups compared with the control group. Resveratrol treatment significantly upregulated these genes relative to both the AD and the AD + Eth groups. In contrast, p53 expression was markedly elevated in all AD-related groups, while Res significantly reduced its expression in the AD + Res group. Nissl staining showed a reduction in neuronal density in the SCN of AD rats, which was partially restored by Res. Res improved spatial learning and memory and partially restored Per1 and Bmal1 expression in the SCN, but a causal relationship was not tested.},
}

Animals
*Resveratrol/pharmacology
*Alzheimer Disease/metabolism/chemically induced/drug therapy/pathology
Male
*Period Circadian Proteins/metabolism/genetics/drug effects
*ARNTL Transcription Factors/metabolism/drug effects/genetics
Rats, Wistar
Disease Models, Animal
*Suprachiasmatic Nucleus/drug effects/metabolism
Rats
Scopolamine/toxicity
*Antioxidants/pharmacology
Stilbenes/pharmacology
Tumor Suppressor Protein p53/metabolism

@article {pmid42961718,
year = {2026},
author = {Li, D and Ding, G and Sun, Z and Qian, Y and Zhang, W and Wang, G and Zhang, F},
title = {Heat-Killed Lactobacillus murinus Attenuates Aβ25-35-Induced Neurotoxicity and Alters Hippocampal 6-Phosphogluconate Metabolism.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42961718},
issn = {1867-1314},
support = {F-1055//Doctor Start Fund of Zunyi Medical University/ ; MS[2025]382, ZK[2024]259//Guizhou Provincial Basic Research Program (Natural Science)/ ; GMULH (2025) 020//Guizhou Science and Technology Department/ ; No. 82460711//the National Natural Science Foundation of China/ ; Nos. ZYD[2025]022, ZD[2026]163 and KJLYRC-[2026]038//the Science and Technology Foundation of Guizhou Province/ ; },
abstract = {The gut microbiota is increasingly recognized as an important contributor to Alzheimer's disease (AD), potentially influencing disease progression through the gut-brain axis. Lactobacillus murinus (L. murinus) is a Gram-positive bacterium with established anti-inflammatory and antibacterial properties; however, the neuroprotective potential of heat-killed L. murinus (H-K L. murinus) in AD models remains unclear. In the present study, we investigated the effects of H-K L. murinus in an Aβ25-35-induced rat model. H-K L. murinus treatment significantly improved behavioral and cognitive performance while attenuating neuronal damage in the hippocampus and cerebral cortex. Untargeted metabolomic analysis identified 6-phosphogluconic acid (6-PGA) as a markedly elevated hippocampal metabolite following H-K L. murinus administration. Exogenous 6-PGA supplementation largely recapitulated the protective effects of H-K L. murinus, improving cognitive performance and preserving neuronal integrity. Mechanistically, both H-K L. murinus and 6-PGA increased NADPH and glutathione (GSH) levels, suppressed reactive oxygen species (ROS) accumulation, down-regulated Bax expression, up-regulated Bcl-2 expression, and ultimately attenuated neuronal apoptosis in Aβ25-35-treated rats. Collectively, these findings demonstrate that H-K L. murinus mitigates Aβ25-35-induced neurotoxicity and highlight hippocampal 6-PGA-associated metabolism as a potential candidate contributor to its neuroprotective effects.},
}

@article {pmid42962081,
year = {2026},
author = {Shafeeque, CM and Cotton, K and Sathyan, S and Ayers, EI and Nunez, V and Marusic, U and Weiss, EF and Ross, D and Yang, J and Blumen, HM and Mahoney, JR and Verghese, J},
title = {An Exceptional Mobility Group Among Older Adults: Protocol for the Super Movers Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e104520},
doi = {10.2196/104520},
pmid = {42962081},
issn = {1929-0748},
mesh = {Humans ; Aged ; Female ; Male ; *Aging/physiology ; Gait/physiology ; Aged, 80 and over ; Brain/physiopathology ; },
abstract = {BACKGROUND: Gait dysfunction is a preclinical marker of Alzheimer disease (AD) and related dementias (ADRD), often emerging years before clinical diagnosis. While much of the existing literature has focused on the pathological mechanisms driving motor and cognitive decline, the neural and biological substrates that confer resilience against such decline remain poorly understood. Individuals who maintain exceptional gait performance into advanced age, termed Super Movers, represent a unique phenotype of resilient aging. Understanding the biological profile of these individuals offers a unique and largely untapped window into the mechanisms underlying healthy aging and resilience to dementia.

OBJECTIVE: This study aims to identify the structural, functional, neurophysiological, and molecular brain characteristics that distinguish older adults with exceptional mobility from their usual and slow-moving peers, and to determine whether these characteristics predict cognitive and physical decline over time. We hypothesize that the interplay between protective and pathological mechanisms in aging gives rise to structural, functional, neurophysiological, and molecular brain changes that manifest along a continuum from resilient gait to gait dysfunction.

METHODS: We aim to enroll 350 adults aged 65 years and older from community and clinic settings. Participants will be classified by gait speed into fast, usual, and slow movers using age- and sex-specific thresholds; fast movers aged 80 years and older will be designated as Super Movers. All participants will undergo comprehensive assessments at baseline, including brain imaging, mobile electroencephalogram (EEG) recorded during walking, multisensory integration (MSI), comprehensive blood profiling, blood-based markers of neurodegeneration, epigenetic and proteomic aging clocks, and detailed cognitive testing. Follow-up assessments will be conducted annually in person and every 6 months by telephone.

RESULTS: This study was funded by the National Institute on Aging (R01AG089096; PI: Joe Verghese) and has received Institutional Review Board (IRB) approval from Stony Brook University. Enrollment is currently underway.

CONCLUSIONS: Fast and Super Movers are expected to demonstrate distinct neural substrates, EEG activation signatures, and favorable biomarker profiles relative to usual and slow movers. By shifting the scientific focus from the biology of gait decline toward the biology of gait resilience, this protocol is uniquely positioned to advance our understanding of healthy aging and inform novel strategies for dementia prevention.},
}

Humans
Aged
Female
Male
*Aging/physiology
Gait/physiology
Aged, 80 and over
Brain/physiopathology

@article {pmid42962364,
year = {2026},
author = {Taghiyeva, A and Lim, J and Biswas, A and Mondal, S and Mukherjee, RU and Basavanakatti, VN and Bayrak, N and Jayaprakash, V and Paik, MJ and Kim, H and TuYuN, AF},
title = {Morpholine-Based Chalcones as Potent and Selective MAO-B Inhibitors With Preliminary CNS Drug-Like Properties.},
journal = {ChemMedChem},
volume = {21},
number = {21},
pages = {},
doi = {10.1002/cmdc.70515},
pmid = {42962364},
issn = {1860-7187},
support = {FDK-2024-40842//the Scientific Research Projects Coordination Unit of Istanbul University/ ; },
mesh = {*Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis/metabolism ; *Chalcones/chemistry/pharmacology/chemical synthesis ; *Monoamine Oxidase/metabolism ; Humans ; Structure-Activity Relationship ; *Morpholines/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Animals ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Molecular Dynamics Simulation ; },
abstract = {A series of morpholine-based chalcone derivatives containing alkoxy substituents was designed and synthesized using a rapid and environmentally friendly microwave-assisted protocol. The synthesized compounds were fully characterised by NMR, FTIR, and HRMS analyses and evaluated in vitro against primarily monoamine oxidases, as well as acetylcholinesterase, butyrylcholinesterase, and β-site amyloid precursor protein cleaving enzyme 1, which are closely associated with neurodegenerative disorders. Although most compounds showed weak inhibition of AChE, BChE, and BACE1, they exhibited potent and selective MAO-B inhibitory activity. Among them, MBC21 emerged as the most potent MAO-B inhibitor (IC50 = 0.069 ± 0.0075 μM; SI 243.33), acting as a competitive and reversible inhibitor. In addition, MBC1, MBC2, and MBC24 displayed notable BChE inhibitory activity, while MBC24 demonstrated multi-target activity against MAO-B, AChE, and BChE. Molecular docking and molecular dynamics simulations revealed that the selectivity of MBC21 towards hMAO-B is associated with stable hydrophobic interactions and π-π stacking with TYR326. Furthermore, in silico ADME prediction, microsomal stability, and PAMPA-BBB studies demonstrated favorable drug-like properties, improved metabolic stability, and moderate brain permeability for MBC21. Taken together, these findings identify MBCs, particularly MBC21, as promising lead candidates for the development of selective MAO-B inhibitors for neurodegenerative disease therapy.},
}

*Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis/metabolism
*Chalcones/chemistry/pharmacology/chemical synthesis
*Monoamine Oxidase/metabolism
Humans
Structure-Activity Relationship
*Morpholines/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
Animals
Butyrylcholinesterase/metabolism
Acetylcholinesterase/metabolism
Molecular Structure
Dose-Response Relationship, Drug
Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
Molecular Dynamics Simulation

@article {pmid42962664,
year = {2026},
author = {Mosconi, L},
title = {The neurobiology of menopause: Implications for brain aging and Alzheimer's risk.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.015},
pmid = {42962664},
issn = {1097-4199},
abstract = {A growing body of evidence implicates the menopausal transition as a neurobiological inflection point in women's brain aging and Alzheimer's disease (AD) vulnerability. Menopause is a midlife neuroendocrine transition characterized by a decline in sex steroid hormones and widespread systemic effects. The brain is not a passive recipient of ovarian hormones but an active endocrine-sensing organ. Menopause, however, does not act in isolation: the ovarian-brain axis is established embryonically, activated at puberty, remodeled during pregnancy and postpartum, and reconfigured during the menopausal transition, with implications for later-life brain aging. This review places menopause within a lifespan neuroendocrine framework, examining mechanisms by which the transition may influence the brain, including altered hormone signaling, bioenergetics, synaptic plasticity, neurovascular function, inflammation, and AD-related pathology. It then reviews evidence linking menopausal timing to neurobiological and AD vulnerability, discusses estrogen therapy, and considers menopause as a biologically plausible window for risk stratification and prevention.},
}

@article {pmid41916749,
year = {2026},
author = {Hong, L and Zeng, Q and Luo, X and Li, K and Liu, X and Li, J and Zhang, M and Cui, F and , },
title = {Distinct Patterns of Cortical Atrophy Predict Cognitive Progression in Age-Related Hearing Loss: A Longitudinal MRI Study.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9326},
pmid = {41916749},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Age-related hearing loss (ARHL) and dementia are common chronic conditions among the elderly, significantly impacting the quality of life of older adults. Additionally, ARHL is an important and modifiable risk factor for dementia. This study aimed to investigate distinct patterns of cortical atrophy in patients with ARHL and mild cognitive impairment (MCI), comparing those with stable cognition (sMCI) with those who progressed to dementia (pMCI), using longitudinal MRI data.

MATERIALS AND METHODS: We included a total of 93 participants from the Alzheimer's Disease Neuroimaging Initiative: 51 sMCI with normal hearing (sMCI+healthy control, group 1), 20 with sMCI with ARHL (sMCI+ARHL, group 2), and 22 with pMCI and ARHL (pMCI+ARHL, group 3). All subjects underwent 3 longitudinal T1-weighted MRI scans at approximately 1-year intervals. Cortical thickness was measured using FreeSurfer 6.0 in regions including the entorhinal cortex, parahippocampal gyrus, and temporal gyri. Repeated-measures ANOVA was used to compare atrophy rates, and receiver operating characteristic analysis evaluated the predictive value of significant regions.

RESULTS: Group 3 showed substantial faster annual atrophy rates in the left entorhinal cortex, left middle temporal gyrus, and bilateral superior temporal gyri compared with group 1. Group 2 also exhibited faster atrophy in temporal regions than group 1. Receiver operating characteristic analysis demonstrated that combined use of these regions improved predictive accuracy for cognitive progression.

CONCLUSIONS: Patients with ARHL with progressive cognitive decline exhibit accelerated atrophy in the auditory and early Alzheimer vulnerable regions. Combined cortical thickness measures may serve as a neuroimaging biomarker to predict cognitive progression in populations with ARHL.},
}

@article {pmid42922083,
year = {2026},
author = {Qin, W and Yang, L and Deng, X and Yuan, W and Guo, D and Xiao, S and Zhang, R and Zhang, Q and Chen, XZ and Zhou, C and Tang, J},
title = {Transcriptional control of autophagy: mechanisms, dynamics, and pharmacological modulation.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/15548627.2026.2753996},
pmid = {42922083},
issn = {1554-8635},
abstract = {The network of transcription factors (TFs) is an integral component of executing macroautophagy/autophagy-lysosome gene expression to maintain cellular homeostasis. Across metazoans, conserved TFs, particularly the helix-loop-helix factor TFEB, convert upstream signals into specific genetic programs through mechanisms ranging from DNA recognition and chromatin remodeling to biomolecular condensates. The dysregulation of TF-governed gene programming disrupts the progression of metabolic disease and cancer, highlighting that dissection of transcriptional regulation makes it a promising therapeutic target. Consequently, instead of indirectly modulating the pathways in which they are involved, targeting these essential TFs directly is becoming a new trend for pharmaceutical development. In this review, we systematically elucidate current mechanisms of the TF-driven autophagic transcriptome, and summarize current small molecules targeting these TFs in various disease.Abbreviations: AD: Alzheimer disease; AFF4: ALF transcription elongation factor 4; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; AR: androgen receptor; ATF4: activating transcription factor 4; ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BRD4: bromodomain containing 4; CRC: colorectal cancer; CREBBP/CBP: CREB binding lysine acetyltransferase; CTNNB1/β-catenin: catenin beta 1; DBD: DNA-binding domain; DDIT3: DNA damage inducible transcript 3; DRAM1: DNA damage regulated autophagy modulator 1; E2F1: E2F transcription factor 1; EHMT2/G9a: euchromatic histone lysine methyltransferase 2; EO: eltrombopag; EP300/p300: EP300 lysine acetyltransferase; ERBB2: erb-b2 receptor tyrosine kinase 2; FOXO3: forkhead box O3; GSH: glutathione; GSK3B/GSK3β: glycogen synthase kinase 3 beta; HD: Huntington disease; KAT2B/GCN5: lysine acetyltransferase 2B; HMGB1: high mobility group box 1; KDACs: lysine deacetylases; KEAP1: kelch like ECH associated protein 1; KLF4: KLF transcription factor 4; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MITF: melanocyte inducing transcription factor; MTORC1: mechanistic target of rapamycin kinase complex 1; MiT/TFE: microphthalmia-transcription factor E; MYC: proto-oncogene, bHLH transcription factor; NDs: neurodegenerative disorders; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; P-TEFb: positive transcription elongation factor b; PARP1: poly(ADP-ribose) polymerase 1; PD: Parkinson disease; PIC: pre-initiation complex; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PTMs: post-translational modifications; POLR2: RNA polymerase II; SIRT1: sirtuin 1; SNAI2: snail family transcriptional repressor 2; STAT3: signal transducer and activator of transcription 3; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TFs: transcription factors; TNKS: tankyrase; TP53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; YWHA/14-3-3: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein; YY1: YY1 transcription factor; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.},
}

@article {pmid42951564,
year = {2026},
author = {Zou, Y and Shi, W and Jiang, F and Liu, T and Liu, Z and Wang, X and Li, Y and Chen, Z and Ao, JP},
title = {Optoelectronically synergized MoS2 field-effect transistor sensor for the detection of Alzheimer's disease biomarker Aβ42.},
journal = {Analytica chimica acta},
volume = {1425},
number = {},
pages = {346329},
doi = {10.1016/j.aca.2026.346329},
pmid = {42951564},
issn = {1873-4324},
mesh = {*Molybdenum/chemistry ; *Amyloid beta-Peptides/analysis ; *Disulfides/chemistry ; *Biosensing Techniques/instrumentation/methods ; *Alzheimer Disease/diagnosis ; *Transistors, Electronic ; *Peptide Fragments/analysis ; Humans ; Biomarkers/analysis ; Limit of Detection ; },
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease (AD) relies heavily on the ultra-sensitive detection of its core biomarker, amyloid-beta 42 (Aβ42). To address this critical need, this paper presents a photoelectric synergistically enhanced field-effect transistor (FET) biosensor based on two-dimensional molybdenum disulfide (MoS2) for the highly sensitive and specific detection of Aβ42.

RESULTS: Experimental results demonstrate that light illumination significantly amplifies the sensing current under identical gate voltages and target concentrations. This enhancement enables the device to effectively overcome the subthreshold region and smoothly transition into the linear operating regime at lower voltages, thereby substantially optimizing signal readout efficiency in low-concentration regions. Benefiting from this photoelectric synergy, the sensor exhibits a markedly enhanced signal response and an optimized dynamic range. The limit of detection decreases to 4.15 × 10[-18] g/mL, representing a 26.29% reduction compared to dark conditions. Furthermore, the relative standard deviation (RSD) of the current response under illumination improves to 2.47% (n = 3), outperforming the 4.86% recorded in the dark and indicating simultaneous enhancements in detection repeatability and device stability. Supported by Silvaco TCAD simulations, the core operating mechanism is elucidated: the specific binding of target Aβ42 molecules inherently introduces localized interface charge perturbations at the MoS2 channel. This alteration of the interfacial charge state fundamentally governs the electrical response of the device, which is synergistically amplified under light illumination to achieve ultra-high sensing sensitivity.

SIGNIFICANCE AND NOVELTY: This study demonstrates that the photoelectric synergistic strategy offers a highly effective pathway to overcome the sensitivity and performance bottlenecks of traditional FET biosensors. Concurrently, it establishes a novel and promising paradigm for the design of high-performance, multimodal photoelectric biomedical diagnostic chips.},
}

*Molybdenum/chemistry
*Amyloid beta-Peptides/analysis
*Disulfides/chemistry
*Biosensing Techniques/instrumentation/methods
*Alzheimer Disease/diagnosis
*Transistors, Electronic
*Peptide Fragments/analysis
Humans
Biomarkers/analysis
Limit of Detection

@article {pmid42951923,
year = {2026},
author = {Ferreira, J},
title = {Alzheimer's disease pathology progression in J20 mice.},
journal = {Lab animal},
volume = {55},
number = {11},
pages = {415},
doi = {10.1038/s41684-026-01827-1},
pmid = {42951923},
issn = {1548-4475},
}

@article {pmid42951976,
year = {2026},
author = {Uffelmann, E and Wightman, DP and Bahrami, S and Shadrin, AA and Fominykh, V and Ojima, T and Jiang, C and Benner, C and Moreno, E and Campos, AI and Thomassen, JQ and Minois-Genin, E and Wu, HM and Walters, GB and Sherva, R and Lin, T and Wang, X and Bryois, J and Krebs, K and Schipper, M and Narita, A and Serretti, A and Simonsen, AH and van Seumeren, AL and Corbett, A and Knapskog, AB and Hartmann, AM and den Braber, A and van Harten, AC and Harder, A and Rongve, A and Madsen, BO and Tijms, BM and Aagaard, B and Lichtwarck, B and Kirsebom, BE and Creese, B and Reynolds, CA and Hägg, S and Karlsson, IK and Erikstrup, C and Mikkelsen, C and Ballard, C and Aarsland, D and Shigemizu, D and Rujescu, D and Gudbjartsson, D and Aakhus, E and Sørensen, E and Stordal, E and Duits, FH and Wolters, FJ and Blanc, F and Biessels, GJ and Selbæk, G and Bråthen, G and Tamiya, G and Waldemar, G and Seelaar, H and Eyjolfsdottir, H and Holstege, H and Bundgaard, H and Zetterberg, H and Ullum, H and Giegling, I and Skoog, I and Medbøen, IT and Saltvedt, I and Rektorova, I and Gaziano, JM and Haavik, J and Hjerling-Leffler, J and Luo, J and Snaedal, J and Vijverberg, EGB and Sealock, JM and Blennow, K and Nordengen, K and Persson, K and Scheffler, K and Matsuda, K and Ozaki, K and Pihlstrøm, L and Athanasiu, L and Pålhaugen, L and Hulsman, M and Waern, M and Averina, M and Wettergreen, M and Moksnes, MR and Huisman, M and Yamamoto, M and Toft, M and Panizzon, MS and Topholm Bruun, M and Ghanbari, M and Franc, M and Pedersen, NL and Bell, NY and Tesi, N and Pedersen, OB and Frei, O and Bousiges, O and Svenningsson, P and Visser, PJ and Li, QS and Hauger, R and Zhang, R and Namba, S and Sando, SB and Kern, S and Djurovic, S and Thordardottir, S and Phung, TN and Truelsen, T and Werge, T and Hansen, TF and Kyosaka, T and Engstad, T and Fladby, T and Merritt, V and Bergh, S and van der Flier, WM and Wang, R and Stahl, EA and Hooli, B and , and , and , and , and , and , and , and , and , and , and , and , and Davis, LK and Logue, MW and Lehto, K and Zettergren, A and Brumpton, BM and Zeng, J and Visscher, PM and O'Reilly, PF and Mahajan, A and Ferreira, M and Okada, Y and van der Lee, SJ and Ostrowski, SR and Frikke-Schmidt, R and Stefansson, H and Heilbron, K and Andreassen, OA and Posthuma, D and , },
title = {Alzheimer's disease genetics converges on microglial and neuronal dysregulation.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42951976},
issn = {1476-4687},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050[1]. AD is highly heritable, with twin-based heritability estimates of 60-80%[2]. Although 1,200 causal loci are predicted to exist for AD[3], approximately 80 loci have been associated with AD in two recent studies[4,5]. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found[6]. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.},
}

@article {pmid42952031,
year = {2026},
author = {Lee, SH and Blecha, J and Kim, JM and Nillo, RM and Flavell, RR and Chao, CK and Forsayeth, JR and Gerdes, JM and VanBrocklin, HF and Wilson, DM},
title = {Copper-Mediated Radiofluorination of the Excitatory Amino Acid Transporter 2 (EAAT2)-Targeted PET Tracer [[18]F]RP-115: Alternate Synthetic Method.},
journal = {Journal of labelled compounds & radiopharmaceuticals},
volume = {69},
number = {13-14},
pages = {},
pmid = {42952031},
issn = {1099-1344},
support = {RC-201810-2017455//Alzheimer's Drug Discovery Foundation/ ; 1R01AG072743-01A1/AG/NIA NIH HHS/United States ; },
mesh = {*Fluorine Radioisotopes/chemistry ; *Positron-Emission Tomography ; *Copper/chemistry ; *Radiopharmaceuticals/chemical synthesis/chemistry ; *Excitatory Amino Acid Transporter 2/metabolism ; Chemistry Techniques, Synthetic ; Halogenation ; },
abstract = {Excitatory amino acid transporter 2 (EAAT2) is a key regulator of extracellular glutamate in the central nervous system. Dysregulated EAAT2 is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), highlighting EAAT2 as a potential target for PET imaging. We previously reported a multistep radiosynthesis of [[18]F]RP-115, a CNS-permeable prodrug that undergoes esterase-mediated hydrolysis in the CNS to yield the active EAAT2-binding carboxylate. Motivated by recent advances in copper-mediated radiofluorination (CMRF), we sought to develop a more efficient late-stage radiosynthesis of [[18]F]RP-115. A two-step radiosynthesis of [[18]F]RP-115 using CMRF provided [[18]F]RP-115 in high radiochemical yield (52.8% ± 2.1 %, decay-corrected from starting [[18]F]fluoride ion, n = 4), high molar activity (355 ± 61 GBq/μmol), and high radiochemical purity (> 99%) with a total synthesis time of 70 min. Chiral HPLC analysis demonstrated that the configuration of the aspartic acid residue remained intact without racemization during both the CMRF and trifluoroacetic acid mediated deprotection. We developed an efficient radiosynthesis of [[18]F]RP-115 via CMRF, achieving high radiochemical yield and molar activity. This efficient synthesis may serve as a basis for the future implementation of a CMRF-based automated radiosynthesis of [[18]F]RP-115.},
}

*Fluorine Radioisotopes/chemistry
*Positron-Emission Tomography
*Copper/chemistry
*Radiopharmaceuticals/chemical synthesis/chemistry
*Excitatory Amino Acid Transporter 2/metabolism
Chemistry Techniques, Synthetic
Halogenation

@article {pmid42952059,
year = {2026},
author = {Cellular Longevity, OMA},
title = {RETRACTION: Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer's Disease in Mice.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {},
pmid = {42952059},
issn = {1942-0994},
}

@article {pmid42952081,
year = {2026},
author = {Velazquez, S and Juber, MC and Brindley, D and Thakur, A and Anasori, B and Lau, E and Ashkarran, AA},
title = {MXene-Protein Corona Interfaces for Molecular Profiling of Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01228},
pmid = {42952081},
issn = {2576-6422},
abstract = {The protein corona (PC) that forms on the surface of nanomaterials upon contact with biological fluids provides a molecular snapshot of the host's physiological and pathological state. Here, we investigate two-dimensional (2D) titanium carbide (Ti3C2Tx) MXene nanosheets as nanobiointerfaces for capturing Alzheimer's disease (AD)-associated plasma protein signatures. Ti3C2Tx MXene flakes were incubated with plasma from clinically diagnosed AD patients and age-matched healthy controls (HC), leading to the formation of Ti3C2Tx MXene-PC complexes. Physicochemical characterization using dynamic light scattering, zeta potential analysis, and transmission electron microscopy revealed disease-dependent changes in hydrodynamic size, surface charge, and PC profile. Proteomic analysis of the isolated PC layers quantified 1,611 proteins without prior fractionation, demonstrating broad plasma proteome coverage. Principal component analysis (PCA) revealed disease-associated separation between AD and HC-derived Ti3C2Tx MXene PC proteomes along specific principal components despite interindividual heterogeneity. Differential abundance analysis identified selective enrichment of heterogeneous nuclear ribonucleoproteins (hnRNPs), annexins, and inflammatory mediators in AD-derived PC, implicating dysregulated RNA metabolism, membrane stress responses, and immune activation, hallmark processes in AD pathology. Our findings demonstrate that Ti3C2Tx MXene-PC interfaces reshape the detectable plasma proteome and enable disease-associated molecular phenotyping, establishing a versatile nanointerface-driven framework for AD-related proteomic fingerprinting and molecular profiling. These results provide a foundation for future studies exploring MXene-based biointerfaces for plasma biomarker discovery and translational diagnostic applications.},
}

@article {pmid42952112,
year = {2026},
author = {Rocha, A and Machado, LS and Soares, C and L Ferreira, PC and Bellaver, B and Carvalho, P and Lazzarotto, G and Vidor, P and Kunach, P and T Venturin, G and Greggio, S and C da Costa, J and Bastos de Mello, F and Milinkeviciute, G and Forner, S and Green, K and Rosa-Neto, P and Pascoal, T and Souza, DO and Zimmer, E},
title = {EXPRESS: Longitudinal FDG-PET reveals early hypermetabolism associated with astrocyte changes in TgF344-AD rats.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261504653},
doi = {10.1177/0271678X261504653},
pmid = {42952112},
issn = {1559-7016},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by alterations in brain glucose metabolism, classically showing [18F]FDG-PET hypometabolism in later stages. However, emerging evidence suggests a transient phase of glucose hypermetabolism early in the disease, for which biological basis remains unclear.

METHODS: We combined longitudinal and cross-sectional approaches in TgF344-AD rats and wild-type controls at 3, 6, 9, and 12 months. Longitudinal assessments included [[1][8]F]FDG-microPET imaging, behavioral testing, and cerebrospinal fluid biomarker analysis. Cross-sectional analyses included amyloid histopathology, western blot and ex vivo glutamate uptake measurements.

RESULTS: TgF344-AD rats exhibited increased cerebral glucose metabolism at 9mo, predominantly in cortical regions. This phase coincided with emerging cognitive impairment and early amyloid deposition. CSF analyses showed increased GFAP at 9-12mo and reduced S100B at 9mo, while microglial/inflammatory markers remained unchanged. WB confirmed region-specific GFAP alterations without changes in neuronal or synaptic markers. Glutamate uptake was increased in the cortex and hippocampus at 9mo.

CONCLUSION: These findings identify a transient phase of increased glucose metabolism early in disease progression, associated with astrocyte-related changes, suggesting that early hypermetabolism may reflect non-neuronal processes. This has implications for the interpretation of [18F]FDG-PET as a biomarker in early AD and for understanding early physiological responses to AD pathology.},
}

@article {pmid42952140,
year = {2026},
author = {Sun, B and Gu, M and Maher, A and DuBois, KN and Kanaan, NM and Bross, J and Koeppe, R and Persad, CC and Murphey, YL and Kavcic, V and Ren, J and Giordani, B and Li, T},
title = {EEG-based brain effective and functional connectivity predict PET-defined amyloid positivity in cognitively normal individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42952140},
issn = {1552-5279},
support = {NSF-2032709//National Science Foundation/ ; NSF-1919154//National Science Foundation/ ; NSF-2535060//National Science Foundation/ ; P30AG072931/NH/NIH HHS/United States ; P30AG024824/NH/NIH HHS/United States ; S10OD034250-01/NH/NIH HHS/United States ; R01AG068338/NH/NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography ; *Brain/diagnostic imaging/physiology/metabolism ; *Electroencephalography/methods ; Female ; *Amyloid beta-Peptides/metabolism ; Male ; Alzheimer Disease/diagnosis ; tau Proteins/blood ; Aged ; Machine Learning ; Cognition/physiology ; Biomarkers ; },
abstract = {INTRODUCTION: Early identification of amyloid-beta (Aβ) pathology is essential for timely intervention in Alzheimer's disease (AD), as Aβ accumulation precedes clinical symptoms by years.

METHODS: We predicted positron emission tomography (PET) -defined Aβ status in cognitively normal individuals using non-invasive resting-state dry electroencephalography (EEG). Brain effective and functional connectivity were quantified to characterize dynamic information transfer between regions. Features derived from dynamic brain connectivity were used to train machine learning models for Aβ classification.

RESULTS: EEG-based models can predict amyloid positivity with accuracy comparable to, or in some cases exceeding, that of plasma p-tau217 and previously reported predictors based on cognitive measures, demographics, and health factors, depending on the model.

DISCUSSION: Beyond near real-time Aβ inference, the framework identifies the most affected brain regions and connections associated with neurodegeneration, offering complementary information to blood-based biomarkers and supporting its potential as an affordable tool for early AD detection in primary care and population screening.},
}

Humans
*Positron-Emission Tomography
*Brain/diagnostic imaging/physiology/metabolism
*Electroencephalography/methods
Female
*Amyloid beta-Peptides/metabolism
Male
Alzheimer Disease/diagnosis
tau Proteins/blood
Aged
Machine Learning
Cognition/physiology
Biomarkers

@article {pmid42952210,
year = {2026},
author = {Hossain, MK and Lee, HY and Kim, HJ and Kim, HR},
title = {The Brain-Tooth Axis as an Early Predictor of Alzheimer's Disease.},
journal = {Biomolecules & therapeutics},
volume = {34},
number = {6},
pages = {1322-1330},
doi = {10.4062/biomolther.2026.165},
pmid = {42952210},
issn = {1976-9148},
abstract = {Alzheimer's disease (AD) is typically diagnosed after irreversible neuronal loss. Recent evidence links oral health deterioration-especially tooth loss, periodontal disease, and reduced masticatory function-to accelerated cognitive decline and dementia risk. Aging also promotes structural and immunological changes in the oral cavity, accelerating periodontal breakdown, microbiome dysbiosis, and functional tooth loss. This emerging "brain-tooth axis" suggests bidirectional interactions between the oral cavity and central nervous system via inflammatory, microbial, and sensory pathways. Periodontal inflammation, oral microbiome dysbiosis, and loss of trigeminal sensory input may promote neuroinflammation, amyloid accumulation, and hippocampal dysfunction. Conversely, early neural degeneration can impair oral maintenance and chewing behavior. This perspective outlines mechanistic hypotheses, clinical implications, and a research roadmap for integrating oral health metrics into multimodal AD risk prediction. Validating this axis could establish oral assessments as accessible biomarkers for early disease detection and prevention strategies.},
}

@article {pmid42952261,
year = {2026},
author = {Lee, S and Purewal, E and Rasgon, N and Kwan, A and Dri, CE and Ho, R and McIntyre, RS},
title = {Sex differences in glucagon-like peptide-1 signalling and the implications for Alzheimer's disease: A narrative review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e49},
doi = {10.1017/S1092852926101291},
pmid = {42952261},
issn = {2165-6509},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Glucagon-Like Peptide 1/metabolism ; *Sex Characteristics ; Signal Transduction/physiology ; Animals ; Female ; Male ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia. Women are differentially affected by AD, and several sex-specific mechanisms have been explored, including hormonal differences (eg, estrogen). Glucagon-like peptide-1 (GLP-1R) are located in brain regions implicated in the pathogenesis of AD and shows preliminary evidence of modulating sex-specific pathways that may underlie differential disease risk and progression. Herein, we synthesize the extant literature on the mechanisms of GLP-1 in neurobiological systems relevant to AD pathology. Metabolic signalling (eg, GLP-1, insulin) intersects with known sex-specific pathways hypothesized to subserve AD progression in women. The preceding effects may be attributable to the disruption of estrogen signalling during the postmenopausal period, which impairs hippocampal insulin receptor function and exacerbates mitochondrial dysfunction. In addition, these mechanisms provide an explanation for AD comorbidities (eg, type 2 diabetes mellitus [T2DM]). The multidimensional effects demonstrated in GLP-1 paradigms provide a compelling rationale for further investigation of the role of metabolic signalling on sex-specific alterations in AD. Evidence across preclinical and early clinical studies suggests that GLP-1RAs may differentially influence neurobiological pathways implicated in AD pathogenesis, particularly those that interact with hormonal and metabolic systems.},
}

Humans
*Alzheimer Disease/metabolism
*Glucagon-Like Peptide 1/metabolism
*Sex Characteristics
Signal Transduction/physiology
Animals
Female
Male
*Brain/metabolism

@article {pmid42952670,
year = {2026},
author = {He, Y and Zhou, J and Wu, X and Sheng, J and Zhang, Z and Feng, Z and Zhang, S},
title = {Peripheral hematological inflammatory signatures in the amyloid-defined Alzheimer's disease continuum: associations with disease stage, cognitive function, and astroglial activation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1959479},
pmid = {42952670},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/blood/diagnosis/psychology/metabolism ; Female ; Male ; Cross-Sectional Studies ; Biomarkers/blood ; Aged ; *Cognition ; *Astrocytes/metabolism/immunology ; Amyloid beta-Peptides/metabolism ; *Inflammation/blood ; Neutrophils/immunology ; Positron-Emission Tomography ; Cognitive Dysfunction ; Aged, 80 and over ; Lymphocytes/immunology ; Disease Progression ; },
abstract = {BACKGROUND: Peripheral immune-inflammatory dysregulation has been implicated in Alzheimer's disease (AD) and cognitive decline. However, whether routinely available hematological inflammatory indices are associated with biological and clinical stages across the AD continuum and provide incremental information beyond established risk factors remains unclear. We aimed to investigate the associations of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and hemoglobin-to-red blood cell distribution width ratio (HRR) with AD continuum stage, cognition, and AD biomarkers.

METHODS: This cross-sectional study included 267 participants who underwent comprehensive cognitive assessment, peripheral blood testing, and amyloid-β positron emission tomography (Aβ-PET) imaging. Participants were categorized into three groups according to cognitive status and available amyloid biomarker profiles: cognitively unimpaired (CU-Aβ[-]), amyloid-positive mild cognitive impairment (MCI-Aβ[+]), and amyloid-positive Alzheimer's disease dementia (AD-Aβ[+]). Hematological inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and hemoglobin-to-red cell distribution width ratio (HRR), were calculated from routine blood parameters. A composite inflammatory index (Inflam_PC1) was derived using principal component analysis. Ordinal logistic regression models were used to examine the associations between inflammatory indices and AD continuum stage after adjustment for demographic, vascular, metabolic, and genetic factors.

RESULTS: Inflammatory profiles differed across the AD continuum, with increased NLR and SII and decreased HRR levels in more advanced stages. Higher NLR (OR = 1.54, 95% CI: 1.25-1.91, P < 0.001) and SII (OR = 1.29 per 100-unit increase, 95% CI: 1.15-1.45, P < 0.001) were independently associated with advanced AD continuum stages, whereas HRR was not. The composite inflammatory signature showed the strongest association (OR = 1.63 per SD increase, 95% CI: 1.30-2.03, P < 0.001) and provided incremental statistical improvement beyond conventional risk factors. Higher inflammatory burden was associated with poorer cognitive and functional performance and correlated with plasma glial fibrillary acidic protein (GFAP) level.

CONCLUSIONS: Peripheral hematological inflammatory signatures were associated with Alzheimer's disease continuum. Higher NLR and SII levels and a composite inflammatory signature were independently associated with more advanced disease stages, cognitive impairment, and functional decline. The association between inflammatory signatures and plasma GFAP, but not amyloid or tau biomarkers, suggests a relationship between peripheral inflammatory profiles and glial-related biomarker alterations that requires further longitudinal investigation.},
}

Humans
*Alzheimer Disease/immunology/blood/diagnosis/psychology/metabolism
Female
Male
Cross-Sectional Studies
Biomarkers/blood
Aged
*Cognition
*Astrocytes/metabolism/immunology
Amyloid beta-Peptides/metabolism
*Inflammation/blood
Neutrophils/immunology
Positron-Emission Tomography
Cognitive Dysfunction
Aged, 80 and over
Lymphocytes/immunology
Disease Progression

@article {pmid42952769,
year = {2026},
author = {Lan, X and Xia, M and Chen, L and Zheng, S and Jin, L and Wang, Y and Lu, S and Xu, J and Xu, L and Li, C and Yan, P},
title = {Family hardiness and associated factors among Chinese family caregivers of people with Alzheimer's disease: an explanatory sequential mixed-methods study.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1940356},
pmid = {42952769},
issn = {1664-1078},
abstract = {AIM: To examine family hardiness and associated factors among Chinese family caregivers of people with Alzheimer's disease (AD), and to explore caregivers' experiences of family adaptation in daily care.

METHODS: An explanatory sequential mixed-methods design was used. In the quantitative phase, 201 family caregivers recruited from a tertiary hospital in Zhejiang Province completed the Family Hardiness Index (FHI) and measures of potential associated factors. Multivariable linear regression examined associations with total and subscale FHI scores. Twelve caregivers subsequently took part in semi-structured interviews. Directed content analysis was used to interpret the quantitative findings in context and identify additional themes. The two phases were integrated through a following-a-thread approach and a convergence coding matrix.

RESULTS: The mean total FHI score was 56.85 ± 6.27. Commitment/responsibility had the highest mean subscale score (26.09 ± 3.71), and challenge the lowest (13.49 ± 2.04). In the final model for total FHI score (adjusted R[2] = 0.477), family resources (β = 0.390, p < 0.001), female patient sex (β = -0.286, p = 0.005), perceived caregiving burden (β = -0.262, p < 0.001), and family meaning-making (β = 0.190, p = 0.003) were independently associated with family hardiness. The qualitative analysis generated eight themes. Integration yielded two convergent findings, five complementary findings, and one exploratory theme found only in the interviews: companion-animal support.

CONCLUSION: Family resources, perceived caregiving burden, family meaning-making, and patient sex were associated with total FHI scores. Interviews provided context on family obligation, changing roles, and urban-rural differences in access to support. Companion-animal support, mentioned by two participants, is reported as a hypothesis-generating observation. Prospective studies are needed to examine causal relationships and the effects of family-support interventions.},
}

@article {pmid42952777,
year = {2026},
author = {Ren, X and Li, T and Liu, S and Li, L and Li, F},
title = {Sex and stage-defined exploratory inflammatory and amyloid-associated readout patterns in female APP/PS1 mice exposed to TAK-242.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1944097},
pmid = {42952777},
issn = {1663-4365},
abstract = {TLR4-related inflammatory signaling has been implicated in Alzheimer's disease-related immune responses, and TAK-242 has been used as an experimental tool in studies examining this signaling context. This exploratory study characterized inflammatory cytokine and amyloid-associated histological readout patterns associated with TAK-242 exposure in female early-stage APP/PS1 mice. Female APP/PS1 mice were assigned to saline, lipopolysaccharide, or TAK-242 exposure conditions for 6 weeks, with age-matched non-transgenic mice serving as reference controls (n = 8/group). Brain TNF-α, IL-1β, and IL-6 levels were measured by ELISA, and 6E10-positive staining area was quantified by immunohistochemistry. Directional differences in cytokine levels and 6E10-positive staining area were observed between APP/PS1 mice exposed to TAK-242 and untreated APP/PS1 mice. However, because a vehicle-matched APP/PS1 control group was not included, these differences cannot be attributed specifically to TAK-242 and were interpreted as exploratory exposure-associated patterns rather than pharmacological efficacy. This study provides a sex and stage-defined exploratory dataset of inflammatory and amyloid-associated readout patterns in female early-stage APP/PS1 mice to inform future vehicle-controlled investigations.},
}

@article {pmid42952837,
year = {2026},
author = {Zhao, Y and Sun, J and Reheman, B and Bai, X and Zhang, C and Ding, W and Zou, B and Zhang, H and Zhang, Z and Zhang, N},
title = {Grey matter atrophy signatures and their genetic associations: a trans-disease study of Alzheimer's disease and multiple sclerosis.},
journal = {Frontiers in neuroimaging},
volume = {5},
number = {},
pages = {1917609},
pmid = {42952837},
issn = {2813-1193},
abstract = {BACKGROUND: Alzheimer's disease (AD) and multiple sclerosis (MS) share neuroimmune mechanisms that drive neurodegeneration. Current clinical interventions are largely confined to a single-disease approach, owing to the absence of trans-disease diagnostic markers and common therapeutic targets.

OBJECTIVE: To map common and disease-specific grey matter (GM) atrophy patterns in AD and MS and identify their genetic correlations.

METHODS: We performed a trans-disease meta-analysis in large-sample neuroimaging data from 2001 to 2024 (2,070 MS versus 1,625 healthy control, and 1,624 AD versus 1,607 healthy control) to map GM atrophy regions. The cross-sample partial least squares regression was applied to integrate gene expression profiles from the Allen Human Brain Atlas with region-specific GM atrophy patterns, achieving cross-scale analysis of identify neurodegeneration-associated genes.

RESULTS: MS-specific atrophy localized to the bilateral dorsomedial thalamic nucleus and precentral gyrus, whereas AD-specific atrophy centered on bilateral hippocampus-amygdala complex in age-unadjusted comparisons. The common atrophy patterns were found in the bilateral superior temporal gyrus, insulae, posterior cingulate cortex, amygdalae, and striatal components. We identified 834 genes whose spatial expression patterns were associated with the common GM atrophy pattern in AD and MS, including PLS2 + and PLS2- subsets, which encompass biological processes such as immunological homeostasis imbalance, cellular stress response, and neurometabolic/functional regulation.

CONCLUSION: Findings establish shared cortical-limbic-striatal atrophy as pivotal neurodegeneration nexus in AD and MS. The identified gene-imaging signatures provide insights into potential pathway-specific mechanisms and may inform future therapeutic target discovery for dual-disease intervention.},
}

@article {pmid42952982,
year = {2026},
author = {Zhang, Y and Li, L and Ouyang, H and Zhao, Z and Mei, X and Qiu, C},
title = {Peripheral serum copper metabolite levels measured by ultrafiltration aid in the clinical screening of Alzheimer's disease.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1954419},
pmid = {42952982},
issn = {1664-0640},
abstract = {BACKGROUND: The number of patients with Alzheimer's disease (AD) is increasing, yet misdiagnosis remains common and early accurate diagnosis is lacking. Previous studies have suggested abnormalities in peripheral serum copper levels in AD patients. This study sought to explore the diagnostic value of peripheral serum copper-related biomarkers for clinically diagnosed AD.

METHODS: Peripheral serum samples were collected from 115 clinically diagnosed AD patients and 96 healthy controls (HC). A preliminary experiment on five samples determined the use of a 10 kDa ultrafiltration membrane. Four serum copper parameters-serum total copper (tot-Cu), free copper (free-Cu), serum immunological ceruloplasmin concentration (iCp), and ceruloplasmin enzymatic activity (eCp)-were quantitatively measured in all samples using ultrafiltration, atomic absorption spectrometry, and ELISA.

RESULTS: Peripheral tot-Cu and free-Cu levels in clinically diagnosed AD patients were significantly elevated in the early stage of the disease, while iCp, eCp, and the iCp/eCp ratio were significantly decreased. The diagnostic efficacy of tot-Cu and free-Cu for these Alzheimer's disease patients was significantly higher than that of the Mini-Mental State Examination (MMSE) score. Nevertheless, these indicators could not distinguish different severity stages of clinically phenotyped AD.

CONCLUSION: Our results indicate that tot-Cu or free-Cu holds promise as biomarkers for the clinical screening of AD; peripheral copper metabolic dysregulation may be involved in the pathogenesis of clinically phenotyped AD.},
}

@article {pmid42953065,
year = {2026},
author = {Xin, J and Teng, X and Su, H and Wang, X and Li, M},
title = {Luteolin for Alzheimer's disease and related cognitive impairment: a systematic review and meta-analysis of efficacy and molecular mechanisms.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1976119},
pmid = {42953065},
issn = {2296-858X},
abstract = {BACKGROUND: The multifactorial pathogenesis of Alzheimer's disease (AD) renders conventional single-target therapies largely ineffective. Luteolin, a natural flavonoid, has demonstrated promising pleiotropic neuroprotective potential. This study aims to systematically evaluate the preclinical efficacy and multi-target mechanisms of luteolin in rodent models of AD and associated cognitive impairment.

METHODS: Eight major electronic databases were systematically searched from January 1, 2000 to June 1, 2026. In vivo preclinical studies evaluating luteolin monotherapy in AD-specific and general cognitive impairment rodent models were included. Methodological quality was assessed using the SYRCLE risk of bias tool. Standardized mean differences and 95% confidence intervals were calculated using a random-effects model.

RESULTS: Fifteen eligible studies were included. Meta-analysis revealed that luteolin significantly ameliorated cognitive and memory impairments in both AD-specific and non-AD cognitive impairment models. Mechanistically, luteolin significantly restored redox homeostasis and suppressed neuroinflammatory cascades at both transcriptional and translational levels. Subgroup analyses indicated that oral administration and prolonged interventions were associated with significant efficacy; however, these observations are heavily influenced by study-level confounding and cannot conclusively establish pharmacokinetic superiority. Furthermore, the certainty of evidence is limited by predominantly unclear risks of bias, substantial statistical heterogeneity, and potential publication bias.

CONCLUSION: Current preclinical evidence suggests that luteolin is a promising multi-target neuroprotective candidate for AD and related cognitive impairments, highlighted by its anti-inflammatory and antioxidant properties. However, given the substantial methodological limitations and extremely large pooled effect sizes, these findings must be interpreted with caution. Future research must prioritize rigorous preclinical designs, advanced brain-targeted delivery systems, and GLP-compliant toxicological profiling before clinical translation.},
}

@article {pmid42953191,
year = {2026},
author = {Deng, L and Zeng, Y and Ou, P and Zhou, S and Gou, Y and Huang, C},
title = {Advances in artificial intelligence-driven MRI research in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1943265},
pmid = {42953191},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Artificial Intelligence ; *Neuroimaging/methods ; Machine Learning ; Deep Learning ; },
abstract = {Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, poses substantial challenges for early diagnosis and longitudinal monitoring-two cornerstones of effective clinical management and therapeutic intervention. Magnetic resonance imaging (MRI), owing to its non-invasiveness and high spatial resolution, has emerged as an indispensable tool in AD research. In recent years, artificial intelligence (AI), particularly deep learning (DL) and machine learning (ML) techniques, has demonstrated remarkable potential for automating MRI analysis, extracting subtle imaging features, and supporting objective disease prediction. This review comprehensively summarizes the latest advances in AI-driven MRI applications for AD diagnosis, staging, prognosis, and adjuvant therapeutic monitoring. It highlights key progress in AI model development, multimodal data processing, and clinical translational value. Furthermore, current bottlenecks, including data heterogeneity, model interpretability, and real-world deployment, are systematically discussed, and future directions are outlined to enhance the precision and clinical utility of AI-assisted MRI in AD. Overall, AI-MRI has evolved from laboratory validation toward early clinical adoption, with explainability and multi-center generalizability identified as critical priorities in the next research phase.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Magnetic Resonance Imaging/methods
*Artificial Intelligence
*Neuroimaging/methods
Machine Learning
Deep Learning

@article {pmid42953259,
year = {2026},
author = {Tábuas-Pereira, M and Silva-Spínola, A and Agostinho, C and Alves, L and Araújo, R and Bernardes, C and Branco, M and Borbinha, C and Cabreira, V and Costa, S and Silva, AD and Durães, J and Faustino, P and Félix, C and Fernandes, A and Ferreira, J and Gago, M and Guarda, C and Ionel, C and Jesus-Ribeiro, J and Laranjinha, I and Leitão, A and Letra, L and Lopes das Neves, P and Maia, LF and Machado, Á and Martins, B and Massano, J and Mendonça, A and Mendonça, M and Miguel, R and Miranda, M and Morgado, J and Nóbrega, C and Coutinho, MP and Oliveira, T and Pita, F and Sabença, F and Rocha, S and Ruano, L and Santos, T and Simões do Couto, F and Taipa, R and Cruz, VT and Valverde, AH and Vélon, A and Verdelho, A and Viana Baptista, M and Vieira, D and Lima, M and Oliveira, TG and Santana, I and , },
title = {Current capacity of Portuguese specialized dementia centers in the era of anti-amyloid antibodies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70513},
pmid = {42953259},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major cause of cognitive decline and societal burden. The recent approval of disease-modifying therapies (DMTs) lecanemab and donanemab represents a paradigm shift in AD treatment. We assessed the preparedness of Portuguese centers to implement DMTs.

METHODS: A nationwide survey-based cross-sectional service-capacity study targeted memory clinics, focusing primarily on National Health System (NHS) centers. Data were collected on clinical capacity, diagnostic access, treatment capability, and research activity.

RESULTS: Among 51 responding units, 20 had organized memory clinics (17 in the NHS), covering 60.7% of the population. In 2024, these centers conducted 21,721 consultations, representing expert care for <10% of the total AD patients estimated to exist in Portugal. Bottlenecks included long waiting times and limited biomarker access (26.2% underwent cerebrospinal fluid or amyloid positron emission tomography). Nationwide, from experts' estimates, 701 patients could currently start treatment.

DISCUSSION: Portugal's current NHS capacity appears insufficient for broad DMT implementation, requiring major investment in diagnostics, training, infrastructure, and research to ensure equitable and effective treatment access.},
}

@article {pmid42953343,
year = {2026},
author = {Liu, Z and Qin, M and Zhao, C and Ding, J and Li, Y and Cheng, W},
title = {Mediterranean Diet Adherence and Cognitive Function in Older Adults: Heterogeneity in the Association Across BMI Categories.},
journal = {International journal of endocrinology},
volume = {2026},
number = {},
pages = {7060250},
pmid = {42953343},
issn = {1687-8337},
abstract = {Cognitive decline is a major public health concern among older adults, and both dietary quality and adiposity have been associated with cognitive health. Using data from the 2011-2014 National Health and Nutrition Examination Survey, we conducted a cross-sectional analysis of 2492 U.S. adults aged ≥ 60 years. Adherence to the Mediterranean diet was quantified using the Mediterranean diet index (MEDI) derived from two 24-h dietary recalls, and body mass index (BMI) was classified into four categories: underweight, normal weight, overweight, and obesity. Global cognitive function was computed by standardizing and summing scores from the Consortium to Establish a Registry for Alzheimer's disease immediate and delayed recall tests, the animal fluency test, and the Digit Symbol Substitution test. After multivariable adjustment, higher MEDI scores were associated with better global cognitive function, with positive associations also observed for verbal fluency and processing speed. Restricted cubic spline analysis supported a positive, approximately linear dose-response association between MEDI score and global cognitive function. However, in the linear interaction analysis, this association differed across BMI categories. Among normal-weight participants, higher MEDI scores were associated with better global cognitive function. Underweight status was associated with poorer immediate and delayed recall, whereas overweight status was associated with lower verbal fluency. Overall, greater adherence to a Mediterranean dietary pattern was associated with better cognitive performance, particularly verbal fluency and processing speed, among older U.S. adults. BMI-related heterogeneity in this association supports prospective longitudinal studies and intervention trials incorporating repeated assessments of diet, adiposity, metabolic health, and cognition.},
}