@article {pmid42471758,
year = {2026},
author = {Zhang, T and Dai, L and Ma, Y and Xu, S and Liu, X and Zhao, M and Li, W and Wang, J and Liu, Y},
title = {Conformational bifurcation of tau R3-R4 oligomers underlies fibril polymorphism.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.07.020},
pmid = {42471758},
issn = {1542-0086},
abstract = {Tau aggregation into amyloid fibrils is a central pathological feature of multiple neurodegenerative diseases, yet identical tau sequences can adopt structurally distinct fibril conformations associated with different disorders. How such disease-specific folds emerge from the same sequence remains poorly understood. Here, we use metadynamics and all-atom molecular dynamics simulations to elucidate the folding mechanisms of tau trimers comprising the R3-R4 region, the minimal aggregation nucleus of tau fibrils. By constructing the folding free-energy landscape within a pre-organized fibril-like scaffold, we identify a shared, partially folded intermediate from which two energetically comparable minimum free-energy pathways diverge, leading to either a compact Alzheimer's disease-like or a more open chronic traumatic encephalopathy-like C-shaped conformation. Structural analysis reveals that the β4-β6 triangular region acts as the central determinant of this bifurcation. Hydrophobic-core rearrangements within this region provide the primary energetic driving force for compaction, whereas the conformational flexibility of the 332PGGG335 hinge modulates whether this tendency can be structurally realized. Additional simulations show that stable formation of the triangular region requires cooperative multichain interactions; reducing oligomer size destabilizes this scaffold and abolishes ordered folding. Together, our results establish a mechanistic framework in which identical tau sequences access alternative folding routes through a common intermediate, explaining the emergence of disease-specific fibril polymorphism at the oligomeric level and highlighting early folding intermediates as potential targets for therapeutic intervention.},
}

@article {pmid42560407,
year = {2026},
author = {Feng, X and Yu, W and Guo, S and Ji, Y and Li, J and Wang, L and Zhong, G and Li, S and Niu, L and Zhu, D and Zhou, K and Du, Y},
title = {Aurantio-Obtusin Attenuates Aβ-Induced Cognitive Impairment and Synaptic Dysfunction by Suppressing Neuroinflammation in Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42560407},
issn = {1557-1904},
support = {82371194//the National Natural Science Foundation of China/ ; CSTB2024NSCQ-QCXMX0004//the Natural Science Foundation of Chongqing Municipality/ ; },
mesh = {Animals ; Male ; Mice ; *Amyloid beta-Peptides/toxicity ; Mice, Inbred C57BL ; *Neuroinflammatory Diseases/drug therapy/chemically induced/metabolism ; *Synapses/drug effects/metabolism ; *Anthraquinones/pharmacology/therapeutic use ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) features Aβ-driven neuroinflammation and synaptic dysfunction that converge on cognitive decline, underscoring the potential value of multi-target interventions. Aurantio-obtusin (AO), a bioactive anthraquinone from Cassia obtusifolia L., exhibits reported anti-inflammatory and antioxidant activities; however, whether AO counteracts Aβ-associated behavioral impairment through coordinated modulation of inflammatory and synaptic alterations remains unclear. Here, we investigated whether AO alleviates Aβ1-42-induced cognitive deficits and examined synapse- and inflammation-related molecular correlates. Male C57BL/6 mice received intracerebroventricular Aβ1-42 to establish an acute AD-like model and were treated with AO (10 mg/kg/day, oral gavage) for consecutive weeks. The results showed that AO improved spatial learning and memory in the Morris water maze, recognition memory in the novel object recognition test, and working memory in the Y-maze, without affecting spontaneous locomotor activity. Furthermore, AO alleviated synaptic dysfunction by restoring synaptophysin expression and upregulating GAD65, and mitigated neuroinflammation by elevating anti-inflammatory factors (IL-4, IL-10, ARG1) and reducing TNF-α. In vitro experiments confirmed that AO was non-cytotoxic to N2A[APP] cells across 0-80 μM, mildly downregulated BACE1 expression, and suppressed the Aβ-induced upregulation of pro-inflammatory mediators (IL-6, iNOS) in BV2 microglial cells. Overall, AO attenuated Aβ1-42-driven behavioral impairment in parallel with improvements in synapse-associated markers and inflammatory readouts. These findings support further evaluation of AO as a natural compound associated with modulation of Aβ-related neuroinflammatory and synapse-associated alterations.},
}

Animals
Male
Mice
*Amyloid beta-Peptides/toxicity
Mice, Inbred C57BL
*Neuroinflammatory Diseases/drug therapy/chemically induced/metabolism
*Synapses/drug effects/metabolism
*Anthraquinones/pharmacology/therapeutic use
*Peptide Fragments/toxicity
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
Maze Learning/drug effects

@article {pmid42560467,
year = {2026},
author = {Brimson, S and Thitilertdecha, P and Kumaree, KK and Brimson, JM},
title = {Sigma-1 Receptor Ligand Blarcamesine (ANAVEX 2-73) for Alzheimer's Disease: A Systematic Review.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {42560467},
issn = {1179-1934},
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and mild-to-moderate AD.

METHODS: A systematic literature search was conducted in PubMed (including MEDLINE), Scopus, and Google Scholar, together with clinical trial registries, with the final search performed in September 2025. Reference sections of manuscripts were searched, and authors were contacted for additional data. Studies investigating only blarcamesine in participants with mild-to-moderate AD were included. Blarcamesine for other diseases or severe AD were excluded. Data were summarised descriptively in accordance with PRISMA guidelines. The risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool (RoB2) for randomised, placebo-controlled trials, and an adapted version of RoB2 for cross-over trials.

RESULTS: One Phase I first-in-human study in healthy volunteers and ten reports describing two randomised clinical trials (NCT02244541, a randomised open-label study, and NCT03790709, a randomized placebo-controlled study) and their associated open-label extension studies (NCT02756858 and NCT04314934) were identified, including two peer-reviewed manuscripts, two preprints, and six conference abstracts. Thirty-two participants were enrolled in the Phase IIa open-label dose-finding study, where outcome measures were compared to baseline (NCT02244541). In the extended open-label study exploring the cognitive effect for another 52 weeks, 21 of 32 remained in the study (NCT02756858). The randomised placebo-controlled trial (NCT03790709) enrolled 509 participants and randomised them into three groups: 167 treated with 30 mg blarcamesine, 168 treated with 50 mg blarcamesine and 168 treated with placebo (for 30 mg blarcamesine, 112 completed the study; for 50 mg blarcamesine, 90 completed the study; and for placebo, 136 completed the study). Subsequently, 300 of 509 participants remained in the open-label extension (NCT04314934). Across these two studies, blarcamesine was generally well tolerated, with adverse events that were predominantly mild, transient, and dose-related. Treatment was associated with slower cognitive and functional decline, improvements in multiple clinical outcome measures, and reduced brain atrophy in genetically defined subgroups. Participants carrying the SIGMAR1 and COL24A1 wild-type genotypes were associated with greater therapeutic benefit, supporting the potential value of pharmacogenomic patient stratification.

CONCLUSIONS: Current clinical evidence suggests that blarcamesine is a promising orally administered therapeutic candidate for early-stage AD with an acceptable safety profile and encouraging efficacy, particularly in genetically defined populations. However, the available evidence is derived from a limited number of clinical studies, including secondary analyses and conference reports. Additional independent randomised clinical trials are required to confirm these findings and further define the role of blarcamesine in the treatment of AD.

PROSPERO REGISTRATION: CRD420251142826.},
}

@article {pmid42560687,
year = {2026},
author = {Joyce, NR and Balog, S and Gaither, R and Pfeiffer, MR and Bhondoekhan, F and Ott, BR and Margolis, SA and Curry, AE and Zullo, AR},
title = {A Motor Vehicle Crash as an Early Signal of Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70630},
pmid = {42560687},
issn = {1532-5415},
support = {R01HD096221//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01AG065722/AG/NIA NIH HHS/United States ; R01AG065722-S1/AG/NIA NIH HHS/United States ; R01AG079295/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: People with Alzheimer's disease and related dementias (ADRD) are at increased risk of motor vehicle crash (MVC) due to cognitive decline, which often begins years before diagnosis. MVC could serve as an indicator of ADRD-related cognitive impairment and facilitate earlier diagnosis.

METHODS: We conducted a matched cohort study of Medicare beneficiaries in New Jersey aged ≥ 69 years with incident ADRD diagnoses from 2010 to 2017 compared to individuals without ADRD and with four other medical conditions: acute myocardial infarction (AMI), asthma, chronic obstructive pulmonary disease (COPD), and diabetes. Comparison groups were sampled with replacement and matched on sex, age, and calendar quarter of diagnosis or claim (for the non-ADRD group). Crash prevalence at 6 months and 1, 2, and 3 years before diagnosis was compared using chi-square tests, and the monthly prevalence was plotted to examine longitudinal trends in crashes.

RESULTS: We identified 43,115 eligible individuals with incident ADRD diagnosis from 2010 to 2017. MVC crash prevalence was higher in the ADRD group than in non-ADRD and negative control groups at all measured pre-diagnosis time points: 6 months (2.99% vs. 2.31%-2.53%), 1 year (5.26% vs. 4.18%-4.65%), 2 years (9.52% vs. 7.88%-8.67%), and 3 years (13.64% vs. 11.29%-12.37%). The ADRD group was more likely to have multiple crashes in the pre-diagnosis period, but multiple events were rare overall (< 3%). Differences were statistically significant but represented small changes in prevalence. Crash prevalence did not reveal a clear signal of cognitive decline in the years leading up to the index diagnosis.

CONCLUSIONS: Older adults with ADRD had slightly higher prevalence of MVC in the 3 years before diagnosis than matched comparison groups, but absolute differences were small and recurrent crashes were rare. MVC alone is too rare to serve as a signal of incipient ADRD, highlighting the need for more sensitive measures.},
}

@article {pmid42560912,
year = {2026},
author = {Zhao, BW and Zhao, HF and Huang, YA and Hu, PW and You, ZH and Hu, L},
title = {A Novel Graph Transformer Framework for Predicting Drug-Disease Associations with Structural Awareness.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3721658},
pmid = {42560912},
issn = {2998-4165},
abstract = {Accurately predicting drug-disease associations (DDAs) is essential for accelerating the discovery of novel therapeutics. Graph representation learning-based computational models have become increasingly popular for this task due to their efficiency and cost-effectiveness. However, existing approaches often suffer from structural inductive biases and a limited ability to capture the rich heterogeneous context of biomedical molecules, which constrains their capacity to learn expressive drug and disease representations. To address this issue, we propose SGTL-DDA, a novel graph transformer framework designed to incorporate structural information and domain-specific knowledge from heterogeneous biological information networks (HBINs). SGTL-DDA integrates a meta-path-guided sampling strategy with a multi-level attention mechanism, enabling the model to jointly learn from both structural dependencies and attribute semantics in an end-to-end manner. Extensive experiments on two benchmark datasets demonstrate that SGTL-DDA consistently outperforms state-of-the-art methods in terms of Accuracy, F1-score, and AUC under a ten-fold cross-validation scheme. Furthermore, case studies on Alzheimer's disease and breast cancer confirm the predictive capability of SGTL-DDA, as it successfully identifies both known therapeutics and novel repositioning candidates, supported by molecular docking results and literature evidence.},
}

@article {pmid42560982,
year = {2026},
author = {Takeoka, C and Yada, T and Yamazaki, T and Kuroiwa, Y and Hirai, T and Fujino, K and Mizusawa, H and Takao, M and Terao, Y and Yamada, M},
title = {Classification of sporadic Creutzfeldt-Jakob disease based on resting state scalp-recorded electroencephalogram-derived indices.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0355367},
pmid = {42560982},
issn = {1932-6203},
mesh = {Humans ; *Creutzfeldt-Jakob Syndrome/classification/diagnosis/physiopathology ; *Electroencephalography/methods ; Aged ; Female ; Male ; *Scalp/physiopathology ; Alzheimer Disease/physiopathology/diagnosis ; Middle Aged ; Rest ; },
abstract = {Prion disease is a general term for a disease that causes cognitive disorders due to the accumulation of abnormal prion protein in the brain. Creutzfeldt-Jakob disease (CJD) is the most common case of prion disease, and sporadic Creutzfeldt-Jakob disease (sCJD) accounts for more than 70% of CJD cases. Early and accurate diagnosis of sCJD remains challenging. The aim of this study is to classify 6 sCJD patients from 10 healthy older adults and 23 Alzheimer's disease (AD) patients using resting-state scalp-recorded electroencephalogram (EEG)-derived indices. Power spectrum, SL values by Synchronization Likelihood (SL), and graph metrics by SL values were calculated for 5 frequency bands as EEG-derived indices. In addition, power spectrum and SL values were standardized and exponentially transformed for each subject and each frequency band. Graph metrics were calculated by these SL values. These indices were used as features for classification. Classifiers were constructed by features selected by Recursive Feature Elimination (RFE). The highest classification accuracy was 97.44% using a 12-dimensional feature. This accuracy was confirmed by indices after standardization and exponential transformation. Additional validation analyses were performed to assess the reliability of the selected classifier. Accuracy of nested LOOCV was 84.62%, supporting meaningful classification ability under a leakage-controlled validation framework. An analysis of robustness removing a group of subjects with high similarity with many others showed that the selected classifier maintained a micro-F1 score of 90.32%. Permutation test indicated that the observed performance was significantly higher than chance level, and repeated stratified 10-fold cross-validation showed relatively stable performance across different data partitions. These findings suggest that resting-state EEG-derived indices may provide useful candidate features for classification of sCJD, AD, and healthy older adults. However, further validation using larger independent cohorts is required to establish the generalizability and clinical reliability of the proposed classifier.},
}

Humans
*Creutzfeldt-Jakob Syndrome/classification/diagnosis/physiopathology
*Electroencephalography/methods
Aged
Female
Male
*Scalp/physiopathology
Alzheimer Disease/physiopathology/diagnosis
Middle Aged
Rest

@article {pmid42561097,
year = {2026},
author = {Paladugu, L and Gharaibeh, A and Kolli, N and Learman, C and Hall, TC and Li, L and Rossignol, J and Maiti, P and Dunbar, GL},
title = {RETRACTED: Paladugu et al. Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer's Disease. Int. J. Mol. Sci. 2021, 22, 860.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
pmid = {42561097},
issn = {1422-0067},
abstract = {The journal retracts the article entitled "Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer's Disease" [...].},
}

@article {pmid42561134,
year = {2026},
author = {Ehn, E and Thonberg, H and Nennesmo, I and Lindstrand, A and Kvarnung, M and Graff, C},
title = {Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.},
journal = {Human molecular genetics},
volume = {35},
number = {16},
pages = {},
doi = {10.1093/hmg/ddag072},
pmid = {42561134},
issn = {1460-2083},
mesh = {Humans ; *Whole Genome Sequencing/methods ; *Neurodegenerative Diseases/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; C9orf72 Protein/genetics ; DNA Copy Number Variations/genetics ; Male ; Middle Aged ; Alzheimer Disease/genetics/diagnosis ; Genetic Predisposition to Disease ; Frontotemporal Dementia/genetics/diagnosis ; Aged ; DNA Repeat Expansion/genetics ; Adult ; Polymorphism, Single Nucleotide ; Phenotype ; },
abstract = {Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.},
}

Humans
*Whole Genome Sequencing/methods
*Neurodegenerative Diseases/genetics/diagnosis
Amyotrophic Lateral Sclerosis/genetics/diagnosis
Female
C9orf72 Protein/genetics
DNA Copy Number Variations/genetics
Male
Middle Aged
Alzheimer Disease/genetics/diagnosis
Genetic Predisposition to Disease
Frontotemporal Dementia/genetics/diagnosis
Aged
DNA Repeat Expansion/genetics
Adult
Polymorphism, Single Nucleotide
Phenotype

@article {pmid42561290,
year = {2026},
author = {Frota, LS and Barbosa, SICG and Prado, JCS and Ishiki, HM and Fontenelle, ROS and Morais, SM},
title = {Evaluation of bioactive compounds from Libidibia ferrea (Mart. Ex Tul) LP Queiroz: Antioxidant and antifungal activities, acetylcholinesterase inhibition, and implications in Alzheimer's disease.},
journal = {Anais da Academia Brasileira de Ciencias},
volume = {98},
number = {2},
pages = {e20250618},
doi = {10.1590/0001-3765202620250618},
pmid = {42561290},
issn = {1678-2690},
mesh = {*Cholinesterase Inhibitors/pharmacology/isolation & purification ; *Antifungal Agents/pharmacology/isolation & purification ; *Antioxidants/pharmacology/isolation & purification ; *Plant Extracts/pharmacology/chemistry ; Microbial Sensitivity Tests ; Alzheimer Disease/drug therapy ; *Candida albicans/drug effects ; Molecular Docking Simulation ; *Burseraceae/chemistry ; Plant Leaves/chemistry ; },
abstract = {Fungal infections caused by Candida albicans represent a global health concern, with increasing antifungal resistance and potential links to neurodegenerative diseases such as Alzheimer's. In this context, this study evaluated the antifungal, antioxidant and acetylcholinesterase inhibitory activities of the hydroethanolic leaf extract of Libidibia ferrea, a species used in traditional medicine. The antioxidant potential was determined using DPPH and ABTS assays, while acetylcholinesterase inhibition was assessed by an in vitro enzymatic assay. Antifungal activity was assessed against Candida albicans strains by broth microdilution and molecular docking was employed to predict the interactions of the main phenolic compounds with acetylcholinesterase and sterol 14-α-demethylase. The extract showed potent antioxidant activity (CI50 = 9.68 ± 0.51 μg/mL for DPPH) and high inhibition of acetylcholinesterase (CI50 = 15.02 ± 0.16 μg/mL). It also showed fungistatic and fungicidal effects, with MIC values ranging from 0.118 to 0.469 mg/mL. In silico analyses highlighted rutin, catechin and ellagic acid as compounds with strong binding affinities to both enzymes, suggesting dual antifungal and neuroprotective effects. These results corroborate Libidibia ferrea as a promising source of bioactive compounds with potential therapeutic applications for fungal infections and neurodegenerative diseases, such as Alzheimer's.},
}

*Cholinesterase Inhibitors/pharmacology/isolation & purification
*Antifungal Agents/pharmacology/isolation & purification
*Antioxidants/pharmacology/isolation & purification
*Plant Extracts/pharmacology/chemistry
Microbial Sensitivity Tests
Alzheimer Disease/drug therapy
*Candida albicans/drug effects
Molecular Docking Simulation
*Burseraceae/chemistry
Plant Leaves/chemistry

@article {pmid42561582,
year = {2026},
author = {Kumari, P and Lipton, RB and Aschenbrenner, AJ and Sperling, R and Donohue, MC and Grober, E},
title = {Stages of objective memory impairment (SOMI) as a predictor of clinical progression in the A4 study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100641},
doi = {10.1016/j.tjpad.2026.100641},
pmid = {42561582},
issn = {2426-0266},
abstract = {BACKGROUND: About one third of amyloid positive, cognitively normal individuals develop mild cognitive impairment or clinical Alzheimer dementia (AD) over 5 years of follow-up. Sensitive cognitive measures, in addition to biomarkers of amyloid pathology, add to the efficiency of secondary prevention trials by identifying cognitively normal individuals at greatest risk of clinical progression. The Stages of Objective Memory Impairment (SOMI) system, based on the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR), predicted clinical progression in two observational studies.

OBJECTIVE: Our objective was to extend SOMI's findings to clinical trials using participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's(A4) study.

METHODS: Eligible participants were cognitively normal, had a Clinical Dementia Rating (CDR) =0, an elevated amyloid level, the pFCSRT+IR, pTau217, and longitudinal data on the CDR. Cox proportional hazards model was used to assess the association of baseline SOMI stage for clinical progression defined by time to the first of 2 consecutive CDRs > 0 or CDR>0 at last assessment. The sample was censored at 4.5 years of follow-up.

RESULTS: Of the 911 eligible participants, mean age was 72 years, 59% were female, 62% were APOE ε4 carriers, and 37% progressed over 4.5 years. Hazard ratios (HR) for progression were estimated with follow-up time as the timescale and the SOMI 0 group as the reference. The HRs for progression across SOMI stage increased from 1.48(1.15-1.92 p=.003) for SOMI-1, to 1.83 (1.32-2.54, p ≤ 0.001) for SOMI-2, and to 3.04 (1.97-4.68, p ≤ 0.001) for SOMI 3/4. SOMI remained an independent and significant predictor when pTau217 was added to the model.

CONCLUSION: SOMI's risk profile in A4 was similar to prior findings in observational cohorts. SOMI provides a low-cost, non-invasive enrichment tool for identifying individuals at risk for early cognitive decline in secondary prevention trials.},
}

@article {pmid42561602,
year = {2026},
author = {Hajeforoosh, P and Moghaddam, AH and Jelodar, SK},
title = {Insulin resistance as a driver of neuroinflammation and oxidative stress in Alzheimer's disease: Mechanistic links and therapeutic approaches.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {202},
number = {},
pages = {119760},
doi = {10.1016/j.biopha.2026.119760},
pmid = {42561602},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and hyperphosphorylated tau protein aggregates, leading to progressive cognitive decline. Growing evidence suggests that AD may also be considered a metabolic disorder closely associated with insulin resistance (IR). Impaired insulin signaling disrupts the PI3K/Akt and GSK3-β pathways, resulting in synaptic dysfunction, neuronal loss, and aberrant protein phosphorylation. Moreover, IR contributes to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation within the central nervous system (CNS). These metabolic alterations, together with impaired energy homeostasis, dysregulate intracellular signaling cascades and exacerbate amyloid and tau pathology. This narrative review examines the mechanistic interplay among insulin resistance, oxidative stress, and neuroinflammation in AD, with particular emphasis on the shared cellular pathways that underlie disease progression. In addition, it summarizes emerging therapeutic strategies targeting insulin signaling, including pharmacological insulin-sensitizing agents, incretin-based therapies, lifestyle interventions, and bioactive natural compounds. The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy. Despite substantial progress, the precise mechanisms linking insulin resistance to neurodegeneration remain incompletely understood. Further mechanistic and translational studies are urgently required to elucidate these interactions and advance the development of effective therapeutic interventions.},
}

@article {pmid42561665,
year = {2026},
author = {Tyagi, P and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and Medhi, B and HariKrishnaReddy, D},
title = {HMGB1 signalling in Alzheimer's disease: pathogenic roles and therapeutic prospects.},
journal = {International immunopharmacology},
volume = {187},
number = {},
pages = {117204},
doi = {10.1016/j.intimp.2026.117204},
pmid = {42561665},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the gradual loss of neurons, especially in the hippocampus and cerebral cortex. This neuronal loss results in cognitive decline, memory problems, and changes in behaviour. It accounts for roughly 90% of all cases, making it the most common reason for dementia worldwide, with a marked rise in its occurrence as one ages. AD is pathologically marked by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and the formation of extracellular amyloid-β plaques. Along with these defining characteristics, oxidative stress and chronic neuroinflammation, which are triggered by prolonged astrocyte and microglia activation and excessive reactive oxygen species production, play crucial roles in the development of the illness. The majority of cases of AD are sporadic late-onset illness, but the less common familial variant is linked to mutations in the APP, PSEN1, and PSEN2 genes that cause aberrant amyloid-β formation. High mobility group box 1 (HMGB1) is a crucial modulator of neuroinflammation in AD, according to new research. By activating the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), HMGB1, especially in its pro-inflammatory disulfide state, hinders memory and learning. RAGE/CaMKKβ-AMPK, ERK1/2, GSK-3β, NF-κB, MAPKs, and NLRP3 inflammasome cascades are among the overlapping downstream signalling pathways that these receptors initiate. Together, these pathways induce tau hyperphosphorylation, amyloid-β buildup, and persistent inflammatory responses. Therefore, a viable treatment approach for reducing neuroinflammation and associated pathologies with AD. is to target HMGB1-mediated signalling networks.},
}

@article {pmid42561776,
year = {2026},
author = {Chen, W and Zhan, K and Xu, C and Sun, S and Yang, X and Lei, H},
title = {Structure-based identification of novel indole-fused polycyclic derivatives as potent acetylcholinesterase inhibitors.},
journal = {Bioorganic & medicinal chemistry},
volume = {142},
number = {},
pages = {118765},
doi = {10.1016/j.bmc.2026.118765},
pmid = {42561776},
issn = {1464-3391},
abstract = {The pathogenesis of Alzheimer's disease (AD) is closely associated with cholinergic neuronal impairment, which is induced by excessive degradation of acetylcholine (ACh) mediated by acetylcholinesterase (AChE). In this study, a series of novel indole-fused polycyclic derivatives (1-28) were designed, synthesized, and assessed for their AChE inhibitory activities. The biological evaluation results demonstrated that most of the compounds exhibited moderate to excellent AChE inhibitory activities. Among them, compounds 8, 9, 21, and 26 showed leading AChE inhibitory activity with IC50 values of 0.29 μM, 1.5 μM, 1.2 μM, and 1 μM, respectively, which were superior to the positive control galantamine (IC50 = 2.2 μM). Furthermore, favorable drug-likeness profiles and optimal pharmacokinetic properties were confirmed for compound 8 through ADME analysis. Stable binding interactions between compound 8 and AChE were validated by the results of 100 ns molecular dynamics simulations. Overall, compound 8 was characterized as a potent and well-qualified AChE inhibitor, and further systematic investigations are warranted for its application in the treatment of AD-related diseases.},
}

@article {pmid42561934,
year = {2026},
author = {Li, W and Rimal, S and Bhurtel, S and Yeung, L and Lu, BG and Grinberg, LT and Spina, S and Sillero, MIC and Seeley, WW and Guo, S and Lu, B},
title = {Tau-induced mitochondrial reverse electron transport drives neurodegeneration.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.07.012},
pmid = {42561934},
issn = {1097-4199},
abstract = {Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD[+]/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience. Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Inhibition of RET ameliorates tau toxicity across species. RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.},
}

@article {pmid42562307,
year = {2026},
author = {Yadav, A and Verma, H and Kumari, S and Gangwar, P and Rao, R and Yadav, B and Kaur, S and Dhiman, M and Mantha, AK},
title = {The emerging role of NADPH oxidases (NOX) in Alzheimer's disease pathogenesis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.08.004},
pmid = {42562307},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a slow-progressing neurodegenerative disease, mainly characterized by the accumulation of amyloid beta (Aβ) plaques and intracellular hyperphosphorylated Tau protein, along with the generation of free radicals. In normal physiology free radicals play a promising role. However, the imbalance in the formation and clearance of the free radicals or reactive oxygen species/reactive nitrogen species (ROS/RNS) disrupts redox homeostasis, resulting in oxidative stress. Cellular disruption through the oxidation of lipids, proteins, and nucleic acids along with the disruption of the blood-brain barrier (BBB) integrity, and neuroinflammation are linked with AD pathogenesis. Albeit there are various ROS-generating sources, notably mitochondria, endoplasmic reticulum (ER), peroxisomes, NADPH oxidase (NOX), and several other oxidases, but out of all, the second most well-studied ROS-generating component after mitochondria is thought to be NOX. It is a multi-subunit enzyme family, activated by the phosphorylation of its cytosolic subunit, culminating in the production of superoxide (O2[•-]) anions. It comprises seven different isoforms, where NOX2 is the most studied isoform found to be the major source of ROS production in the brain. Therefore, inhibiting NOX-induced oxidative stress in the brain might be a promising therapeutic approach for AD. Thus, the current review enlightens the role of NOX in neurodegenerative AD progression, Aβ pathology and focusing on the therapeutic interventions by employing different phytochemicals as natural inhibitors and the synthetic inhibitors to combat the pathogenicity associated with NOX in the case of AD.},
}

@article {pmid42562385,
year = {2026},
author = {Gauch, M and Ablinger, I and Corsten, S and Dörr, F and Flöel, A and Grewe, T and Foede, J and Heinrich, I and Knels, C and Köb, AL and Meinzer, M and Rosenkranz, A and Schmischke, A and Unger, N and Volkmer, A and Wuttke, T and Rysop, AU},
title = {Mapping PPA Care: Results of a Survey Study on Speech and Language Therapy for People With Primary Progressive Aphasia Across Germany.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261473983},
doi = {10.1177/14713012261473983},
pmid = {42562385},
issn = {1741-2684},
abstract = {Background: Primary Progressive Aphasia (PPA) is a rare condition characterised by a gradual loss of language due to neurodegenerative processes including frontotemporal lobar degeneration and Alzheimer's disease. Speech and language therapy is one of the main treatment options for people with PPA (PwPPA). International survey studies among speech and language therapists (SLTs) have revealed considerable shortcomings in treatment options for this patient group. To date, there has been no survey on speech and language therapy for PwPPA in Germany. Methods: We translated a survey that was originally developed to describe speech and language therapy for PPA in the UK into German and adapted it to the German healthcare system. The final 32-item survey covering demographics of SLTs and PwPPA, referral patterns, as well as diagnostic and therapeutic procedures, was distributed online. Results: Data from 46 SLTs, from 10 of Germany's 16 federal states with experience in treating PwPPA were included. These 46 SLTs had treated 158 PwPPA in the last 24 months and reported working with PwPPA for >20 sessions on average. PwPPA were most frequently referred to speech and language therapy 2-3 years after symptom onset with word finding difficulties. Qualitative content analysis revealed barriers on multiple levels to access speech and language therapy. Informal assessments, including analysis of spontaneous speech, interviews with PwPPA and/or carers and screening of language and communication skills were reported as most frequently used. SLTs rated life story work, activity and participation-focused therapy and symptom-focused therapy. for language disorders as the most commonly used for PwPPA. Discussion: This study provides an overview of the current state of speech and language therapy for PwPPA in Germany. It shows that there is currently no clear pathway for PPA care that covers all levels of the International Classification of Functioning Disability and Health and encompasses both assessment and treatment approaches. A comparison of the results obtained from this survey study with those from other similar studies in the UK, Turkey and Italy revealed both similarities and differences. Our findings underscore the need for further research, the development of standardized, evidence-based assessment and intervention tools, and targeted professional training.},
}

@article {pmid42562450,
year = {2026},
author = {Mendes Ferreira, V and Viana-Baptista, M},
title = {Family history of cognitive impairment as a diagnostic clue in Fragile X-associated tremor/ataxia syndrome.},
journal = {BMJ case reports},
volume = {19},
number = {8},
pages = {},
doi = {10.1136/bcr-2026-273818},
pmid = {42562450},
issn = {1757-790X},
mesh = {Humans ; Male ; *Fragile X Syndrome/diagnosis/genetics/complications ; *Tremor/genetics/diagnosis ; *Ataxia/genetics/diagnosis/complications ; Fragile X Messenger Ribonucleoprotein 1/genetics ; *Cognitive Dysfunction/genetics/diagnosis/etiology ; Magnetic Resonance Imaging ; Diagnosis, Differential ; Middle Aged ; },
abstract = {Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by premutation alleles (55-200 CGG repeats) in the FMR1 gene, typically presenting in later adulthood with intention tremor, cerebellar ataxia and cognitive impairment. We report a male patient in his 5th decade presenting with progressive bilateral action tremor initially suggestive of essential tremor. Neurological examination revealed postural and intention tremor with mild dysdiadochokinesia. A family history of early-onset cognitive decline in a first-degree relative prompted brain MRI, which demonstrated bilateral T2 hyperintensities of the middle cerebellar peduncles, suggestive of FXTAS. Subsequent genetic testing confirmed an FMR1 premutation with 115 CGG repeats, establishing the diagnosis of FXTAS. Review of the brother's records revealed progressive cognitive impairment previously attributed to Alzheimer's disease, raising the possibility of unrecognised FXTAS. This case highlights the importance of family history and neuroimaging in distinguishing FXTAS from more common tremor disorders and dementia syndromes.},
}

Humans
Male
*Fragile X Syndrome/diagnosis/genetics/complications
*Tremor/genetics/diagnosis
*Ataxia/genetics/diagnosis/complications
Fragile X Messenger Ribonucleoprotein 1/genetics
*Cognitive Dysfunction/genetics/diagnosis/etiology
Magnetic Resonance Imaging
Diagnosis, Differential
Middle Aged

@article {pmid42562606,
year = {2026},
author = {Karagianni, S and Moscoso, A and Raghavan, S and van Essen, M and Mainta, I and Camacho, V and Rodríguez-Fonseca, O and Silva-Rodríguez, J and Perissinotti, A and Gu, Y and Yun, J and Franzmeier, N and Grothe, MJ and Seo, SW and Frisoni, GB and Garibotto, V and Schwarz, CG and Petersen, RC and Jack, CR and Vemuri, P and Schöll, M},
title = {Concordance Between [[18]F]Flortaucipir PET Visual Reads and CenTauR-Based Quantification.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.126.272722},
pmid = {42562606},
issn = {1535-5667},
abstract = {Tau PET imaging with [[18]F]flortaucipir allows for the visualization and mapping of aggregated tau deposits, a key neuropathologic feature of Alzheimer disease (AD). A visual interpretation method for [[18]F]flortaucipir was approved by the Food and Drug Administration and European Medicines Agency and has been implemented for a standardized, clinically usable definition of tau PET positivity. The CenTauRz method, on the other hand, offers the possibility to harmonize the definition of tau PET positivity across different radiotracers using quantitative metrics, but its concordance with clinically relevant [[18]F]flortaucipir visual reads remains unclear. Methods: A convenience sample of 3991 participants, including cognitively unimpaired (CU) and cognitively impaired (CI) individuals (i.e., those with mild cognitive impairment or AD dementia), underwent [[18]F]flortaucipir PET imaging. Each [[18]F]flortaucipir scan was assessed by 3 trained readers using the approved visual interpretation method and quantified using the CenTauRz quantification pipeline in different regions of interest (ROIs). Concordance between positive visual reads and CenTauRz-defined positivity (i.e., >2 on the CenTauRz scale) was assessed using Cohen κ. Receiver-operating-characteristic (ROC) analysis evaluated the discriminative power of continuous CenTauRz values in distinguishing between negative and positive visual reads. Generalized additive models examined clinical progression on the basis of visual and CenTauRz-based assessments of tau PET positivity. Results: Concordance between visual reads and CenTauRz-based assessments of tau PET positivity was moderate, particularly in CU individuals (κ = 0.23-0.55 for CU participants, κ = 0.57-0.82 for CI participants, depending on the ROI). ROC analysis revealed that the agreement remained moderate, independent of the CenTauRz cut point used (area under the ROC curve, 0.72-0.87 vs. 0.87-0.97 for CU and CI individuals, respectively). Among discordant cases, participants with visually positive/CenTauRz-negative tau PET scans were more frequently amyloid-positive and exhibited faster clinical progression compared with visually negative/CenTauRz-positive individuals. Conclusion: Our findings highlight the relatively limited agreement between the visual assessment of [[18]F]flortaucipir PET images and CenTauRz-based quantification, particularly in CU individuals. Participants with visually positive/CenTauRz-negative tau PET scans showed a high frequency of amyloid positivity and faster clinical progression, suggesting that visual reads are more sensitive to heterogeneous, clinically relevant tau accumulation patterns not captured by ROI-based methods. These findings underscore the need for new quantification approaches to better capture the complex patterns of tau deposition, important for early AD detection and monitoring.},
}

@article {pmid42562773,
year = {2026},
author = {Zheng, X and Zhang, N and Wang, L and Zhao, H and Liu, C and Wang, J and Zhao, W and Zhao, J and Yang, P and Robinson, L and Hunt, L and Lokken, A and Lin, L and Nelson, PT and Kofler, J and Xie, H and Xia, H and Mao, Q},
title = {A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag085},
pmid = {42562773},
issn = {1554-6578},
support = {GC-202008-2020689//Alzheimer's Drug Discovery Foundation/ ; R21AG080502/AG/NIA NIH HHS/United States ; R21AG088509/AG/NIA NIH HHS/United States ; R01AG097508/AG/NIA NIH HHS/United States ; },
abstract = {TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.},
}

@article {pmid42562777,
year = {2026},
author = {Shao, R and Li, W and Su, H and Zhou, S and Lan, M and Li, D},
title = {Impact of Narrative Nursing and Cognitive Behavioral Rehabilitation on Cognitive Function and Anxiety in Patients With Alzheimer's Disease.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70719},
doi = {10.1111/ggi.70719},
pmid = {42562777},
issn = {1447-0594},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/psychology/rehabilitation ; *Cognitive Behavioral Therapy/methods ; Aged ; *Quality of Life ; *Cognition/physiology ; *Anxiety/etiology ; Activities of Daily Living ; Treatment Outcome ; *Narrative Therapy/methods ; Middle Aged ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) progressively impairs cognitive function and quality of life (QoL). Patients frequently experience anxiety, which may accelerate cognitive decline. This study aimed to investigate the effects of narrative nursing combined with cognitive behavioral rehabilitation on cognitive function and anxiety in AD patients.

METHODS: In this randomized controlled trial, 172 AD patients were assigned to a control group (conventional care, n = 86) or an observation group (additional 6-month narrative nursing and cognitive behavioral rehabilitation, n = 86). Outcomes were assessed at baseline and after the 6-month intervention using validated Chinese versions of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Generalised Anxiety Disorder-7 (GAD-7), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Quality of Life in Alzheimer's Disease (QoL-AD) scales.

RESULTS: Baseline characteristics, including age (mean: 68.5 ± 10.2 years), sex distribution (57.6% men), body mass index (22.95 ± 3.44 kg/m[2]), disease duration (5.32 ± 0.79 years), and baseline cognitive scores (MMSE: 19.25 ± 2.88; MoCA: 17.00 ± 2.55), did not differ significantly between groups. After 6 months of intervention, the observation group demonstrated greater improvement in cognitive function (MMSE: F = 4.461, p = 0.039; MoCA: F = 5.441, p = 0.040), anxiety (GAD-7: F = 14.937, p < 0.001), ADL (ADCS-ADL: F = 11.967, p < 0.001), and QoL (QoL-AD: F = 7.307, p < 0.001) than the control group. Adherence was high (92%), with no significant group differences. Missed sessions were primarily attributable to acute illness, transportation difficulties, or family commitments. Medication regimens (cholinesterase inhibitors, memantine, and antidepressants) remained stable between groups, with no significant interaction with the intervention.

CONCLUSION: Narrative nursing combined with cognitive behavioral rehabilitation can effectively increase cognitive function, reduce anxiety, and improve the ADL and QoL of patients with AD.

TRIAL REGISTRATION: ISRCTN10742199.},
}

Humans
Male
Female
*Alzheimer Disease/psychology/rehabilitation
*Cognitive Behavioral Therapy/methods
Aged
*Quality of Life
*Cognition/physiology
*Anxiety/etiology
Activities of Daily Living
Treatment Outcome
*Narrative Therapy/methods
Middle Aged

@article {pmid42562893,
year = {2026},
author = {Khaki, PSS and Guillen-Poza, PA and Wong, C and Kan, C and Sharma, R and Sugimura, R and Robinson, AC and Valbuena, A and Ng, RC and Yang, Y and Hervas, R},
title = {Distinct amyloid-β filament fold in individuals with APP Flemish mutation.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {42562893},
issn = {1545-9985},
abstract = {The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide. Although tau paired helical filaments were present, the predominant filaments comprise Aβ40-A21G, assembled as two identical protofilaments (D1-V40) packed with two-start helical symmetry. Aβ40-A21G and wild-type Aβ42 filaments share a substructure preceding the substitution site (Y10-F19); however, loss of the methyl group at residue 21 gives rise to a distinct arrangement, termed the 'Flemish fold', which differs from all previously characterized Aβ folds and is defined by a unique hydrophobic interface. Using a cell-based assay, we find that this distinctive fold is associated with the vascular tropism characteristic of the Flemish variant. Together, our structural and cellular data define a familial Alzheimer-disease-associated amyloid fold and provide insight into the molecular basis of Flemish-type dementia and cerebral hemorrhage.},
}

@article {pmid42562894,
year = {2026},
author = {},
title = {Alzheimer's disease-linked Flemish APP mutation defines a distinct amyloid-β fold.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {42562894},
issn = {1545-9985},
}

@article {pmid42563066,
year = {2026},
author = {Almirón, RS and Tettamanti, C and Martinez, S and Antonino, M and Marmo, P and Debiagge, Á and Toselli, D and Moro, L and Allemandi, D and Lorenzo, A and Quinteros, DA and Bignante, EA},
title = {Gallein-Loaded Albumin Nanoparticles Prevent Amyloid-β-Induced Amyloidogenic APP Processing, Synaptic Loss, and Dendritic Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42563066},
issn = {1559-1182},
support = {ANPCyT PICT 2021-GRF-TI-00561//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; ANPCyT PICT 2019-282//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; PIDTA-SECYT 2023-2027//Secretaria de Ciencia y Tecnología - Universidad Nacional de Córdoba/ ; PIP 2022-2024//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PIP 2020-2022//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; AARGD-22-926476/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Nanoparticles/chemistry ; *Amyloid beta-Peptides/toxicity/metabolism ; Humans ; *Synapses/pathology/drug effects/metabolism ; *Dendrites/pathology/drug effects/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Mice ; Rats ; *Albumins ; Neurons/metabolism/drug effects/pathology ; Cell Line, Tumor ; },
abstract = {Alzheimer's disease (AD) is a multifactorial and highly debilitating disorder with a long clinical course. The development of new therapeutic strategies capable of mitigating or delaying disease progression remains a major challenge. We previously identified the amyloid precursor protein (APP) as a receptor for aggregated amyloid-β (Aβ) species that signals through a Go/Gβγ-dependent pathway, thereby promoting amyloidogenesis and neurotoxicity. In this context, gallein (GAL), a selective inhibitor of Gβγ signaling, has demonstrated robust neuroprotective effects in preclinical AD models. However, GAL exhibits poor stability and limited aqueous solubility, which may restrict brain bioavailability. To overcome these limitations, a nanotechnology-based formulation strategy was implemented. Here, we report the design and generation of human serum albumin-based nanoparticles (HSA NPs) loaded with GAL (NP-GAL) using a green desolvation method followed by thermal stabilization. Using murine neuroblastoma cells, primary rat cortical neurons, and human iPSC-derived neurons, we demonstrate that NP-GAL effectively prevents Aβ-induced amyloidogenic APP processing, dendritic dystrophy, and presynaptic loss. In addition, both empty NPs and NP-GAL exhibit association with Aβ aggregates, suggesting an additional benefit, as these nanoparticles mitigate amyloid-associated toxicity. Notably, the nanoparticles themselves exert beneficial effects on dendritic morphology and provide protection against neurotoxic insults beyond amyloid pathology, including those induced by rotenone, a widely used experimental model of Parkinson's disease. Together, these in vitro findings suggest that HSA-based nanoparticles hold potential as a platform to stabilize GAL and exert intrinsic neuroprotective effects. These results provide a proof-of-concept for exploring nanoparticle-mediated Gβγ inhibition to counteract Aβ-induced neuronal dysfunction and synaptic pathology.},
}

Animals
*Nanoparticles/chemistry
*Amyloid beta-Peptides/toxicity/metabolism
Humans
*Synapses/pathology/drug effects/metabolism
*Dendrites/pathology/drug effects/metabolism
*Amyloid beta-Protein Precursor/metabolism
Mice
Rats
*Albumins
Neurons/metabolism/drug effects/pathology
Cell Line, Tumor

@article {pmid42563554,
year = {2026},
author = {Asghariahmadabad, M and Metanat, P and Thomas, M and Bonham, LW and Lam, T and Kurt, M and Nguyen, H and Ellingson, T and Zucchelli, M and Casagranda, S and Lu, Q and Rauschecker, AM and Sugrue, L and Savastano, LE and Hess, CP and Ranasinghe, K and Josephson, SA and Miller, BL and Yokoyama, JS and Rabinovici, GD and Ljubenkov, PA and VandeVrede, L and Nael, K},
title = {Arterial Spin-Labeling MRI at the Cortical-CSF Interface: A Novel Biomarker in Alzheimer Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70498},
pmid = {42563554},
issn = {2328-9503},
abstract = {BACKGROUND/OBJECTIVE: Arterial spin-labeling (ASL) MRI can measure perfusion signal adjacent to CSF spaces and may provide information regarding CSF-adjacent water transport physiology. We developed an automated pipeline to extract cortical-CSF interface (IF) perfusion for comparison between Alzheimer disease (AD) and cognitively normal controls.

METHODS: In this retrospective study, participants with AD and cognitively normal controls with ASL and 3D T1-weighted MRI were included. Parenchymal cerebral blood flow (CBF) was evaluated globally (whole brain, gray matter, white matter) and across 12 brain regions. IF-perfusion values were quantified using an automated pipeline with tissue segmentation, registration, partial-volume-aware masking, and arterial-signal exclusion. Multivariable sensitivity analysis was performed, adjusting for age, sex, scanner vendor, and acquisition site. Predictive modeling was performed using LASSO-regularized logistic regression with nested repeated stratified cross-validation, and feature contributions were summarized using SHAP.

RESULTS: A total of 51 patients with AD, age (median: 73 years) and 53 cognitively normal subjects (median age: 69) were included. Global CBF did not differ between groups. However, IF-perfusion values were significantly lower in AD (median 4.4, IQR 3.2-4.8) than in controls (median 5.2, IQR 4.5-6.3; p < 0.001). In multivariable analysis, AD remained independently associated with lower IF-perfusion after adjustment for age, sex, scanner vendor, and acquisition site (β = -1.88, 95% CI: -3.52 to -0.25; p = 0.025). In LASSO-regularized logistic regression model, only IF-perfusion and cuneus-CBF remained as significant contributing features for the prediction of AD probability with the highest contribution from IF. The final model showed mean ROC-AUC 0.81 in the training and AUC of 0.78 in the testing dataset.

CONCLUSION: ASL-derived IF-perfusion is reduced in AD and may represent a promising imaging marker of altered CSF-adjacent water transport physiology. Further validation against established biomarkers of CSF dynamics and clearance pathways is warranted.},
}

@article {pmid42563724,
year = {2025},
author = {Yun, JE and Choi, S},
title = {Expanding the health belief model on dementia knowledge, fear, and preventive behaviors among older adults in Korea: a cross-sectional descriptive study.},
journal = {Journal of Korean biological nursing science},
volume = {27},
number = {1},
pages = {60-71},
pmid = {42563724},
issn = {2383-6423},
abstract = {PURPOSE: This study aimed to expand the health belief model by incorporating dementia knowledge and fear and to assess the effects of these variables on dementia prevention behaviors among older adults.

METHODS: In total, 199 elderly individuals from 10 senior centers in Korea completed a structured questionnaire assessing characteristics, dementia knowledge, fear, health beliefs, and prevention behaviors. Measures included the Alzheimer's Disease Knowledge Scale, the Korean version of the Fear of Alzheimer's Disease Scale, and the Korean version of the Motivation to Change Lifestyle and Health Behavior for Dementia. Hierarchical polynomial regression was conducted to examine the impact of integrating dementia knowledge and fear into the health belief model.

RESULTS: Hierarchical polynomial regression across four models revealed significant effects of various factors on dementia prevention behaviors, explaining 12%-36% of the variance. Perceived barriers significantly decreased dementia prevention behaviors, while higher levels of self-efficacy and cues to action had a positive influence. Additionally, a nonlinear relationship was identified between dementia knowledge and prevention behaviors, with the positive impacts of increased knowledge potentially diminishing beyond a certain point.

CONCLUSION: Our findings underscore the necessity of modifying the health belief model to integrate dementia knowledge and fear, which play critical roles in shaping preventive behaviors among older adults. Future investigations should examine the optimal level of dementia knowledge to promote these behaviors and elucidate the intricate relationship between knowledge and actions.},
}

@article {pmid42563959,
year = {2026},
author = {Liu, Y and Yi, M and Tang, C and Wang, T and Li, X},
title = {MEOX2: a homeobox transcription factor with multifaceted biological functions and broad disease associations.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1895187},
pmid = {42563959},
issn = {2296-634X},
abstract = {The mesenchymal homeobox transcription factor MEOX2 is recognized for its roles in development and homeostasis, but the full landscape of its complex and often contradictory functions in human diseases, along with its potential unifying regulatory logic, remains to be systematically elucidated. This Review synthesizes current evidence to provide a comprehensive overview of MEOX2's widespread roles in both neoplastic and non-neoplastic diseases. MEOX2 is remarkably context-dependent: it acts as an oncogene in glioblastoma and lung cancer, but as a tumour suppressor in breast cancer, hepatocellular carcinoma and other tumour types. Its dysregulation is also linked to neurovascular deficits in Alzheimer disease (AD), cardiovascular disorders, metabolic fibrosis and developmental malformations. This functional versatility stems from MEOX2's role as a key signalling integrator, subject to fine-tuned regulation by epigenetic mechanisms, non-coding RNA networks and core pathways including PI3K/AKT, ERK and Hedgehog (Hh). Given the strong association between MEOX2 expression and clinical outcomes, it has emerged as a potential diagnostic and prognostic biomarker for several diseases. Intervention strategies targeting MEOX2 and its regulatory networks show translational promise. This Review proposes a conceptual framework placing MEOX2 as a 'cross-disease core regulatory node', systematically delineates its complex disease associations and molecular mechanisms, and charts a course for the future development of precision medicine strategies targeting MEOX2.},
}

@article {pmid42564156,
year = {2026},
author = {Ali, N and Chakbazof, N and Ghasem Pour, S and Contreras, L and Estrada, J and Alexander, GE and Raichlen, DA and Yassine, HN},
title = {APOE ε4, physical activity, and the brain: a review of systematic reviews.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1798639},
pmid = {42564156},
issn = {1663-4365},
abstract = {BACKGROUND: Physical activity (PA) is often proposed as a modifiable strategy to reduce cognitive decline and dementia risk, particularly among individuals at elevated genetic risk for Alzheimer's disease (AD). However, it remains unclear whether the existing literature tests PA at the disease stage and in the populations most likely to show benefit.

OBJECTIVE: This umbrella review evaluated whether associations between PA and cognitive, fluid biomarker, neuroimaging, and vascular/metabolic outcomes differ by apolipoprotein E ε4 (APOE ε4) genotype across stages of cognitive aging, with particular attention to how study design and baseline cognitive status shape interpretation of the evidence.

METHODS: Systematic reviews and meta-analyses were screened for primary studies examining PA in adults classified by baseline cognitive status as cognitively unimpaired, mild cognitive impairment (MCI), or dementia. Primary studies reporting APOE ε4-stratified outcomes were extracted and qualitatively synthesized by outcome domain, cognitive stage, and study design.

RESULTS: Of 2,100 records identified, seven systematic reviews met inclusion criteria, yielding 68 unique primary studies. Favorable associations between PA and cognitive, biomarker, neuroimaging, and vascular/metabolic outcomes were most often reported in observational studies of younger or cognitively unimpaired adults. Several studies suggested stronger associations among APOE ε4 carriers, including midlife cognitive associations, neuroimaging markers, and vascular/metabolic outcomes such as lipid profiles. In contrast, randomized controlled trials were few, generally enrolled older adults with MCI or dementia, included small APOE ε4 subgroups, and reported largely null or mixed genotype-specific effects.

CONCLUSION: The current evidence does not establish a definitive APOE ε4-specific preventive effect of PA. Future studies may be most informative if they target earlier-stage, low-active, or metabolically at-risk APOE ε4 carriers using objective PA measures and proximal vascular, metabolic, imaging, or blood-based biomarker outcomes.},
}

@article {pmid42564234,
year = {2026},
author = {Macías, M and Escriche, E and Molina, M and Esnaola, I and Jiménez, A and Razquin-Sola, S and Roldan, M and Urdánoz-Casado, A and Sobrino, N and Fernández, C and Rubio, I and Aspra, D and Jáuregui, C and Muñoz, R and Herrera, M and Mendioroz, M},
title = {Association of acute-phase plasma pTau217 levels with long-term post-stroke cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1839662},
pmid = {42564234},
issn = {1663-4365},
abstract = {BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common complication affecting stroke survivors, yet early biomarkers for risk stratification remain scarce. Plasma pTau217 has emerged as a specific biomarker for Alzheimer's disease pathology. This study explores whether acute-phase pTau217 levels are associated with PSCI.

METHODS: We conducted a nested case-control study including 48 patients who developed PSCI within 5 years and 48 age and sex-matched patients as controls without cognitive decline. Plasma pTau217 was measured within 24 h after stroke onset using SIMOA. Statistical analysis included multivariable logistic regression, dose-response assessment via quartile stratification, and ROC curves.

RESULTS: Plasma pTau217 levels were significantly higher in PSCI cases than controls [0.313 (0.196-0.562) vs. 0.203 (0.126-0.343) pg/mL; p-value < 0.01]. Notably, pTau217 levels were not correlated with stroke severity (NIHSS at baseline) or atrial fibrillation, suggesting that pTau217 may reflect baseline neurobiological vulnerability. In multivariable models, ln-pTau217 levels were independently associated with PSCI risk (OR = 2.28; 95%CI = 1.19-4.37; p-value < 0.05). A significant linear dose-response relationship was observed, with PSCI risk increasing from 29.2% in the lowest quartile to 64.0% in the highest (p-value for trend < 0.05). The biomarker alone showed a significant discriminative capacity for clinically documented PSCI (AUC = 0.660; 95%CI = 0.552-0.768; p-value < 0.01). Furthermore, sex-stratified analysis revealed that the association was primarily driven by females.

CONCLUSION: Higher acute-phase pTau217 levels were associated with an increased likelihood of clinically documented cognitive impairment during follow-up. These exploratory findings suggest that acute-phase pTau217 may be associated with long-term cognitive outcomes after stroke, although larger prospective studies, integrating additional biomarkers with standardized neuropsychological assessment are needed.},
}

@article {pmid42564239,
year = {2026},
author = {Cretin, B and Philippi, N and Bousiges, O and Dibitonto, L and Blanc, F},
title = {The impact of long-term antiseizure treatment on cognitive decline in late-onset epileptic prodromal Alzheimer's disease: an exploratory study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1786247},
pmid = {42564239},
issn = {1663-4365},
abstract = {BACKGROUND: The well-documented bidirectional relationship between Alzheimer's disease (AD) and epilepsy suggests that seizures are not merely a complication of AD but may also contribute to disease progression. Emerging evidence indicates that antiseizure medications (ASMs) could potentially slow the disease course and act as disease-modifying agents if initiated early.

OBJECTIVES: We investigated the long-term cognitive and functional effects of ASMs when introduced at the prodromal stage of AD.

METHODS: Twenty-two sporadic epileptic prodromal AD patients (epADs) and 21 matched subjects without epilepsy (nepADs) were followed for a median of 7 years. Baseline cognition, daily functioning, clinical/paraclinical features, and pharmacological profiles were compared. Annual assessments included cognition, pharmacological burden, and functional impairment.

RESULTS: At the final follow-up, epADs evidenced more preserved cognition than nepADs, reflecting a significantly slower annual rate of cognitive decline (-1.2 ± 0.9 vs. -2.7 ± 2.4 points/year on the MMSE score, respectively; p = 0.01). They were also less likely to require neuroleptics (9.1% vs. 47.6%, p < 0.01) or memantine (0% vs. 28.6%, p < 0.01). However, epADs and nepADs had the same proportion of Alzheimer's dementia at the final follow-up visit (90.9% vs. 90.5%, p = 0.96). Despite being significant, these results had low statistical power due to our small sample size and should be considered exploratory.

CONCLUSION: Our findings support the idea that early ASM treatment may attenuate cognitive decline in sporadic prodromal AD patients with comorbid epilepsy. However, these benefits were not accompanied by a lower dementia rate at the final follow-up visit, suggesting that ASMs alone are insufficient for sustained disease modification. Combinatorial therapeutic strategies may be needed to achieve long-term neuroprotection in AD.},
}

@article {pmid42564294,
year = {2026},
author = {Zhao, M and Sui, X and Li, J and Wang, Q and Sun, Y and Zheng, H and Li, B},
title = {Ferroptosis-related biomarkers for diagnosis and mechanistic insights into Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1857642},
pmid = {42564294},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) lacks reliable early diagnostic biomarkers and effective disease-modifying therapies. Ferroptosis has been increasingly implicated in AD pathogenesis; however, ferroptosis-related genes with diagnostic and mechanistic relevance remain insufficiently characterized.

METHODS: Transcriptomic datasets were obtained from the GEO database and analyzed using differential expression analysis and WGCNA, followed by integration with ferroptosis-related gene sets. Key targets were identified through PPI networks and machine learning approaches, including LASSO regression and random forest. A diagnostic model was constructed and its discriminative performance was assessed across independent datasets by cohort-specific refitting. Functional roles were explored using GSEA, and experimental validation was conducted by qPCR in Aβ-treated PC12 cells. Potential therapeutic compounds were predicted using the CMAP database.

RESULTS: A total of 52 ferroptosis-related candidate genes were identified. Among these, three genes, NFKBIA, ATP6V1E1, and SUB1, were consistently selected as core features by machine learning algorithms. A diagnostic model based on these genes demonstrated strong performance in the training cohort (AUC > 0.8) and reproducible discriminative ability across external datasets, albeit with cohort-dependent variability. Functional analysis suggested that these genes are involved in pathways related to neuroinflammation, lysosomal activity, and oxidative stress, indicating a potential link between ferroptosis and key pathological processes in AD. qPCR validation confirmed the differential expression trends of these genes. In addition, several candidate compounds, including etomoxir and tubastatin A, were predicted to potentially modulate these pathways.

CONCLUSION: Three ferroptosis-related genes, NFKBIA, ATP6V1E1, and SUB1, were identified in Alzheimer's disease and showed consistent discriminative ability across multiple cohorts, with links to neuroinflammation, lysosomal function, and oxidative stress. These findings highlight their potential as candidate biomarkers warranting further investigation, although prospective validation in independent cohorts is required to confirm their diagnostic utility.},
}

@article {pmid42564336,
year = {2026},
author = {Chi, M and Zhao, A and Zhang, Y and Fan, L and Wang, Q and Tang, B and Tao, M},
title = {Electroencephalography for early Alzheimer's disease diagnosis: from advanced feature engineering to interpretable ai and clinical translation.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1819726},
pmid = {42564336},
issn = {1664-0640},
abstract = {OBJECTIVE: This review aims to comprehensively review the methodologies and advancements in using electroencephalography (EEG) for the early diagnosis of Alzheimer's disease (AD), addressing the limitations of traditional diagnostic tools.

METHODS: We conducted a comprehensive analysis of current research, encompassing the complete EEG analysis pipeline from signal acquisition and preprocessing to feature extraction-including time-frequency and brain network metrics-and the application of machine learning and deep learning algorithms.

RESULTS: Characteristic EEG alterations, such as spectral slowing and reduced signal complexity, are associated with early AD. Advanced feature extraction combined with intelligent algorithms significantly enhances diagnostic performance, with some studies reporting classification accuracies exceeding 95%. Integration of EEG with multimodal data (e.g., MRI, genetic markers) further improves diagnostic robustness.

CONCLUSIONS: EEG is a promising, non-invasive, and cost-effective tool for early AD detection in appropriate clinical and research settings. The integration of advanced signal processing with intelligent algorithms can significantly improves diagnostic precision, though clinical translation requires standardized protocols and validation on larger, diverse cohorts.

SIGNIFICANCE: This work highlights the potential of EEG to facilitate accessible, early-stage AD screening, which is crucial for timely intervention and may contribute to reducing the disease's future socioeconomic burden.},
}

@article {pmid42564343,
year = {2026},
author = {Liu, H and Liu, X and Chen, Y and Pan, M and Fu, Y and Ma, C and Ge, W},
title = {Serum elemental profile-based machine learning models for Alzheimer's disease identification and cognitive score prediction.},
journal = {Neuroprotection (Chichester, England)},
volume = {},
number = {},
pages = {},
pmid = {42564343},
issn = {2770-730X},
abstract = {BACKGROUND: Current diagnostic approaches for Alzheimer's disease (AD) largely rely on cerebrospinal fluid biomarkers and neuroimaging, which may be invasive, costly, and not readily accessible in routine clinical settings. We investigated whether serum elemental profiling combined with machine learning could provide complementary information for AD identification and exploratory cognitive score prediction.

METHODS: This retrospective cross-sectional study included 874 participants enrolled between 2017 and 2023 from the Brain Aging National Cohort-Peking Union Medical College cohort, comprising 427 cognitively normal controls (NCs) and 447 patients with clinically defined AD. Serum concentrations of 20 elements were quantified by inductively coupled plasma mass spectrometry. Associations between serum element concentrations and AD status were evaluated using age- and sex-adjusted logistic regression models with false discovery rate (FDR) correction. Associations with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were assessed using linear regression models with FDR correction. Machine learning classification models were developed for AD identification, whereas regression models were developed for exploratory MMSE and MoCA score prediction. Model performance was evaluated in an internal hold-out test set.

RESULTS: Age did not differ significantly between NC and AD participants (66.4 ± 9.9 vs. 67.1 ± 9.0 years; t(872) = -1.13, p = 0.260), whereas the proportion of women was higher in the AD group than in the NC group (255/447 [57.0%] vs. 211/427 [49.4%]; χ [2](1) = 5.11, p = 0.024). MMSE scores were significantly lower in patients with AD than in NC participants (AD: n = 277, median [interquartile range (IQR)] = 24 [19-27]; NC: n = 427, median [IQR] = 30 [30-30]; Mann-Whitney U = 3043.5, p < 0.001), as were MoCA scores (AD: n = 240, median [IQR] = 18.00 [14.00-20.25]; NC: n = 427, median [IQR] = 30 [30.00-30.00]; Mann-Whitney U = 13.5, p < 0.001). After adjustment for age and sex, higher serum lead (Pb) and tin (Sn) levels were associated with increased odds of AD (Pb: odds ratio [OR] = 4.95, 95% confidence interval [CI]: 3.42-7.37; Sn: OR = 1.45, 95% CI: 1.20-1.78), whereas higher serum antimony, nickel, manganese, cobalt, selenium, and calcium levels were associated with lower odds of AD (OR range: 0.50-0.81; all FDR-adjusted p-values < 0.05). Among the eight classification models evaluated in the internal hold-out test set, the random forest model showed the highest apparent performance for distinguishing AD from NC, achieving an accuracy of 88% and an area under the receiver operating (AUC) (acharacteristic curv of 0.94. Among the three regression models evaluated, the random forest regression showed the highest apparent performance for cognitive score prediction, yielding the strongest correlations between predicted and observed scores for both MMSE (r = 0.48, p < 0.001) and MoCA (r = 0.62, p < 0.001).

CONCLUSION: Serum elemental profiles combined with machine learning may provide a minimally invasive and accessible complementary approach for AD identification and cognitive assessment.},
}

@article {pmid42564398,
year = {2026},
author = {Shi, P and Wang, S and Zang, Z and Wang, D and Yang, C and Tao, J and Liu, J and Sun, J and Shen, W and Wang, R and Sun, M},
title = {Barrier-to-Autointegration Factor 1: a key regulator of nuclear envelope integrity, genome stability, and disease progression.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1870828},
pmid = {42564398},
issn = {1664-3224},
mesh = {Humans ; *Genomic Instability ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Nuclear Envelope/metabolism/genetics ; *Nuclear Proteins/genetics/metabolism ; Disease Progression ; Neoplasms/genetics/pathology/metabolism ; DNA Repair ; Neurodegenerative Diseases/genetics/metabolism ; cGAS-STING Signaling Pathway ; },
abstract = {Barrier-to-Autointegration Factor 1 (BANF1) is a self-associating protein encoded within the q13.1 locus of chromosome 11. It is integral to multiple cellular processes, including cell cycle regulation, chromatin organization, gene expression modulation, nuclear envelope (NE) repair, DNA damage repair (DDR), innate immune function, and viral infection control. While prior investigations have provided preliminary phenotypic and bioinformatic characterizations of BANF1 across various disease states, comprehensive analyses detailing its functional roles and mechanistic underpinnings in diverse pathological contexts remain scarce. In cancer, BANF1 is frequently upregulated, with cancer cells leveraging its functions to preserve NE integrity, inhibit activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) immune pathway, and facilitate epithelial-mesenchymal transition (EMT). These activities contribute to enhanced genomic stability and promote tumor cell proliferation and migration, thereby conferring oncogenic properties. In neurodegenerative diseases, BANF1 is implicated in disease pathogenesis, exemplified by its mediation of glutamate-induced oxidative stress and apoptosis in neuronal cells, as observed in Alzheimer's disease (AD). Additionally, rare mutations in BANF1 are associated with hereditary conditions: the recessive Ala12Thr (A12T) variant causes Néstor-Guillermo progeria syndrome (NGPS), whereas the dominant Gly16Arg (G16R) mutation results in dominant motor neuronopathy. This review further synthesizes recent progress in exploring BANF1 as a therapeutic target, encompassing the development of small-molecule inhibitors, immunomodulatory approaches, and its potential applications in cancer treatment. Overall, this article provides a comprehensive overview of BANF1's structural features, cellular functions, and involvement in disease initiation and progression, with particular emphasis on its expression profiles in malignancies and the therapeutic promise of BANF1-directed interventions.},
}

Humans
*Genomic Instability
*DNA-Binding Proteins/genetics/metabolism
Animals
*Nuclear Envelope/metabolism/genetics
*Nuclear Proteins/genetics/metabolism
Disease Progression
Neoplasms/genetics/pathology/metabolism
DNA Repair
Neurodegenerative Diseases/genetics/metabolism
cGAS-STING Signaling Pathway

@article {pmid42564476,
year = {2026},
author = {Allaham, SMI},
title = {Diagnostic Accuracy of MRI-Based Artificial Intelligence Models for Distinguishing Alzheimer's Disease and Mild Cognitive Impairment From Cognitively Normal Controls: A Systematic Review and Meta-Analysis.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {3},
pages = {141-151},
pmid = {42564476},
issn = {2384-0757},
abstract = {Magnetic resonance imaging (MRI)-based artificial intelligence (AI) models are increasingly applied to brain MRI for diagnosing Alzheimer's disease (AD) and mild cognitive impairment (MCI), but their overall diagnostic performance remains unclear. We systematically searched PubMed/MEDLINE, Embase, Web of Science, Scopus, and IEEE Xplore until February 15, 2026, for diagnostic accuracy studies of machine-learning or deep-learning models using structural brain MRI to distinguish AD vs. cognitively normal (CN) controls and MCI or late mild cognitive impairment (LMCI) vs. CN controls. Seven studies met inclusion criteria, contributing five AD vs. CN and two MCI/LMCI vs. CN tasks, predominantly using deep-learning architectures applied to Alzheimer's Disease Neuroimaging Initiative cohorts. For AD vs. CN (five studies), pooled sensitivity was 0.96 (95% confidence interval [CI], 0.93-0.97) and pooled specificity was 0.95 (95% CI, 0.92-0.97), indicating excellent discrimination. For MCI/LMCI vs. CN (two studies), sensitivity was consistently high (0.91-0.93), whereas specificity varied widely (0.54-0.98), limiting the interpretability of pooled estimates. MRI-based AI models therefore show strong performance for established AD but heterogeneous specificity for MCI, underscoring the need for larger, externally validated studies in diverse populations.},
}

@article {pmid42564518,
year = {2026},
author = {Park, J},
title = {Druggable Pathophysiologic Targets in Alzheimer Disease: From Amyloid and Tau to Biomarker-Guided Multimodal Therapy.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {3},
pages = {152-163},
pmid = {42564518},
issn = {2384-0757},
abstract = {Alzheimer disease (AD) is no longer viewed only as a clinical syndrome of memory impairment but as a biological disease continuum driven by interacting amyloid-β, tau, glial, vascular, metabolic, and synaptic mechanisms. This shift has practical therapeutic consequences. Symptomatic agents such as cholinesterase inhibitors and memantine remain useful for selected patients, but they do not directly modify the core neurodegenerative process. In contrast, amyloid-β monoclonal antibodies have provided proof that biomarker-confirmed early AD can be slowed, although the magnitude of clinical benefit is modest, treatment is restricted to carefully selected patients, and amyloid-related imaging abnormalities require structured monitoring. Tau pathology, neuroinflammation, blood-brain barrier dysfunction, mitochondrial and oxidative stress, and impaired proteostasis are therefore increasingly important druggable axes rather than secondary background phenomena. A staged, biomarker-guided druggability framework can evaluate each target by biological proximity to clinical decline, biomarker measurability, therapeutic modifiability, implementation feasibility, and suitability for sequencing or combination therapy. Validated and emerging targets are summarized with emphasis on how biomarkers reshape patient selection and outcome assessment and how anti-amyloid therapy can be integrated with stage-specific interventions targeting tau propagation, glial activation, vascular injury, clearance failure, and metabolic vulnerability. The central conclusion is that AD drug development should move from a single-target rescue model toward biomarker-guided, mechanism-matched, and combination-ready strategies that can be tested earlier in the disease course while maintaining realistic safety and implementation standards.},
}

@article {pmid42564648,
year = {2026},
author = {Lee, S and Woo, SH and Nam, KC and Moon, C and Lee, K and Kim, KK and Kim, HR and Suh, J},
title = {Gait Analysis Using Wearable Sensors in Patients With Alzheimer's Dementia: A Preliminary Report.},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {3},
pages = {178-190},
pmid = {42564648},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Gait dysfunctions have been frequently observed in patients with Alzheimer's disease (AD). Previous studies have used various methods to assess the gait impairment in AD. Here, we developed a wearable gait sensor, a Smart-insole, which is embedded in shoe insoles. We evaluated whether gait parameters measured using the Smart-insole were associated with cognitive performance in patients with AD.

METHODS: Participants aged 45-90 years, who were either cognitively unimpaired (CU) or had Alzheimer's disease dementia (ADD) were recruited from a hospital-based outpatient clinic, between January and December 2023. Participants performed three gait tasks (walk straight and turn test, timed up and go test, and ramp and stair test) while wearing the Smart-insole. The association of gait parameters with individual's cognitive status (CU vs. ADD) and cognitive test scores (Mini-Mental State Examination [MMSE] and various domain-specific cognitive tests from the Seoul Neuropsychological Screening Battery, 2[nd] Edition) was assessed.

RESULTS: Patients with ADD demonstrated decreased gait pace, rhythm, and stability as evidenced by longer task, cycle, and stance times, a higher number of steps, greater variability in swing time, and lower cadence during the gait task. Furthermore, gait parameters showed nominal associations with individual's MMSE score and each cognitive domain score (fronto-executive, memory, and language function).

CONCLUSIONS: Smart-insole wearable sensors showed exploratory gait-related alterations in patients with ADD. These hypothesis-generating findings suggest that wearable insole-based gait assessment may provide complementary information for characterizing gait and cognitive dysfunction in ADD.},
}

@article {pmid42564689,
year = {2026},
author = {Chen, L and Zhou, X and Zhang, B and Hou, Y and Sun, Y and Peng, D and , },
title = {Thalamic volume alterations mediate glymphatic function and cognitive dysfunction in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70304},
pmid = {42564689},
issn = {2352-8737},
abstract = {INTRODUCTION: Glymphatic dysfunction is implicated in Alzheimer's disease (AD), but its mechanism remains unclear. This study investigated the associations of the analysis along the perivascular space (ALPS) index, brain reserve, and cognitive outcomes across the AD continuum.

METHODS: This study enrolled two cohorts from the local hospital (n = 95) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 178). We calculated the diffusion tensor image ALPS to assess the whole-brain glymphatic function and evaluated its associations with cognition and brain structure.

RESULTS: A higher ALPS index was positively associated with better executive, memory, and language abilities (p < 0.05). A lower ALPS index correlated with thalamic atrophy, involving the anterior, lateral, ventral, and midline thalamic nuclei. Thalamic atrophy mediated the link between glymphatic dysfunction and worse cognition via structural association of full or part mediation.

CONCLUSIONS: Glymphatic system deterioration correlates with cognitive decline, potentially mediated by thalamic atrophy. The thalamic nuclei may be critical in this pathway.},
}

@article {pmid42564853,
year = {2026},
author = {Zelek, MC and Walker, JQ and Sabbagh, MN},
title = {Management of multimorbidity in the midst of cognitive decline through clinical decision-support software.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70395},
pmid = {42564853},
issn = {2352-8729},
abstract = {INTRODUCTION: Multimorbidity - the coexistence of multiple chronic conditions - is common among older adults with cognitive impairment but is rarely addressed in an integrated manner.

METHODS: We analyzed 17,915 adults aged 55 to 84 years (8997 receiving uMETHOD clinical decision-support care plans and 8918 from the National Health and Nutrition Examination Survey). The mean age was 69.0 years (SD 7.65; 95% CI: 68.86 to 69.1). Multimorbidity was quantified from diagnoses, labs, medications, vitals, and platform-inferred conditions. Associations with cognitive impairment were modeled using age- and sex-adjusted logistic regression.

RESULTS: Cognitive impairment was reported in 25.91% of participants (97.5% with ≥2 conditions); each additional condition was associated with higher odds (odds ratio: 1.069; 95% CI: 1.061 to 1.077; p < 0.0001). Prominent clusters included vascular-metabolic disorders and micronutrient deficiencies.

DISCUSSION: Cognitive vulnerability rises stepwise with disease burden. Precision, multimorbidity-aware decision support that integrates multidomain data can align cognitive and systemic care in real-world practice.},
}

@article {pmid42564867,
year = {2026},
author = {Mancy, AS},
title = {SIRT6 signaling as an underexplored mechanistic node in nanoformulation-based neuroinflammation therapy for Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70305},
pmid = {42564867},
issn = {2352-8737},
abstract = {Chronic microglial neuroinflammation is a core driver of Alzheimer's disease (AD). Wei et al. recently reported a blood-brain barrier (BBB)-penetrating, microglia-targeting nanomodulator (Res@TcMNP/ASO) that simultaneously suppressed NF-κB signaling and enhanced NRF2-dependent antioxidant defense in chronically activated microglia, yet the molecular node coupling these two opposing circuits was not identified. In this perspective, drawing on primary literature spanning microglial inflammation, neuronal genome maintenance, tau regulation, and oncology, I propose that sirtuin 6 (SIRT6) is a plausible upstream candidate for this coordinated effect. SIRT6, a NAD[+]-dependent chromatin deacetylase, restrains NF-κB through H3K9 deacetylation at RELA target promoters and, in parallel, deacetylates and stabilizes NRF2 to amplify antioxidant transcription; its decline in the aging and AD brain promotes DNA damage and GSK3-driven tau hyperphosphorylation. Because a microglia-restricted carrier confines pathway modulation to the relevant cell population, this delivery strategy is well matched to a SIRT6-centered mechanism, while the context-dependent, potentially oncogenic nature of systemic SIRT6 activation reinforces the rationale for such restricted delivery. I outline specific loss- and gain-of-function experiments to test whether microglial SIRT6 mediates the dual-pathway effects of Res@TcMNP/ASO, offering a falsifiable hypothesis to guide future mechanistic and therapeutic work.},
}

@article {pmid42564896,
year = {2026},
author = {Kadaba Sridhar, S and Eastman, A and Wilson, P and Mishra, S and Broadbent, C and Truwit, C and Kuang, R and Samadani, U},
title = {Automatic coarse-to-fine AC-PC localization on CT using registration-guided 3D-UNets.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1853412},
pmid = {42564896},
issn = {1662-5196},
abstract = {INTRODUCTION: Automatically localizing the Anterior Commissure (AC) and Posterior Commissure (PC) is foundational for CT-based algorithmic disease screening, yet robust computational methods for this on CT remain lacking. We developed a registration-guided 3D-UNet framework for CT-based AC-PC localization, demonstrating its utility in computing ventriculomegaly features for Normal Pressure Hydrocephalus (NPH) detection.

METHODS: Framework development and evaluation were on an internal cohort of scans from patients with NPH, Alzheimer's disease, post-traumatic volume loss, and headache (Veterans Affairs [VA]-Cohort, n = 427). External validation was on separate datasets (VA-ExtCohort, University of California, Santa Barbara [UCSB]-ExtCohort). AC-PC reference standard definition, model development, and evaluation were on 1 mm[3]-resampled scans.

RESULTS: On 1-mm[3] resampled scans, test-set AC-PC mean radial errors (MREs) were 1.64/1.49 mm on the VA-Cohort, 2.42/1.79 mm on the VA-ExtCohort (n = 40), and 2.31/1.93 mm on the UCSB-ExtCohort (n = 43). Notably, the upper limits of the 95% confidence intervals (CIs) for localization errors across all cohorts were well below 3.2 mm; we empirically determined this to be a clinically relevant threshold beyond which the discriminative power of AC-PC-referenced ventriculomegaly features degrades. Ventriculomegaly features assessed using our framework's predictions successfully distinguished NPH from Alzheimer's disease, post-traumatic volume loss, and headache on a chart-verified VA-Cohort subset (n = 238) with a test-set Area Under the Receiver Operating Characteristic Curve (AUC) of 0.95, closely matching the performance of features assessed using manual AC-PC localization.

CONCLUSION: The proposed registration-guided 3D-UNet framework accurately and automatically localizes the AC-PC on CT despite varied structural degeneration, enabling standardized radiological feature computation. This approach can augment neurodegenerative disease screening on CT, the primary modality for elderly patients evaluated for falls and altered mentation.},
}

@article {pmid42564946,
year = {2026},
author = {Gardener, SL and Al Shamsi, HSS and Rainey-Smith, SR and Sohrabi, HR and Taddei, K and Masters, CL and Martins, RN and Binosha Fernando, WMAD and , },
title = {The moderating effect of dietary fiber and protein on the relationship between symptoms of depression and anxiety and cognitive decline.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70292},
pmid = {42564946},
issn = {2352-8737},
abstract = {INTRODUCTION: Depression and anxiety often co-occur with Alzheimer's disease, exacerbating the associated cognitive impairment. This study examined moderating effects of dietary protein and fiber intake on relationships between depressive and anxiety symptoms, and cognitive decline.

METHODS: Cognitively unimpaired (n = 553; 39.4% male, 70.6 ± 9.6 years) provided baseline fiber and protein intake, and had repeated cognitive testing and symptoms of depression/anxiety measured (baseline and up to eight follow-ups over 144 months). Moderation and simple slope analyses were employed in the cohort as a whole and following stratification by sex.

RESULTS: Fiber intake moderated the relationship between change in depressive symptoms and decline in language (β = -0.005, p < 0.001) and Preclinical Alzheimer Cognitive Composite (PACC); scores (β = -0.003, p = 0.010). In males, fiber intake moderated the relationship between change in anxiety symptoms and executive function decline (β = -0.003, p = 0.018), with protein intake moderating change in depressive symptoms and decline in attention (β = 0.006, p = 0.011).

DISCUSSION: Adequate dietary fiber and protein intake moderated association between depressive and anxiety symptoms and cognitive decline, supporting their potential role within multidomain strategies aimed at maintaining cognitive health in older adults.},
}

@article {pmid42565151,
year = {2026},
author = {Ramireddy, VVS and Shaikh, RG and Pednekar, AR and Tripathi, D and Munde, CT and Wagh, K},
title = {A Systematic Literature Review of Emerging Advances in Neurological Disorders: Diagnostic Innovations, Therapeutic Strategies, and Future Directions.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112202},
pmid = {42565151},
issn = {2168-8184},
abstract = {Neurological disorders remain a major clinical burden because they affect cognition, movement, vascular function, behavior, psychological health, and long-term independence. Recent advances in imaging, biomarkers, artificial intelligence, regenerative therapy, immunotherapy, and targeted pharmacology have expanded diagnostic and therapeutic possibilities, yet the evidence remains dispersed across different neurological conditions and study designs. This review aimed to synthesize emerging advances in neurological disorders, focusing on diagnostic innovations, therapeutic strategies, and future clinical directions. A systematic literature review approach was applied using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based screening principles. Eleven studies were included, covering ischemic stroke, glioblastoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, motor neuron disease, episodic migraine, transient ischemic attack, and postoperative delirium. Data were extracted on study design, condition, intervention or diagnostic method, comparator, outcomes, and key findings. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized trials, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized, uncontrolled, post hoc, feasibility, and biomarker-monitoring studies, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic and radiomics studies. Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy. Several studies reported promising clinical or biomarker signals, while others clarified treatment limitations in specific disease subtypes. Overall, the findings suggest an emerging shift toward precision-oriented neurology, but larger controlled trials, prospective biomarker validation, standardized outcomes, and longer follow-up are required before routine implementation.},
}

@article {pmid42565245,
year = {2026},
author = {Lynch, SY and Wang, Y and Wang, D and Bachhav, SS and Xiong, H and Boiser, J and Stage, E and Bannon, AW and Graff, O and Florian, H},
title = {A randomized phase 1b/2 trial of ABBV-916 in adults with early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71715},
doi = {10.1002/alz.71715},
pmid = {42565245},
issn = {1552-5279},
support = {//AbbVie Inc./ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Female ; Male ; Double-Blind Method ; Aged ; Amyloid beta-Peptides ; Positron-Emission Tomography ; Dose-Response Relationship, Drug ; Middle Aged ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics ; Treatment Outcome ; Biomarkers/blood ; },
abstract = {INTRODUCTION: ABBV-916, an anti-amyloid immunotherapy, was evaluated in patients with early Alzheimer's disease (AD).

METHODS: This phase 1b/2, double-blind, placebo-controlled study consisted of two stages: multiple ascending dose (Stage A) and dose expansion (Stage B). In Stage A, patients were randomized to one of six planned cohorts to receive intravenous ABBV-916 (10 mg to 3000 mg) or placebo monthly through week 24. Assessments included amyloid PET, blood-based biomarkers, pharmacokinetics (PK), and safety. Dose selection for Stage B was to be based on results from Stage A.

RESULTS: One hundred six patients were randomized to ABBV-916 or placebo. The 3000 mg dose was reduced to 2000 mg and subsequently to 900 mg after safety review. Dose-proportional PK were observed, and amyloid reduction was observed over 24 weeks at doses ≥300 mg. Most adverse events were non-serious amyloid-related imaging abnormalities. The program ended before dose expansion due to business considerations.

DISCUSSION: Amyloid clearance rate and safety of ABBV-916 were generally comparable to approved anti-amyloid AD therapies.

NCT05291234.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Female
Male
Double-Blind Method
Aged
Amyloid beta-Peptides
Positron-Emission Tomography
Dose-Response Relationship, Drug
Middle Aged
Aged, 80 and over
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics
Treatment Outcome
Biomarkers/blood

@article {pmid42565246,
year = {2026},
author = {Kolling, LJ and Wang, R and Gaudencio, GS and Fishbeyn, JS and James, TD and Mason, SM and McCoy, RO and Song, Z and McConnell, IP and Ziemke, K and Janik, KM and Xu, Y and Bierlein-De La Rosa, G and Ismail, S and Marcinkiewcz, CA},
title = {Dorsal raphe tau pathology disrupts sleep-wake orchestration and sleep architecture in a sex-specific manner.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71687},
doi = {10.1002/alz.71687},
pmid = {42565246},
issn = {1552-5279},
support = {//Alzheimer's Association and the Michael J. Fox Foundation for Parkinson's Research: 26BFDN-1576146A/ ; //Iowa Neuroscience Institute Research Program of Excellence (RPOE)/ ; R01 AG070841/AG/NIA NIH HHS/United States ; F32AG084196-01/AG/NIA NIH HHS/United States ; //Pappajohn Biomedical Institute/ ; //University of Iowa/ ; },
mesh = {Animals ; Male ; Female ; *Dorsal Raphe Nucleus/pathology/metabolism ; *tau Proteins/metabolism ; Mice ; Electroencephalography ; *Sleep/physiology ; *Sleep Wake Disorders/pathology/physiopathology/etiology ; *Sex Characteristics ; Serotonin/metabolism ; Alzheimer Disease ; *Tauopathies/pathology ; Wakefulness/physiology ; },
abstract = {INTRODUCTION: Sleep disturbances are frequent symptoms of Alzheimer's disease (AD), mirrored by early pathology in the dorsal raphe nucleus (DRN). Whether early DRN pathology can drive sleep disturbances, and the relative contributions of serotonin (5-HT) and sex, has not been directly tested.

METHODS: We isolate tau pathology to whole DRN (DRN[Tau]), serotonin neurons of the DRN (5-HT[Tau]), or non-serotonergic neurons of the DRN (non5HT[Tau]). We use longitudinal EEG recordings, in male and female mice, to determine the contributions of DRN neuronal subtypes to sleep disruption within the context of prodromal AD.

RESULTS: DRN[Tau], 5-HT[Tau], and non5HT[Tau] disrupt sleep architecture. 5-HT[Tau] and non5HT[Tau] further disrupt sleep-wake orchestration and exhibit sex-dependent alterations that coincide with changes in delta wave power.

DISCUSSION: Tau-mediated sleep dysfunction may be driven by various cellular subtypes of the DRN, are primarily sexually divergent, and may resultant in changes in 5-HT activity and relative spectral brain wave contributions.},
}

Animals
Male
Female
*Dorsal Raphe Nucleus/pathology/metabolism
*tau Proteins/metabolism
Mice
Electroencephalography
*Sleep/physiology
*Sleep Wake Disorders/pathology/physiopathology/etiology
*Sex Characteristics
Serotonin/metabolism
Alzheimer Disease
*Tauopathies/pathology
Wakefulness/physiology

@article {pmid42565249,
year = {2026},
author = {Kim, YM and Colcord, K and Sajjadi, SA and Andrews, EJ and Schneider, JA and Kawas, CH and Corrada, MM},
title = {Hormone replacement therapy and its association with LATE-NC in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71730},
doi = {10.1002/alz.71730},
pmid = {42565249},
issn = {1552-5279},
support = {P30AG072975/NH/NIH HHS/United States ; R01AG17917/NH/NIH HHS/United States ; R01AG067482/NH/NIH HHS/United States ; R01AG042210/NH/NIH HHS/United States ; UCI MIND/WAM 01-2024//Women's Alzheimer's Movement (WAM)/ ; },
mesh = {Humans ; Female ; *Hormone Replacement Therapy ; Male ; Aged, 80 and over ; Aged ; Aging ; Dementia ; TDP-43 Proteinopathies ; },
abstract = {INTRODUCTION: Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is a cause of dementia resembling Alzheimer's disease (AD). The 90+ Study found women using hormone replacement therapy (HRT) two to three decades before death had lower odds of LATE-NC. We attempted to replicate this finding in a different cohort.

METHODS: Participants (n = 2056) included males (n = 640) and females (n = 1416) aged ≥65 from the Religious Orders Study and Memory and Aging Project with HRT and neuropathology data. We examined the association between HRT and LATE-NC in males and females and between HRT-related and reproductive variables in relation to LATE-NC in females using logistic regression.

RESULTS: HRT use within 5 years before or after menopause (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.50 to 0.98, p = 0.03) or for 8 to 16 years (OR = 0.44, 95% CI = 0.24 to 0.79, p = 0.006) was associated with lower odds of LATE-NC.

DISCUSSION: This finding identifies a potential factor related to LATE risk and highlights the importance of HRT timing and duration for its potential neuroprotective effects.},
}

Humans
Female
*Hormone Replacement Therapy
Male
Aged, 80 and over
Aged
Aging
Dementia
TDP-43 Proteinopathies

@article {pmid42565262,
year = {2026},
author = {Collins, EC and Lu, M and Beck, R and Hendrix, J and Hodsdon, ME and Hansson, O},
title = {Plasma P-tau217 for detecting amyloid clearance after donanemab in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71740},
doi = {10.1002/alz.71740},
pmid = {42565262},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; *tau Proteins/blood ; Positron-Emission Tomography ; Biomarkers/blood ; Phosphorylation ; Female ; Male ; Aged ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; ROC Curve ; Antibodies, Monoclonal, Humanized ; },
abstract = {INTRODUCTION: This analysis of the phase 3 TRAILBLAZER-ALZ 2 trial examined whether plasma tau protein phosphorylated at threonine 217 (p-tau217) level can reliably monitor treatment-related amyloid clearance (TRAC) after donanemab treatment in early symptomatic Alzheimer's disease (AD).

METHODS: Amyloid positron emission tomography (PET) and plasma p-tau217 levels were assessed at baseline and longitudinally during study treatment. The diagnostic performance of p-tau217 in detecting post-treatment TRAC (< 24.1 Centiloids [CL]) was evaluated by receiver operating characteristic (ROC) analysis.

RESULTS: Plasma p-tau217 showed suboptimal performance in detecting TRAC by PET in donanemab-treated participants (N = 830), with an area under the ROC curve of 0.61 at 52 weeks.

DISCUSSION: Despite reductions in plasma p-tau217 with donanemab treatment, this biomarker cannot currently be used to accurately detect TRAC by PET (< 24.1 CL) in individuals with early symptomatic AD.},
}

Humans
*Alzheimer Disease/drug therapy/blood/diagnostic imaging
*tau Proteins/blood
Positron-Emission Tomography
Biomarkers/blood
Phosphorylation
Female
Male
Aged
*Amyloid beta-Peptides/metabolism
*Amyloid/metabolism
ROC Curve
Antibodies, Monoclonal, Humanized

@article {pmid42565396,
year = {2026},
author = {Alpidovskaya, OV and Tikhonov, BV},
title = {[Clusterin as a biomarker for Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {7},
pages = {22-28},
doi = {10.17116/jnevro202612607122},
pmid = {42565396},
issn = {1997-7298},
mesh = {Humans ; *Clusterin/blood/metabolism ; *Alzheimer Disease/diagnosis/blood/metabolism ; Biomarkers/blood ; Oxidative Stress ; },
abstract = {OBJECTIVE: To examine and systematically review the existing literature regarding clusterin (CLU) as a potential biomarker for Alzheimer's disease.

MATERIAL AND METHODS: A comprehensive analysis of data, including generalization, comparison, and systematization, was conducted to review findings from both Russian and international publications. The study included a thorough search of the PubMed (MEDLINE) database and other scientific information sources over the last decade. The collected data underwent analytical scrutiny to elucidate the potential significance of CLU in AD pathogenesis.

RESULTS: This article presents evidence indicating that clusterin (CLU) may play a significant role in AD pathogenesis through various mechanisms, including regulation of inflammation, modulation of cellular apoptosis, facilitation of clearance of pathological proteins, and affecting oxidative stress and the aggregation and folding of extracellular proteins. CLU plays a vital role in promoting cell survival under stressful conditions. It offers protection against oxidative stress, ensuring both immediate resistance to damage and prolonged cellular viability. A loss of soluble clusterin (sCLU) protective function in response to ROS-induced damage may render neurons more susceptible to additional insults, such as Aβ, which generates H2O2 and other reactive oxygen species. Furthermore, CLU can activate the PI3K/Akt signaling pathway, which functions as an effector of mTOR and NF-κB. Inhibition of mTOR has been associated with a slowing of AD progression. Notably, elevated plasma levels of CLU in healthy older adults may precede significant Aβ deposition in the brain by as much as ten years, suggesting an early elevation of CLU within the pathogenesis of AD and its potential pathological implications.

CONCLUSIONS: Clusterin should be considered a significant biomarker for Alzheimer's disease, supporting the use of enzyme-linked immunosorbent assays to measure plasma CLU concentrations. This approach may serve as an additional tool for early screening and therapeutic interventions in Alzheimer's disease.},
}

Humans
*Clusterin/blood/metabolism
*Alzheimer Disease/diagnosis/blood/metabolism
Biomarkers/blood
Oxidative Stress

@article {pmid37496245,
year = {2024},
author = {Singh, M and Panda, SP},
title = {The Role of Monosodium Glutamate (MSG) in Epilepsy and other Neurodegenerative Diseases: Phytochemical-based Therapeutic Approa-ches and Mechanisms.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {2},
pages = {213-229},
doi = {10.2174/1389201024666230726161314},
pmid = {37496245},
issn = {1873-4316},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/chemically induced/metabolism ; *Sodium Glutamate/adverse effects ; Animals ; *Epilepsy/drug therapy/chemically induced/metabolism ; *Phytochemicals/therapeutic use/pharmacology ; Glutamic Acid/metabolism ; },
abstract = {Epilepsy is a common neurological disease affecting 50 million individuals worldwide, and some forms of epilepsy do not respond to available treatments. Overactivation of the glutamate pathway and excessive entrance of calcium ions into neurons are proposed as the biochemical mechanisms behind epileptic seizures. However, the overactivation of neurons has also been associated with other neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, Huntington's, and multiple sclerosis. The most widely used food ingredient, monosodium glutamate (MSG), increases the level of free glutamate in the brain, putting humans at risk for NDDs and epilepsy. Glutamate is a key neurotransmitter that activates nerve cells. MSG acts on glutamate receptors, specifically NMDA and AMPA receptors, leading to an imbalance between excitatory glutamate and inhibitory GABA neurotransmission. This imbalance can cause hyperexcitability of neurons and lead to epileptic seizures. Overuse of MSG causes neuronal cells to become overexcited, which in turn leads to an increase in the flow of Ca[2+] and Na[+] ions, mutations, and upregulation in the enzymes superoxide dismutase 1 (SOD-1) and TDP43, all of which contribute to the development of NDDs. While TDP43 and SOD-1 protect cells from damage, a mutation in their genes makes the proteins unprotective and cause neurodegeneration. Yet to what extent mutant SOD1 and TDP43 aggregates contribute to neurotoxicity is generally unknown. This study is focused on neuroprotective herbal medications that can pass the blood-brain barrier and cure MSGinduced NDDs and the factors that influence MSG-induced glutaminergic, astrocyte, and GABAergic neuron abnormalities causing neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/drug therapy/chemically induced/metabolism
*Sodium Glutamate/adverse effects
Animals
*Epilepsy/drug therapy/chemically induced/metabolism
*Phytochemicals/therapeutic use/pharmacology
Glutamic Acid/metabolism

@article {pmid37537932,
year = {2024},
author = {Semwal, BC and Singh, B and Murti, Y and Singh, S},
title = {Therapeutic Potential of Ascorbic Acid in the Management of Alzheimer's Disease: An Update.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {2},
pages = {196-212},
doi = {10.2174/1389201024666230804102617},
pmid = {37537932},
issn = {1873-4316},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Ascorbic Acid/therapeutic use/pharmacology ; Humans ; Animals ; *Antioxidants/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Ascorbic acid is a potent natural antioxidant that protects against oxidative stress and performs various bodily functions. It is commonly found in fruits and vegetables.

OBJECTIVE: The manuscript has been written to provide valuable insights into ascorbic acid in managing Alzheimer's disease.

METHODS: The data has been gathered from web sources, including PubMed, Science Direct, Publons, Web of Science, and Scopus from 2000-2022 using AA, ascorbic acid, Alzheimer's diseases, memory, dementia, and antioxidant keywords.

RESULTS: In the present manuscript, we have summarized the impact of ascorbic acid and its possible mechanism in Alzheimer's disease by, outlining the information currently available on the behavioral and biochemical effects of ascorbic acid in animal models of Alzheimer's disease as well as its usage as a therapeutic agent to slow down the progression of Alzheimer disease in human beings. Oxidative stress plays a significant role in the advancement of AD. AA is a wellknown antioxidant that primarily reduces oxidative stress and produces protein aggregates, which may help decrease cognitive deficits in Alzheimer's disease. The current paper analyses of ascorbic acid revealed that deficiency of ascorbic acid adversely affects the central nervous system and leads to cognitive defects. However, the results of clinical studies are conflicting, but some of the studies suggested that supplementation of ascorbic acid improved cognitive deficits and decreased disease progression.

CONCLUSION: Based on clinical and preclinical studies, it is observed that ascorbic acid supplementation improves cognitive deficits and protects the neurons from oxidative stress injury.},
}

*Alzheimer Disease/drug therapy/metabolism
*Ascorbic Acid/therapeutic use/pharmacology
Humans
Animals
*Antioxidants/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid42554889,
year = {2026},
author = {Shi, C and Liu, Y and Zhu, Y},
title = {DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42554889},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/immunology/therapy/pathology ; *Immunity, Innate/immunology ; Animals ; *Disease Progression ; *Signal Transduction ; Innate Immunity Recognition ; *DNA/metabolism/immunology ; cGAS-STING Signaling Pathway ; Toll-Like Receptor 9/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; },
abstract = {DNA sensors are emerging regulators of innate immune activation in Alzheimer's disease (AD). In addition to detecting microbial DNA, these pattern-recognition receptors can respond to cytosolic or endosomal self-DNA generated by DNA damage, mitochondrial dysfunction, impaired DNA repair, cellular stress, or neuronal injury. Aberrant activation of DNA-sensing pathways may amplify neuroinflammation through type I interferon (IFN-I) signaling, inflammasome activation, pyroptosis, and microglial dysfunction, thereby contributing to amyloid pathology, tau-related inflammation, synaptic loss, and cognitive decline. In this review, we summarize current evidence linking major DNA sensors, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9) to AD pathogenesis. We emphasize the strongest available evidence for cGAS-STING and AIM2, discuss the context-dependent roles of TLR9, and highlight less-established sensors requiring further validation. Finally, we evaluate therapeutic strategies targeting DNA-sensing pathways, including pathway inhibition and controlled immune activation, and discuss translational challenges such as blood-brain barrier penetration, off-target effects, dose dependency, and disease-stage-specific modulation.},
}

Humans
*Alzheimer Disease/immunology/therapy/pathology
*Immunity, Innate/immunology
Animals
*Disease Progression
*Signal Transduction
Innate Immunity Recognition
*DNA/metabolism/immunology
cGAS-STING Signaling Pathway
Toll-Like Receptor 9/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase

@article {pmid42554922,
year = {2026},
author = {Fang, Y and Zhou, R},
title = {Two-stage deep learning framework for the restoration of incomplete-ring PET images.},
journal = {Medical & biological engineering & computing},
volume = {},
number = {},
pages = {},
pmid = {42554922},
issn = {1741-0444},
support = {12175212//Innovative Research Group Project of the National Natural Science Foundation of China/ ; },
abstract = {Positron Emission Tomography (PET) is an important molecular imaging tool widely used in medicine. Traditional PET systems rely on complete detector rings for full angular coverage and reliable data collection. However, incomplete-ring PET scanners have emerged due to hardware failures, cost constraints, or specific clinical needs. Standard reconstruction algorithms often suffer from performance degradation with these systems because of reduced data completeness and geometric inconsistencies. We present a two-stage deep-learning framework that, without incorporating any time-of-flight (TOF) information, restores high-quality images from data with about 50% missing coincidences-double the loss levels previously addressed by CNN-based methods. The pipeline operates in two stages: a projection-domain Attention U-Net first predicts the missing sections of the sinogram by leveraging spatial context from neighbouring slices, after which the completed data are reconstructed with OSEM algorithm and passed to a cascaded U-Net & warm-start diffusion model for image refinement. This module starts the reverse diffusion process from the U-Net coarse prediction rather than pure Gaussian noise. Using 613 simulated brain volumes from real scans (196 healthy brain samples, 217 Alzheimer's disease samples, and 200 Mild Cognitive Impairment samples), the results show that our model successfully preserves most anatomical structures and tracer distribution features with PSNR of 38.18 to 38.59 dB and SSIM of 0.9904 to 0.9925. Our two-stage deep-learning framework effectively restores high-quality PET images from over 50 % incomplete-ring data, achieving near-complete anatomical fidelity and robust performance without requiring TOF information.},
}

@article {pmid42554925,
year = {2026},
author = {Lin, K and Sachdev, PS and Jiang, J and , },
title = {The Associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-beta across the Alzheimer's disease spectrum.},
journal = {Brain imaging and behavior},
volume = {20},
number = {4},
pages = {},
pmid = {42554925},
issn = {1931-7565},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/blood ; *White Matter/diagnostic imaging/pathology/metabolism ; Female ; *Cerebrovascular Circulation/physiology ; Male ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging/pathology/metabolism ; Longitudinal Studies ; Aged, 80 and over ; Perfusion Magnetic Resonance Imaging ; Biomarkers/blood ; },
abstract = {Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-β PET, and plasma assay tests for amyloid-β 42, amyloid-β 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-β quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-β at baseline, but the associations were significantly attenuated after further adjusting for amyloid-β and tau, respectively. Plasma amyloid-β 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-β, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-β and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology/metabolism/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/blood
*White Matter/diagnostic imaging/pathology/metabolism
Female
*Cerebrovascular Circulation/physiology
Male
Cross-Sectional Studies
Positron-Emission Tomography
Aged
Magnetic Resonance Imaging
Brain/diagnostic imaging/pathology/metabolism
Longitudinal Studies
Aged, 80 and over
Perfusion Magnetic Resonance Imaging
Biomarkers/blood

@article {pmid42554945,
year = {2026},
author = {Yang, S and Li, Y and Guo, Y and Li, Y and Li, M and Li, H and Zhang, Y},
title = {GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42554945},
issn = {1559-1182},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/pathology ; *Amyloid beta-Peptides/metabolism/toxicity ; *Receptors, G-Protein-Coupled/deficiency/metabolism ; *Microglia/metabolism/pathology ; *Phagocytosis/drug effects ; *Biomarkers/metabolism ; Disease Models, Animal ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Signal Transduction ; },
abstract = {Dysregulation of brain cholesterol homeostasis is increasingly recognized as a critical driver of Alzheimer's disease (AD) pathogenesis. G protein-coupled receptor 146 (GPR146) has emerged as a pivotal regulator of systemic cholesterol metabolism; however, its role in the central nervous system and AD remains elusive. Here, we report that GPR146 deficiency in mice modulates ERK/PKA signaling without affecting baseline physiology or general behavior. Following intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)42 oligomers, GPR146 was associated with altered Aβ42-evoked ERK/PKA/Akt signaling both in vivo and in vitro. Mechanistically, Gpr146 ablation potentiated microglial Aβ phagocytosis, which correlated with the transcriptional upregulation of phagocytic receptors, including TREM2, GPR34, P2Y6, and CR3, alongside increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, GPR146 deficiency was linked to elevated levels of blood-brain barrier (BBB)-associated markers Cldn-5 and Glut-1 protein levels, while attenuating Aβ‑induced inflammatory responses in brain endothelial cells. At the metabolic level, GPR146 knockout modulated the expression of key enzymes governing glucose (GLUT1, GLUT3, G6PD, PFK, HK) and lipid (HMGCS1, ACACA, FASN, SCD1) metabolism and markedly reduced Aβ‑elicited lipid droplet accumulation in the cortex and hippocampus. Collectively, our findings establish GPR146 as a novel neurometabolic regulator whose deficiency correlates with enhanced Aβ phagocytosis, maintenance of BBB-associated proteins, and altered cerebral metabolism, thereby presenting a potential therapeutic axis for early AD intervention.},
}

Animals
*Blood-Brain Barrier/metabolism/pathology
*Amyloid beta-Peptides/metabolism/toxicity
*Receptors, G-Protein-Coupled/deficiency/metabolism
*Microglia/metabolism/pathology
*Phagocytosis/drug effects
*Biomarkers/metabolism
Disease Models, Animal
Mice, Knockout
Mice, Inbred C57BL
Male
Signal Transduction

@article {pmid42554959,
year = {2026},
author = {Welsh, TJ and Chen, Y and Kennelly, SP and Quinn, TJ and Religa, D and Shenkin, SD and Soysal, P and Roitto, HM},
title = {From memory clinics to Brain Health Services: implications for older adults and the future of cognitive care in Europe.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {42554959},
issn = {1878-7649},
abstract = {AIM: To explore the implications of transitioning from traditional memory clinics to Brain Health Services (BHS) for older adults, and to advocate for a geriatric-informed, equitable, and function-oriented approach to brain health care.

METHODS: This perspective article draws on discussions within the EuGMS Brain Health and Dementia Specialist Interest Group and relevant literature to examine the implications of emerging Brain Health Services for older adults.

RESULTS: The emergence of Brain Health Services represents a significant shift in cognitive healthcare, moving beyond traditional memory clinic models focussed primarily on dementia diagnosis and management towards prevention, risk reduction, and maintenance of cognitive function. Potential benefits include earlier engagement with cognitive care, multidomain lifestyle interventions, reduction of stigma surrounding dementia, and facilitation of access to emerging disease-modifying therapies. However, substantial challenges remain. Biomarker-driven approaches may overemphasise Alzheimer's disease-centric frameworks despite the high prevalence of mixed pathologies and complex comorbidity in older adults. Ethical concerns surrounding risk disclosure, inequitable access, and resource allocation are also considerable, particularly if services disproportionately benefit younger, healthier, or socioeconomically advantaged populations.

CONCLUSIONS: Brain Health Services should be reframed through a gerontologically informed lens that prioritises function, independence, quality of life, and equitable access alongside prevention. Integration with comprehensive geriatric assessment and existing older persons' care pathways is essential. Future research should focus on pragmatic real-world evaluation, inclusive outcome measures, and personalised approaches that account for heterogeneity in ageing. Ultimately, the success of BHS will depend on their ability to support healthy ageing while remaining responsive to the lived realities and priorities of older adults.},
}

@article {pmid42554972,
year = {2026},
author = {Wang, X and Tao, Y and Li, Q and Yang, J and Liu, Q and Xu, A},
title = {The Therapeutic Efficacy of Gold Needle "Regulating Spirit" Acupuncture for Amnestic Mild Cognitive Impairment: Protocol for a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e96326},
pmid = {42554972},
issn = {1929-0748},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods/instrumentation ; *Needles ; *Gold/therapeutic use ; Aged ; Female ; Male ; Middle Aged ; Treatment Outcome ; Biomarkers/blood ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), the predominant subtype of mild cognitive impairment, carries the highest risk of progression to Alzheimer disease among all mild cognitive impairment subtypes. Currently, clinical practice lacks an established, authoritative treatment method for this condition. Prior clinical evidence indicates acupuncture may enhance cognitive function in individuals with mild cognitive impairment. Further clinical evidence suggests Gold Needle therapy demonstrates significant therapeutic effects for challenging and refractory conditions; however, a critical gap exists: no clinical trials currently ascertain whether Gold Needle therapy surpasses conventional acupuncture in treating aMCI. This trial aims to rigorously evaluate the therapeutic efficacy and safety of the Gold Needle "Regulating Spirit" method for clinical symptoms in patients with aMCI, alongside investigating its underlying imaging and biochemical mechanisms.

OBJECTIVE: This proposed study aims to identify imaging and laboratory biomarkers for the early diagnosis of aMCI, thereby providing a theoretical foundation for clinical practice.

METHODS: This randomized controlled trial will recruit 90 patients diagnosed with aMCI from the Beijing Hospital of Traditional Chinese Medicine, affiliated with Capital Medical University, alongside 20 healthy volunteers. The 90 patients with aMCI will be randomly allocated to 1 of 3 groups: the Gold Needle "Regulating Spirit" group uses gold-based needles, the general acupuncture "Regulating Spirit" group, or a sham acupuncture control group. The Gold Needle "Regulate Spirit" group uses gold-based needles, the general acupuncture "Regulate Spirit" group uses standard needles, and the sham acupuncture group administers Park needles. Participants will undergo 3 sessions per week of their assigned acupuncture or placebo treatment over a continuous 12-week period.

RESULTS: This study was initiated on September 1, 2023. As of October 30, 2025, 110 eligible participants had been enrolled, and data collection had been completed in full. Data analysis is currently underway, and the preliminary results are expected to be available by June 2025. We hypothesize that, compared with the filiform needle-based mind-regulating acupuncture group, the golden needle-based mind-regulating acupuncture group will demonstrate superior efficacy in improving cognitive impairment. This superiority will be reflected in multiple key outcome measures, including Montreal Cognitive Assessment and Mini-Mental State Examination scores, plasma biomarkers, and functional magnetic resonance imaging findings.

CONCLUSIONS: We anticipate that by the end of the trial, we will be able to definitively ascertain whether the gold acupuncture needle technique for "regulating spirit" offers a significant advantage in treating aMCI, and further investigate the nature of this therapeutic benefit, to offer a more efficacious intervention for the clinical management of aMCI and the prevention of Alzheimer disease.},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods/instrumentation
*Needles
*Gold/therapeutic use
Aged
Female
Male
Middle Aged
Treatment Outcome
Biomarkers/blood

@article {pmid42554979,
year = {2026},
author = {Fang, JR and Vogel, AP and Velakoulis, D and Yuan, Y and Nayler, D and Loi, SM and Joubert, L},
title = {Interventions for caregivers of persons with young-onset dementia in hospital environments: A systematic scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469822},
doi = {10.1177/13872877261469822},
pmid = {42554979},
issn = {1875-8908},
abstract = {BackgroundCaregivers of patients with young-onset dementia (YOD), most commonly Alzheimer's disease and frontotemporal dementia, face unique challenges balancing employment, childcare, finances, and complex care responsibilities. Tailored interventions delivered in hospital environments may provide timely support and optimize caregiver preparedness, but evidence regarding these interventions remains limited.ObjectiveTo map and synthesize evidence on interventions supporting caregivers of individuals with YOD within hospital environments offering diagnostic services, multidisciplinary care, and opportunities for caregiver engagement. Intervention types, delivery modes, outcomes, and evidence gaps will be highlighted.MethodsA systematic scoping review adhering to PRISMA-ScR guidelines was conducted. Medline, Embase, PsycINFO, EBM Reviews, SocINDEX, CINAHL, and Scopus were searched for studies published up to 2025. Peer-reviewed studies in English describing or evaluating interventions for YOD caregivers were included. Data on study characteristics, intervention type, delivery, outcomes, and key findings were extracted and synthesized narratively.ResultsEight studies met the inclusion criteria. Interventions were largely focused on psychoeducation and support groups. Most studies targeted spouses with few including other caregiver types. Interventions addressed caregiver functions such as task management, safety, information, and caregiver needs related to emotional support and burden reduction, but rarely were both comprehensively addressed. Quantitative outcomes were mixed while qualitative findings consistently reported improved preparedness, support, and coping.ConclusionsEvidence on caregiver interventions in hospital environments is limited and largely exploratory. Future work should embed supports within diagnostic pathways, incorporate structured assessment, tailor interventions by subtype and caregiver role, and use outcome measures sensitive to early, meaningful changes.},
}

@article {pmid42554980,
year = {2026},
author = {Goldstein, FC and Hales, CM and Parker, MW and Trammell, AR and Manzanares, CM and Heldenberg, SC and Hanfelt, JJ and Levey, AI and Lah, JJ},
title = {Performance of the participant self-rating version of the Quick Dementia Rating System in a racially diverse cohort of non-demented older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471427},
doi = {10.1177/13872877261471427},
pmid = {42554980},
issn = {1875-8908},
abstract = {BackgroundEarly detection of clinical Alzheimer's disease and related dementias is a public health priority. The Clinical Dementia Rating is used for staging but is time intensive. The Quick Dementia Rating System (QDRS) is a brief, self-administered alternative, although studies have focused on informant rather than patient ratings.ObjectiveThis study evaluated the clinical utility of the QDRS Participant Self-Rating version for classifying cognitive status of White and Black/African Americans.MethodsParticipants (79 White, 95 Black/African American) enrolled in the Goizueta Alzheimer's Disease Research Center with Clinical Dementia Rating (CDR) Global scores of 0.0 or 0.5 completed the QDRS. Concordance rates and associations with the Montreal Cognitive Assessment (MoCA) were examined.ResultsAgreement between QDRS and CDR Global scores was 69% (κ = 0.36), and comparable between racial groups. QDRS Sum of Boxes demonstrated moderate correlations with CDR Sum of Boxes for the full sample and each group. Participants classified as impaired on the QDRS had lower MoCA Total and Memory Index scores, with similar effect sizes between racial groups. ROC analyses demonstrated good discrimination of CDR 0.0 versus 0.5 for the overall sample (AUC = 0.789, SE = 0.040, 95% CI = 0.711-0.866) and for White (AUC = 0.792, SE = 0.055, 95% CI = 0.683-0.900) and Black/African American participants (AUC = 0.777, SE = 0.058, 95% CI = 0.663-0.891). Positive predictive value of the QDRS Global score was 50%, and negative predictive value was 85%.ConclusionsThe QDRS Participant Self-Rating version is a clinically useful prescreening tool to rule out cognitive impairment in both White and Black/African American persons with early cognitive impairment.},
}

@article {pmid42554985,
year = {2026},
author = {Sánchez-Juan, P and García-Arcelay, E and Almagro, M and Balasa, M and Piñol-Ripoll, G and Boada, M and Landete, L and Abellan, I and Berbel, A and Espejo, B and Baquero, M and Marin, J and Franco-Macias, E and Villarejo-Galende, A and Viñuela Fernández, F and Feria Vilar, I and Perez-Vieitez, C and Rodríguez-Espinosa, N and Puig-Pijoan, A and Bargay Pizarro, E and Rodríguez-Rodríguez, E and Rodrigo, J and Maurino, J and Manzano, S},
title = {Burden, perception of stigma, and gender differences among informal care partners of individuals with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474135},
doi = {10.1177/13872877261474135},
pmid = {42554985},
issn = {1875-8908},
abstract = {BackgroundCaring for individuals with mild cognitive impairment (MCI) is increasingly recognized as a significant clinical challenge. However, the latent burden, driven by perceived stigma and gender-specific vulnerabilities, remains poorly characterized during these early stages of cognitive decline.ObjectiveThis study aimed to evaluate the prevalence of care partner strain and affiliate stigma, and to identify independent correlates of psychological distress and protective factors among informal care partners of individuals with MCI.MethodsWe conducted a multicenter, observational, cross-sectional study across 19 memory clinics in Spain. Care partners (n = 196) were evaluated using the Zarit Burden Interview, Affiliate Stigma Scale, and validated instruments assessing resilience, relationship quality, coping strategies, and psychological distress. Multivariate logistic regression models identified independent predictors of burden and stigma.ResultsSignificant care partner strain affected 59.7% of the cohort, while 39.3% perceived themselves as stigmatized. Multivariate analysis revealed that high burden was independently associated with anxiety symptoms (OR = 1.13, p = 0.017) and perceived stigma (OR = 1.07, p = 0.007). High resilience served as the primary determinant protecting the 60.7% of partners who did not report significant stigma (OR = 1.05, p < 0.001). Compared to their male counterparts, female care partners were significantly younger and reported higher levels of burden, anxiety, and stigma.ConclusionsCare partner strain and affiliate stigma are correlated phenomena that emerge long before formal patient dependency. These findings underscore the need for gender-sensitive clinical frameworks and specific interventions that actively strengthen resilience immediately upon MCI diagnosis to mitigate early psychological deterioration.},
}

@article {pmid42554989,
year = {2026},
author = {Qiu, J and Zhang, Y and Shang, Y and Shang, Q and Li, L and Chen, Y and Dai, S and Ai, M and Xi, X and Huang, W and Zhang, J and Liu, X},
title = {Impact of SARS-CoV-2 infection on the progression of Alzheimer's disease: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469118},
doi = {10.1177/13872877261469118},
pmid = {42554989},
issn = {1875-8908},
abstract = {BackgroundSARS-CoV-2 infection is associated with neurological sequelae and may accelerate Alzheimer's disease (AD) progression through neuroinflammation and protein aggregation. However, longitudinal evidence regarding the cognitive impact of COVID-19 in patients with AD remains scarce, and this interaction requires further clarification.ObjectiveTo explore whether COVID-19 accelerates cognitive decline in patients with AD.MethodsA total of 120 participants were enrolled, including 63 in the COVID-19 group and 57 in the non-COVID-19 group. The primary outcomes were disease decline and disease deterioration over three months, assessed using CDR-SB. Disease deterioration indicated clinically meaningful worsening, whereas disease decline captured subtler progression. Multivariable logistic regression adjusted for demographic, clinical, lifestyle, genetic, and disease severity factors. Overlap-Weighted Propensity Score Matching was additionally performed to reduce confounding during the 3-month follow-up.ResultsCOVID-19 significantly increased the risk of disease decline (OR = 10.39, 95% CI:3.87 to 27.87, p < 0.001) and disease deterioration (OR = 10.37, 95% CI: 2.71 to 39.65, p = 0.001). APOE ε4 carrier status was associated with a higher risk of deterioration (OR = 1.72), while those with unknown APOE status exhibited an even greater risk (OR = 5.20, 95% CI:1.32 to 20.53, p = 0.019). Secondary analyses confirmed that COVID-19 patients experienced significantly greater increases in CDR-SB scores compared to non-COVID-19 patients.ConclusionsSARS-CoV-2 infection was associated with greater short-term cognitive worsening over a three-month period in patients with AD, underscoring its potential public health relevance and the need for early surveillance to guide timely clinical management.},
}

@article {pmid42554990,
year = {2026},
author = {Baird, KT},
title = {Thermodynamic impedance mismatch in neurodegeneration: A biophysical framework for the prediction of amyloid-related imaging abnormalities.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474112},
doi = {10.1177/13872877261474112},
pmid = {42554990},
issn = {1875-8908},
abstract = {Amyloid-related imaging abnormalities (ARIA) represent a significant iatrogenic complication of anti-amyloid monoclonal antibody therapies. To address this, we propose the Impedance Mismatch Theory as a theoretical framework and hypothesis, reframing neurodegeneration as a network-level thermodynamic failure characterized by localized thermal runaway (Neural Physiological Load Index (NLI) greater than or equal to 1.0). Within this framework, amyloid-β (Aβ) is modeled not only in its established biological context, but as a potential thermodynamic heat sink and bio-conductive electrical shunt deployed to protect hyper-metabolic neural hubs. Utilizing the Pennes bioheat equation, we formalize the NLI and map its theoretical values to absolute [1]H-magnetic resonance spectroscopy thermometry signatures. Our model suggests that clearing Aβ in the setting of unresolved energetic mismatch could contribute to localized mechanical and thermal instability. We hypothesize that these upstream physical dynamics precipitate the downstream inflammatory cascades clinically observed as ARIA. If validated, these theoretical considerations suggest that effective disease modification may require thermodynamic normalization as a prerequisite to, or in parallel with, plaque clearance.},
}

@article {pmid42554993,
year = {2026},
author = {Palmer, AM and Francis, PT and Sims, NR},
title = {Fifty years of the cholinergic hypothesis: David Bowen's legacy in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag261},
pmid = {42554993},
issn = {1460-2156},
}

@article {pmid42555084,
year = {2026},
author = {Knox, S and Dooley, M and Cutty, M and Simpson, KN},
title = {Beyond binary classification: A tiered claims-based algorithm for Alzheimer's disease and related dementias in Medicare.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471874},
doi = {10.1177/13872877261471874},
pmid = {42555084},
issn = {1875-8908},
abstract = {BackgroundAdministrative data is widely used to identify Alzheimer's disease and related dementias (ADRD), yet commonly applied algorithms (e.g., the Chronic Conditions Warehouse [CCW] algorithm) rely on binary classification that may obscure heterogeneity in likelihood and care needs.ObjectiveTo examine whether a tiered ADRD classification algorithm using Medicare home health data yields cohorts with more clearly distinguishable clinical and sociodemographic characteristics compared with the CCW-27 algorithm.MethodsWe conducted a retrospective cohort study of 2,252,040 Medicare Fee-for-Service beneficiaries with home health encounters. The novel algorithm applied episode-level and individual-level criteria to classify individuals into one of three mutually exclusive groups (ADRD-highly likely, ADRD-possible, ADRD-unlikely). Using descriptive statistics, we compared socio-demographic characteristics and OASIS-based cognitive and functional measures across groups defined by the novel algorithm and the CCW-27 algorithm.ResultsThe CCW-27 algorithm classified 34.3% of individuals as ADRD-positive, whereas the novel algorithm classified 7.6% as ADRD-highly likely, 29.3% as ADRD-possible, and 63.1% as ADRD-unlikely. The ADRD-highly likely group demonstrated greater cognitive and functional impairment than the CCW-27 ADRD-positive group. Discordant classifications revealed important sociodemographic differences: individuals classified as ADRD-highly likely by the novel algorithm but ADRD-negative by the CCW-27 algorithm were more frequently Medicare/Medicaid dual-eligible (52.9%) and non-White (39.5%) than concordant and alternative discordant groups.ConclusionsA tiered claims-based ADRD classification provides greater resolution than binary approaches and reveals clinically and sociodemographically distinct groups within the Medicare home health population. Such approaches may support more nuanced characterization of ADRD when clinical gold standards are unavailable.},
}

@article {pmid42555228,
year = {2026},
author = {Kaur, G and Goyal, B},
title = {Leveraging molecular dynamics to unravel the inhibition mechanism of potential β-secretase (BACE1) inhibitors.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp01160h},
pmid = {42555228},
issn = {1463-9084},
abstract = {Alzheimer's disease (AD) remains a formidable global health challenge, driving the urgent need for potent and selective therapeutics targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme involved in the generation of amyloid-β (Aβ) peptide and a promising target for disease-modifying interventions. In this work, approximately 16 million small molecules from diverse databases were subjected to ligand-based virtual screening (LBVS), using LY3202626 as a reference compound, to identify new potent inhibitors of BACE1. LY3202626 is a highly potent, central nervous system (CNS) penetrant BACE1 inhibitor (IC50 = 0.615 nM) that has progressed to clinical trials, demonstrating efficacy at low doses against BACE1 activity. The lead candidates identified using ensemble molecular docking displayed stronger binding affinities (-11.2 to -9.6 kcal mol[-1]) to BACE1 as compared to LY3202626. Notably, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis revealed high-affinity binding of ChEMBL3667410 (C1), ChEMBL3667414 (C2), and ChEMBL3976114 (C5) with binding affinities of -32.9 ± 0.8, -33.6 ± 1.8, and -36.1 ± 1.7 kcal mol[-1], respectively, to BACE1 as compared to LY3202626 (-29.9 ± 1.8 kcal mol[-1]). Furthermore, MD simulations demonstrated enhanced structural stability and reduced residual fluctuations in BACE1 on the incorporation of C1, C2, and C5, as compared to apo-BACE1 and BACE1-LY3202626. Interestingly, the conformational snapshots, flap distances, and free energy landscape (FEL) analyses highlighted a closed flap, Val67-Glu77 (non-active) conformation in BACE1-C5 in comparison to an open flap (active) conformation in apo-BACE1, and partial restriction in the access to the active site of BACE1 due to the flap movement noticed in the presence of LY3202626, C1, and C2. Notably, conformational microstate analysis revealed key hydrogen bond interactions of C5 with the 10s loop (Gly11, Gly13), flap residues (Trp76), the catalytic residue (Asp228), Gly230, and Thr231 of BACE1, depicting its high-affinity binding to key residues of BACE1 and its potential as an effective inhibitor of BACE1 activity. The comprehensive in silico methodology in this work illuminated the inhibitory mechanism of LY3202626 and top hit compounds against BACE1 activity for the first time, which, in turn, will be highly valuable in further optimization and structural refinement using various functional group modifications to yield more potent next-generation therapeutic candidates against BACE1 in AD.},
}

@article {pmid42555262,
year = {2026},
author = {Prokopiou, PC and Van Egroo, M and Riphagen, JM and Baillet, M and Ashton, NJ and Janelidze, S and Sperling, RA and Johnson, KA and Blennow, K and Hansson, O and Zetterberg, H and Jacobs, HIL},
title = {Astrocyte reactivity modifies the effects of locus coeruleus norepinephrine-related dysfunction on tau and its impact on cognition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71703},
pmid = {42555262},
issn = {1552-5279},
support = {WE.03-2019-02//Alzheimer Nederland/ ; R01AG062559/NH/NIH HHS/United States ; R01AG068062/NH/NIH HHS/United States ; R01AG082006/NH/NIH HHS/United States ; R21AG074220/NH/NIH HHS/United States ; R21AG081681/NH/NIH HHS/United States ; R01AG068398/NH/NIH HHS/United States ; A20211016F//BrightFocus Foundation/ ; 101109451//Marie Skłodowska Curie Actions/ ; AARF-23-1145963/ALZ/Alzheimer's Association/United States ; ZEN-21-848495/ALZ/Alzheimer's Association/United States ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 2017-00915//Swedish Research Council/ ; 101053962//European Union's Horizon Europe Research and Innovation Program/ ; ALFGBG-71320//Swedish State/ ; ALFGBG-715986//Swedish State/ ; ALFGBG-965240//Swedish State/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF)/ ; RDAPB-201809-2016615//Alzheimer Drug Discovery Foundation (ADDF)/ ; JPND2021-00694//European Union Joint Programme-Neurodegenerative Disease Research/ ; JPND2019-466-236//European Union Joint Programme-Neurodegenerative Disease Research/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; AF-930351//Swedish Alzheimer Foundation/ ; AF-939721//Swedish Alzheimer Foundation/ ; AF-968270//Swedish Alzheimer Foundation/ ; FO2022-0270//Hjärnfonden, Sweden/ ; 860197//Hjärnfonden, Sweden/ ; FO2017-0243//Hjärnfonden, Sweden/ ; ALZ2022-0006//Hjärnfonden, Sweden/ ; ADSF-21-831376-C//AD Strategic Fund/ ; ADSF-21-831381-C//AD Strategic Fund/ ; ADSF-21-831377-C//AD Strategic Fund/ ; ADSF-24-1284328-C//AD Strategic Fund/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; 860197//European Union's Horizon 2020 Research and Innovation Programme/ ; },
mesh = {*Locus Coeruleus/metabolism/physiopathology/diagnostic imaging ; Humans ; *Astrocytes/metabolism/physiology ; *tau Proteins/blood/metabolism ; Male ; Glial Fibrillary Acidic Protein/blood ; *Norepinephrine/metabolism ; Female ; *Cognition/physiology ; Aged ; *Cognitive Dysfunction/metabolism/physiopathology ; Magnetic Resonance Imaging ; Biomarkers/blood ; },
abstract = {INTRODUCTION: Animal models demonstrated that pharmacologically-induced lesioning of the locus coeruleus (LC), the brain's primary source of norepinephrine, triggered astrocyte reactivity, exacerbating Alzheimer's disease (AD) pathology and cognitive deficits. We examined whether astrocyte reactivity modulates the relationship between LC dysfunction, tau pathology, and cognitive decline in humans.

METHODS: We combined ultra-high-field LC functional imaging during an affective task with plasma biomarkers of glial fibrillary acidic protein (GFAP) and hyperphosphorylated tau (p-tau), and longitudinal cognitive data from 78 asymptomatic individuals. Associations between LC activity and norepinephrine transporter-enriched LC functional connectivity (LCFC) with p-tau, GFAP, and cognitive decline were examined.

RESULTS: Lower LC activity and LCFC were related to elevated plasma p-tau217, particularly at elevated GFAP. Lower LC FC was also associated with cognitive decline in individuals with elevated plasma p-tau217 and GFAP.

DISCUSSION: LC-norepinephrine system dysfunction may contribute to emerging tau pathology and cognitive decline, with astrocytes playing a critical gating role.},
}

*Locus Coeruleus/metabolism/physiopathology/diagnostic imaging
Humans
*Astrocytes/metabolism/physiology
*tau Proteins/blood/metabolism
Male
Glial Fibrillary Acidic Protein/blood
*Norepinephrine/metabolism
Female
*Cognition/physiology
Aged
*Cognitive Dysfunction/metabolism/physiopathology
Magnetic Resonance Imaging
Biomarkers/blood

@article {pmid42555275,
year = {2026},
author = {Qi, X and Liu, R and Belsky, DW and Tian, Q and Luo, H and Liu, Y and Xu, Z and Langa, KM and Wu, B},
title = {Edentulism, blood-based neurodegenerative biomarkers, and 10-year dementia risk: A mediation analysis in a nationally representative United States cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71731},
pmid = {42555275},
issn = {1552-5279},
support = {R01AG089856/NH/NIH HHS/United States ; //Intramural Research Program of the National Institute on Aging/ ; },
mesh = {Humans ; *Dementia/blood/epidemiology ; Biomarkers/blood ; United States/epidemiology ; Female ; Male ; Glial Fibrillary Acidic Protein/blood ; Amyloid beta-Peptides/blood ; Aged ; *Mouth, Edentulous/epidemiology/blood ; tau Proteins/blood ; Cohort Studies ; Cognitive Dysfunction/blood/epidemiology ; Risk Factors ; Neurofilament Proteins ; },
abstract = {INTRODUCTION: Tooth loss is associated with dementia risk, but mechanisms remain unclear. We examined whether blood-based neurodegenerative biomarkers mediate the edentulism-cognition association.

METHODS: Among 4238 Health and Retirement Study participants aged 50+, we linked edentulism (2012), biomarkers (neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], phosphorylated tau-181, and amyloid-β [Aβ] 42/40; 2016), and 10-year cognitive outcomes (2012-2022).

RESULTS: Edentulism was associated with higher NfL (β = 4.21) and GFAP (β = 8.06), but not pTau-181 or Aβ42/40, and predicted cognitive impairment (hazard ratio [HR] 1.49) and dementia (HR 1.28). GFAP mediated 9.8% and 12.0% of the cognitive impairment and dementia associations, respectively; NfL mediated 9.8% of the dementia association but not cognitive impairment.

CONCLUSION: In this observational cohort, elevated NfL and GFAP were associated with, and accounted for a small proportion of, the edentulism-cognition association. These associative findings support further study of oral health in dementia prevention but do not establish a causal effect.},
}

Humans
*Dementia/blood/epidemiology
Biomarkers/blood
United States/epidemiology
Female
Male
Glial Fibrillary Acidic Protein/blood
Amyloid beta-Peptides/blood
Aged
*Mouth, Edentulous/epidemiology/blood
tau Proteins/blood
Cohort Studies
Cognitive Dysfunction/blood/epidemiology
Risk Factors
Neurofilament Proteins

@article {pmid42555875,
year = {2026},
author = {Prodan, CI and Yabluchanskiy, A},
title = {The Challenge of Atypical Alzheimer Disease Phenotypes.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218533},
doi = {10.1212/WNL.0000000000218533},
pmid = {42555875},
issn = {1526-632X},
}

@article {pmid42555876,
year = {2026},
author = {Shir, D and Corriveau-Lecavalier, N and Jones, DT and Ramanan, VK and Lachner, C and Knopman, DS and Petersen, RC and Josephs, KA and Day, GS and Graff-Radford, J and Graff-Radford, NR},
title = {Eligibility for Anti-Amyloid Therapies in Patients With Biomarker-Confirmed Atypical Alzheimer Disease Phenotypes.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218347},
pmid = {42555876},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Phenotype ; Aged ; Male ; Retrospective Studies ; Biomarkers ; Aged, 80 and over ; *Patient Selection ; Middle Aged ; *Eligibility Determination ; },
abstract = {BACKGROUND AND OBJECTIVES: Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown.

METHODS: We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes.

RESULTS: The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes.

DISCUSSION: Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.},
}

Humans
*Alzheimer Disease/drug therapy
Female
Phenotype
Aged
Male
Retrospective Studies
Biomarkers
Aged, 80 and over
*Patient Selection
Middle Aged
*Eligibility Determination

@article {pmid42555976,
year = {2026},
author = {Xu, T and Zhang, C and Yang, Y and Shen, Z and Zhong, Z},
title = {Esketamine alleviates neuroinflammation and cognitive impairment in male 3xTg-AD mice by regulating the TAOK1/IL-17 axis.},
journal = {Canadian journal of physiology and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1139/cjpp-2025-0340},
pmid = {42555976},
issn = {1205-7541},
abstract = {Beyond its antidepressant effects, esketamine (ESK) has the potential to enhance neuroplasticity, facilitating the reconnection with emotional and cognitive processes, improving social cognition, and promoting resilience. However, not much is known about its role in Alzheimer's disease (AD). This study aims to explore the potential mechanism of ESK in AD treatment. The potential targets of ESK were predicted by bioinformatics analysis, and 3xTg-AD male mice were subjected to adeno-associated virus and ESK treatment. Cognitive ability, neuronal damage, and proinflammatory factors in 3xTg-AD mice were evaluated. An inflammatory model was established by inducing mouse cortical neurons with mouse IL-17A protein. Neuronal viability was assessed after treatment with different concentrations of ESK. TAOK1 knockdown or IL-17RA knockdown was performed on 3xTg-AD mice and neurons. TAOK1 was highly expressed in the cerebral cortex of ESK-treated 3xTg-AD mice. ESK improved IL-17-induced neuronal inflammation and DNA damage in a TAOK1-dependent manner. TAOK1 interacted with IL-17RA. IL-17RA knockdown improved DNA damage and inflammatory responses in cells and alleviated cognitive impairment and neuroinflammation in AD mice. Overall, ESK protects against DNA damage-mediated neuroinflammation by promoting TAOK1 and inhibiting IL-17 signaling, thereby improving cognitive dysfunction in 3xTg-AD mice.},
}

@article {pmid42556030,
year = {2026},
author = {Rodriguez, A and Judge, B and Shelley, N and Mehta, V and Friedrichsen, K and Strain, J and Benzinger, TL and Schindler, SE and Holtzman, DM and Cross, AH and Brier, MR},
title = {Clinical features of older MS patients with and without Alzheimer disease biomarkers.},
journal = {Multiple sclerosis and related disorders},
volume = {114},
number = {},
pages = {107406},
doi = {10.1016/j.msard.2026.107406},
pmid = {42556030},
issn = {2211-0356},
abstract = {Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammatory demyelination and axonal injury. Magnetic resonance imaging (MRI) plays a central role in MS diagnosis. Recent work suggests that biomarkers indicative of Alzheimer's disease (AD) are markedly reduced in people with MS. Whether differences in AD biomarkers are related to different features of MS, including MRI characteristics or treatment history, is unclear. In this study, 100 MS patients from Washington University in St. Louis underwent review of their most recent MRI as well as their prior and present MS disease-modifying treatment (DMT) exposures. We then ascertained the relation of MRI features and DMT to plasma AD biomarker measurements, with only a small subset (N=7) demonstrating APS2+ biomarker evidence of AD. Lesion distribution across MS topographies and total white matter lesion (WML) burden were both similar across MS patients with and without biomarker evidence of AD. Central vein sign (CVS), a recently integrated imaging biomarker of MS, was highly prevalent across the MS cohort and did not differ by AD biomarker status or MS clinical typicality at diagnosis, supporting the MS diagnoses even for people with atypical initial presentations. DMT exposure history showed associations with AD biomarkers: longer exposure to B cell-depleting anti-CD20 monoclonal antibody therapies (BCDT) corresponded to lower levels of amyloid pathology as measured by plasma biomarkers, and longer exposure to interferon-beta corresponded to a less pathological Aβ42/40 ratio. These findings indicate that structural MRI features do not explain differences in AD biomarker profiles in MS, whereas treatment-related immunologic effects may contribute to variation in AD pathology risk in MS patients.},
}

@article {pmid42556278,
year = {2026},
author = {Shi, Z and Cheng, X and Zhang, C and Hu, J and He, X and Chen, S and Wu, H and Tian, M and Yan, C and He, L},
title = {Vorinostat ameliorates cognitive impairment and Tau pathology in an AAV-P301L-Tau-induced tauopathy mouse model: insights into neuroinflammation and PI3K/AKT/GSK3β signaling.},
journal = {International immunopharmacology},
volume = {187},
number = {},
pages = {117216},
doi = {10.1016/j.intimp.2026.117216},
pmid = {42556278},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.},
}

@article {pmid42556319,
year = {2026},
author = {Koldamova, R and Fitz, NF and Lefterov, I},
title = {When less is more and when it isn't: Microglial Spi1 and the limits of what we know.},
journal = {Neuron},
volume = {114},
number = {15},
pages = {2669-2671},
doi = {10.1016/j.neuron.2026.06.017},
pmid = {42556319},
issn = {1097-4199},
mesh = {Animals ; *Microglia/metabolism ; Proto-Oncogene Protein Spi-1 ; *Trans-Activators/genetics/metabolism ; *Proto-Oncogene Proteins/metabolism/genetics ; Mice ; *Alzheimer Disease/metabolism/pathology ; Humans ; Amyloid beta-Peptides/metabolism ; },
abstract = {Microglia are key players in Alzheimer's disease, but the transcriptional control of their phagocytic function remains unclear. Kim et al. show that mouse microglial Spi1 deletion worsens amyloid pathology by impairing Aβ clearance through Syk, Lyn, and Fcgr1, providing new insight into PU.1-dependent regulatory networks and microglial functions in neurodegeneration.},
}

Animals
*Microglia/metabolism
Proto-Oncogene Protein Spi-1
*Trans-Activators/genetics/metabolism
*Proto-Oncogene Proteins/metabolism/genetics
Mice
*Alzheimer Disease/metabolism/pathology
Humans
Amyloid beta-Peptides/metabolism

@article {pmid42556344,
year = {2026},
author = {Villareal, JAB and Bathe, T and Rosa, A and Sharma, RV and Hernández Gómez, EO and Ryan, AM and Hawkinson, TR and Tuzzolo, AM and Medina-Parrilla, E and Phillips, JL and Tsering, W and Iturbe, AA and Giasson, BI and Sun, RC and Gentry, MS and Prokop, S},
title = {Corpora amylacea profiling reveals disease stage and brain region-specific alterations in glycogen metabolism in Alzheimer's disease patient brains.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102968},
doi = {10.1016/j.xcrm.2026.102968},
pmid = {42556344},
issn = {2666-3791},
abstract = {Increasing evidence indicates that shifts in brain polysaccharide metabolism can influence the progression of multiple neurodegenerative diseases. Here, we profile corpora amylacea (CA) in 230 postmortem human brains, revealing significantly higher densities in Alzheimer's disease (AD) patients when compared with patients with other or no neurodegenerative diseases and a tight correlation of CA density with neurofibrillary tangle (NFT) pathology. Immunohistochemical profiling using an anti-glycogen antibody confirms the polysaccharide nature of CA and reveals plaque-like glycogen patches (GPs) and densely aggregated intraneuronal glycogen in AD patient brains correlated with the emergence of NFT pathology. matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) orthogonally verifies the polysaccharide identity of these structures and that GPs can be consistently observed at early neuropathological disease stages. GPs are also observed in murine models of AD-like pathology, correlating with tau pathology. The identification of these AD-associated glycogen pathologies in the human brain implies that alterations in glycogen metabolism are tightly associated with AD pathogenesis.},
}

@article {pmid42556454,
year = {2026},
author = {Xue, M and Pan, H and He, Y and Li, H and Zhou, H and Cheng, K and Xiao, C and Zhao, J and Jia, X and Li, Y and Liu, D and Yan, K},
title = {An accessible digital single-molecule sensing platform for plasma P-tau217 quantification in Alzheimer's disease screening.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {593},
number = {},
pages = {121255},
doi = {10.1016/j.cca.2026.121255},
pmid = {42556454},
issn = {1873-3492},
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) necessitates affordable and accessible blood biomarkers. Plasma phosphorylated tau 217 (P-tau217) is promising, but low-cost platforms for large-scale screening remain limited.

METHODS: We validated a Digital Single-Molecule Sensing (DiSMS) platform for plasma P-tau217 quantification. A reference interval was established in Cohort I (discovery, n = 325, comprising 143 cognitively unimpaired controls, 80 CE, 34 frontotemporal dementia [FTD], and 68 subcortical ischemic vascular dementia [SIVD] patients). Diagnostic performance was validated in Cohort II (n = 242; 77 CE, 165 controls). Cross-platform concordance was assessed against the Simoa HD-X in 137 paired samples.

RESULTS: The healthy reference interval was 0.09-0.51 pg/mL. In Cohort II, P-tau217 strongly distinguished AD from controls (accuracy 93.4% [95% CI: 90.3%-96.5%], sensitivity 92.2% [95% CI: 83.2%-96.8%], specificity 93.9% [95% CI: 88.8%-96.9%]). A two-cutoff approach (< 0.40, 0.40-0.50, > 0.50 pg/mL) yielded 94.1% accuracy and 95.9% sensitivity, leaving 8.4% of cases in the intermediate zone. DiSMS exhibited strong concordance with the Simoa (concordance rate = 94.9%; Spearman r = 0.94, P < 0.001). Plasma P-tau217 was significantly higher in AD than FTD (median 0.25 pg/mL) and SIVD (median 0.36 pg/mL) (both P < 0.001). Age-adjusted AUC was moderate for AD versus SIVD (0.777) but limited for AD versus FTD (0.665; sensitivity/specificity below 65%).

CONCLUSIONS: The DiSMS platform enables accurate, cost-accessible plasma P-tau217 quantification for AD screening, meeting consensus guidelines (≥90%). The limited P-tau217 performance for differentiating AD from FTD (AUC = 0.665) highlights the need for integration with complementary biomarkers or clinical assessments.},
}

@article {pmid42556482,
year = {2026},
author = {Lu, QX and Guan, W},
title = {A role for apolipoprotein E4 (ApoE4) in the pathogenesis of depressive symptoms and Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118316},
doi = {10.1016/j.bcp.2026.118316},
pmid = {42556482},
issn = {1873-2968},
abstract = {Depression is a chronic mental disorder that is often difficult to diagnose and mostly left untreated. Apolipoprotein E (ApoE) is a lipid transport protein that plays a central role in the metabolism of plasma lipoproteins and the transport of lipids within tissues. Among its three major isoforms, only ApoE4 has a unique structural variant that confers significant neurotoxicity not present in the other two subtypes. ApoE4 not only disrupts lipid metabolism but also interferes with neuroimmune regulation and mitochondrial dynamics, thereby impairing synaptic integrity. It is a major genetic risk factor for Alzheimer's disease (AD) and accelerates its age of onset. Although developing depression in midlife may be a risk factor for AD, the underlying mechanisms by which ApoE4 influences depression or depression-related behaviors associated with AD remain fragmented, and systematic integrative reviews on this topic are scarce. We integrate existing evidence to elucidate the role of ApoE4 in depression or AD-associated prodromal depressive-like behaviors, with a focus on how its dysfunction disrupts cellular lipid homeostasis, impairs synaptic plasticity, and damages mitochondrial function. We also explored specific therapeutic strategies targeting the pathological defects of ApoE4 that enhance synaptic resilience, and utilizing conformational modulating small molecules such as EZ-482 and ALZ-801 to treat depressive symptoms in early AD. Thus, these findings indicate that ApoE4 may influence the progression of depressive phenotypes through multiple pathological pathways, making it a promising therapeutic target for treating depression comorbid with early AD.},
}

@article {pmid42556648,
year = {2026},
author = {Huang, W and Huang, J and Kuang, N and Wu, J and Feng, F and Luo, Y and Huang, N},
title = {Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103290},
doi = {10.1016/j.arr.2026.103290},
pmid = {42556648},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.},
}

@article {pmid42556890,
year = {2026},
author = {Giuliani, C and Schmidlin, PR and Fakheran, O},
title = {THE ROLE OF PERIODONTITIS IN THE INITIATION AND PROGRESSION OF COGNITIVE DISORDERS: AN UMBRELLA REVIEW.},
journal = {The journal of evidence-based dental practice},
volume = {26},
number = {3},
pages = {102307},
doi = {10.1016/j.jebdp.2026.102307},
pmid = {42556890},
issn = {1532-3390},
mesh = {Humans ; *Periodontitis/complications ; Disease Progression ; *Cognition Disorders/etiology ; Risk Factors ; Alzheimer Disease/etiology ; Systematic Reviews as Topic ; },
abstract = {BACKGROUND: Cognitive disorders are a major cause of morbidity worldwide, and accumulating evidence indicates that chronic systemic inflammation may play a key role in their initiation and progression. Periodontitis, a prevalent chronic inflammatory oral disease, has been increasingly recognized as a potential risk factor for cognitive disorders.

OBJECTIVE: This umbrella review synthesized evidence from systematic reviews and meta-analyses investigating the association between periodontitis and cognitive disorders, including Alzheimer's disease (AD), dementia and cognitive impairment.

METHODS: Following JBI methodological guidance for umbrella reviews, a comprehensive search was conducted across seven databases (Medline, Embase, Cochrane Library, CINAHL, PsycINFO, Web of Science, Scopus) from inception to April 2025 to identify systematic reviews and meta-analyses on the association between periodontitis and cognitive disorders in humans. Two reviewers independently performed study selection, data extraction, and quality appraisal using the JBI Critical Appraisal Tool. Due to heterogeneity, findings were synthesized narratively.

RESULTS: Twenty systematic reviews and meta-analyses comprising 333 primary studies were included. Most reviews reported a significant association between periodontitis and AD or dementia. Meta-analyses consistently found increased risk estimates, with the strongest associations for severe periodontitis. Biological plausibility was supported by shared inflammatory pathways and detection of periodontal pathogens in brain tissue. However, evidence was predominantly observational, with substantial heterogeneity in diagnostic criteria.

CONCLUSION: Evidence suggests a potential link between periodontitis and cognitive disorders, though results are inconsistent and causality remains unproven. Inflammatory and microbial mechanisms are proposed, but well-designed longitudinal and interventional studies with standardized criteria are needed.},
}

Humans
*Periodontitis/complications
Disease Progression
*Cognition Disorders/etiology
Risk Factors
Alzheimer Disease/etiology
Systematic Reviews as Topic

@article {pmid42557116,
year = {2026},
author = {Wei, M and Zhang, J and Shi, J and Li, T and Yao, L and Li, F and Xiao, W and Ni, J and Tian, J},
title = {Temporal order of clinical symptoms in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100253},
doi = {10.1016/j.inpsyc.2026.100253},
pmid = {42557116},
issn = {1741-203X},
abstract = {BACKGROUND: Understanding the temporal order of clinical symptoms is critical for improving disease progression assessment in biomarker-defined Alzheimer's disease (AD). However, the sequential emergence of cognitive, neuropsychiatric, and functional manifestations remains incompletely characterized. The purpose of this study is to characterize the population-level sequence in which Alzheimer's disease symptoms appear, to help understand how the disease is progressing.

METHODS: We analyzed 932 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 546 amyloid-positive individuals across the AD continuum and 386 amyloid-negative individuals in the comparison group. Longitudinal cumulative incidence was analyzed to estimate the temporal emergence of major clinical symptoms. Any symptom onset was defined using a > 50% cumulative incidence threshold. Cross-sectional relationships between the sequence of clinical symptoms and Mini-Mental State Examination (MMSE) scores were analyzed using locally estimated scatterplot smoothing (LOESS). The concordance between the clinical symptom sequence and PET-derived Braak staging was assessed using weighted kappa statistics.

RESULTS: A reproducible temporal ordering of clinical symptoms was observed across longitudinal and cross-sectional analyses. Memory impairment emerged earliest, affecting 63.75% of participants at baseline, followed by behavioral and affective symptoms. At intermediate stages, executive dysfunction and instrumental activities of daily living (IADL) impairment affected 52.44% and 54.85% of participants, respectively. Language and visuospatial impairments appeared later, affecting 51.25% and 51.54% of participants, respectively, followed by psychotic symptoms and severe functional decline in basic activities of daily living (BADL), which suggests the disease has reached its late stage. The order in which different symptom groups appear-from memory to executive function and instrumental abilities, then language and visuospatial skills, and finally psychotic symptoms and basic abilities-shows moderate consistency respectively with CDR staging (κ = 0.596, 95%CI: 0.524-0.668), and the PET-derived Braak staging (κ = 0.517, 95%CI: 0.436-0.598).

CONCLUSION: Clinical symptoms in AD tend to emerge in a temporal sequence. This finding may help to better characterize disease progression clinically, serving as a symptom-staging framework for symptomatic AD and providing interpretable turning points for clinical assessment and individualized management.},
}

@article {pmid42557118,
year = {2026},
author = {Xu, S and Yang, Z and Zhi, Y and Yu, S and Zhang, T and Jiang, J and Tang, J and He, H and Lu, M and Wang, X and Wu, Q and Zhao, X},
title = {Retraction notice to "The effects of antimony on Alzheimer's disease-like pathological changes in mice brain" [Sci. Total Environ. 760 (2021) 143235].},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {182162},
doi = {10.1016/j.scitotenv.2026.182162},
pmid = {42557118},
issn = {1879-1026},
}

@article {pmid42557399,
year = {2026},
author = {Zhang, Y},
title = {Exercise-Mediated Modulation of the NLRP3 Inflammasome in Aging and Neurodegenerative Diseases: Mechanisms, Microglial Crosstalk, and Translational Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42557399},
issn = {1559-1182},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Microglia/metabolism/pathology ; *Aging/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Inflammasomes/metabolism ; *Exercise/physiology ; },
abstract = {Regular engagement in physical exercise has been recognized as a formidable non-pharmacological intervention aimed at mitigating age-associated neuroinflammation and neurodegenerative phenomena. A fundamental mechanism that underpins these advantageous effects pertains to the modulation of the NLRP3 inflammasome, which serves as a pivotal regulator of innate immune responses within microglial cells. The aging process is marked by a state of chronic low-grade inflammation, commonly referred to as "inflammaging," which is instigated by mitochondrial dysfunction, oxidative stress, and metabolic disturbances; these factors collectively facilitate the activation of NLRP3 and the subsequent secretion of pro-inflammatory cytokines, notably IL-1β. Contemporary research findings suggest that physical exercise diminishes NLRP3 inflammasome activation through various interrelated pathways. These pathways encompass the reduction of reactive oxygen species production, the inhibition of TXNIP-mediated assembly of the inflammasome, and the modulation of metabolites derived from the gut, such as trimethylamine N-oxide. In addition, factors circulating as a result of exercise, which include irisin and meteorin-like protein, play a significant role in promoting systemic and central anti-inflammatory responses, thereby impacting the functional dynamics of microglia. In experimental paradigms investigating the phenomena of aging and neurodegenerative disorders (NDDs), notably Alzheimer's and Parkinson's diseases, physical activity has been shown to diminish amyloid accumulation, tau pathology, and microglial activation, primarily through the attenuation of NLRP3 signaling pathways. Collectively, these observations underscore the role of exercise as a pivotal regulator of neuroimmune equilibrium, thereby providing mechanistic elucidation of its potential therapeutic efficacy in alleviating inflammaging and decelerating the progression of NDDs.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Microglia/metabolism/pathology
*Aging/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Humans
*Inflammasomes/metabolism
*Exercise/physiology

@article {pmid42557842,
year = {2026},
author = {Rubtsova, K},
title = {Age-Associated B Cells: Origins, Regulation, and Tissue-Specific Pathogenic Contributions in Autoimmune, Metabolic, and Neurological Diseases.},
journal = {Immunological reviews},
volume = {341},
number = {1},
pages = {e70144},
doi = {10.1111/imr.70144},
pmid = {42557842},
issn = {1600-065X},
mesh = {Humans ; Animals ; *Autoimmune Diseases/immunology/metabolism ; *B-Lymphocytes/immunology/metabolism ; *Aging/immunology ; *Nervous System Diseases/immunology/metabolism ; Cell Differentiation ; Organ Specificity ; Autoimmunity ; Signal Transduction ; },
abstract = {Age-associated B cells (ABCs) are a distinct B cell population characterized by coexpression of T-bet and CD11c. First described in aged female mice and autoimmune-prone strains, ABCs are now recognized to be associated with multiple human autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, where their frequency correlates with disease activity. Their differentiation requires toll-like receptor (TLR) signaling, IFN-γ, IL-21, BCR engagement, with ZEB2 emerging as the nonredundant transcriptional master regulator of ABC identity. Here we review requirements for ABC differentiation, their defining phenotypic and functional features, and their tissue-specific distribution and pathogenic contributions in diverse inflammatory settings. A central theme is that ABCs are tissue-homing cells whose contribution extends beyond blood and lymphoid organs. In kidney, inflamed synovium, salivary glands, and adipose tissue, ABCs drive pathology through locally differentiated autoantibody-secreting cells, stromal activation, antigen presentation, and cytokine production. We further discuss roles for ABCs in neurological diseases, including their enrichment in the cerebrospinal fluid in multiple sclerosis (MS) and their contribution to neuroinflammation in Alzheimer's disease, and highlight the EBV-ABC axis as a mechanism linking viral infection to autoimmunity. In summary, ABCs are multi-functional, tissue-adaptable pathogenic effectors whose contributions to human disease extend beyond classical autoimmunity into metabolic dysfunction and neurodegeneration.},
}

Humans
Animals
*Autoimmune Diseases/immunology/metabolism
*B-Lymphocytes/immunology/metabolism
*Aging/immunology
*Nervous System Diseases/immunology/metabolism
Cell Differentiation
Organ Specificity
Autoimmunity
Signal Transduction

@article {pmid42557858,
year = {2026},
author = {Li, X and Yang, F and Jiang, Y and Zhao, F and Liu, F},
title = {HNRNPC Succinylation Influences the Neurodegeneration of Alzheimer's Disease Through YME1L1-Mediated Mitochondrial Metabolism.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70646},
doi = {10.1111/acel.70646},
pmid = {42557858},
issn = {1474-9726},
support = {Z2023168//National Key Clinical Specialty Scientific Research Project/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Mitochondria/metabolism ; Mice ; Mice, Transgenic ; Sirtuins/metabolism ; Humans ; Disease Models, Animal ; *Mitochondrial Proteins/metabolism ; Metalloendopeptidases ; },
abstract = {Mitochondrial dysfunction and abnormal energy metabolism are important pathological features of Alzheimer's disease (AD). This study investigates how mitochondrial protease YME1L1 affects mitochondrial function and its upstream regulation in the pathogenesis of AD. The AD model was established by using APP/PS1 transgenic mice, primary neurons treated with Aβ1-42, and HT22 cells. The silencing of YME1L1 was achieved to evaluate its effects on mitochondrial function and OPA1 protein hydrolysis. RIP-qPCR and RNA pull-down test were used to evaluate the interaction between HNRNPC and YME1L1 mRNA. The protein succinylation level was detected by proteomic analysis of succinylation, and co-immunoprecipitation (Co-IP) was used to verify the succinylation of HNRNPC. Cognitive ability was tested by behavioral tests, including the Morris water maze, Y-maze, object recognition test, and olfactory test. Finally, the therapeutic potential of SIRT5 was studied by an overexpression experiment in an AD model. YME1L1 was significantly upregulated in the AD model, which promoted mitochondrial dysfunction and neuronal damage through OPA1 hydrolysis. HNRNPC enhances the stability of YME1L1 mRNA through an m6A-dependent mechanism, while its own K50 succinylation enhances the stability of HNRNPC by competitively inhibiting TRIM25-mediated ubiquitination, further amplifying the expression of YME1L1. SIRT5 downregulation in AD elevated HNRNPC succinylation levels. SIRT5 overexpression promoted HNRNPC desuccinylation, reduced YME1L1 expression, restored mitochondrial function, and ameliorated Aβ deposition and cognitive deficits in AD mice. The SIRT5-HNRNPC-YME1L1 axis contributes to AD pathogenesis by disrupting OPA1 proteolysis and mitochondrial dynamics. Targeting HNRNPC succinylation represents a promising therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*Mitochondria/metabolism
Mice
Mice, Transgenic
Sirtuins/metabolism
Humans
Disease Models, Animal
*Mitochondrial Proteins/metabolism
Metalloendopeptidases

@article {pmid42557872,
year = {2026},
author = {Vaughan, DP and Jensen, MT and Real, R and Fumi, RG and Wu, L and Lux, D and Hodgson, M and Jones, PS and Holland, N and Scotton, WJ and Serrano-Assensio, O and Quattrone, A and Heslegrave, AJ and Veleva, E and Swann, O and Zetterberg, H and Lynch, T and Mir, P and Stamelou, M and Seppi, K and Vandenberghe, R and Warner, TT and Lees, A and Bhatia, KP and Church, A and Kobylecki, C and Leigh, PN and Hu, MT and Taba, P and Matsalu, T and Pavese, N and Ghosh, BCP and Picillo, M and Wallin, J and Svenningson, P and Sánchez-Gómez, A and Fernández, M and Cámara, A and Planellas, L and Compta, Y and , and Quaegebeur, A and Jaunmuktane, Z and Revesz, T and Jabbari, E and Rohrer, JD and Rowe, JB and Morris, HR},
title = {Defining the underlying pathology of corticobasal syndrome using clinical features and biomarkers.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag257},
pmid = {42557872},
issn = {1460-2156},
abstract = {Corticobasal degeneration (CBD) is a late onset progressive neurodegenerative condition of the 4-repeat-tauopathy-type, classically presenting with asymmetrical rigidity, dystonia and myoclonus. In the most recent diagnostic criteria, Armstrong and colleagues (2013) described four clinical phenotypes associated with this pathology, including corticobasal syndrome (CBS), through a large retrospective analysis of published cases and confirmed brain bank cases of CBD. However, predicting CBD pathology remains challenging. With the advent of disease-modifying therapies, it has become particularly important to distinguish Alzheimer's disease pathology from other underlying pathologies. We therefore combined two prospectively recruited cohorts of patients with CBS and analysed their key demographic, clinical and biomarker features. We included a separate cohort from UK brain banks who were diagnosed with CBS in life. We divided patients into three groups: CBS-Alzheimer's (CBS-AD), CBS-non-Alzheimer's (CBS-non-AD) and CBS-indeterminate (CBS-IDT) based on biomarkers and pathology, comparing clinical features, regional volumetric MRI measures and Nucleic Acid-Linked Immuno-Sandwich Assay with detection by next generation sequencing (NULISAseq) blood protein levels between groups. We performed additional analyses of pathologically verified cases. We included 397 participants, of which 57.7% were female. The mean age at symptom onset was 65.9 years. AD biomarkers and pathology permitted classifying 47 (11.8%) of the cases as CBS-AD, 134 (33.8%) as CBS-non-AD and 216 (54.4%) as CBS-IDT. Patients with CBS-AD had a younger age at onset (61.8 years vs 66.1 years, P < 0.01 and less severe motor deficits (non-significantly lower scores on MDS-UPDRS and PSPRS) and more severe cognitive impairment (non-significantly lower scores on MoCA). Patients with CBS-AD had higher rates of cortical sensory impairment (P = 0.087) and lower rates of limb dystonia (P < 0.01) and falls (P < 0.01) compared to the CBS-non-AD group. Volumetric MRI analysis revealed smaller parietal lobe volumes in CBS-AD (P = 0.01). The most common pathological diagnoses were PSP, CBD and AD. Limb dystonia was more common in people with CBD and PSP pathology (P = 0.077). Falls, impaired verbal fluency and impaired vertical saccades were confirmed as more common in PSP (P = 0.046, P = 0.040, P = 0.012, respectively). In summary, younger onset, less parkinsonism and more cognitive and cortical sensory impairment, along with reduced MRI parietal volumes point to CBS-AD, while limb dystonia, falls and worse verbal fluency relate to CBS-non-AD. Clinical, imaging and blood-biomarkers in can augment the Armstrong criteria in predicting the underlying pathology of corticobasal syndromes.},
}

@article {pmid42557882,
year = {2026},
author = {Pini, L and Imbimbo, BP and Corbetta, M},
title = {Reply: The disconnectome as target in Alzheimer disease: a promising framework or a premature end-point?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag263},
pmid = {42557882},
issn = {1460-2156},
}

@article {pmid42557932,
year = {2026},
author = {Wu, H and Chen, Q and Fang, M and Tang, H and Liu, H and Liu, J and Zhang, J and Chi, L and Liu, S and Xin, J and Leng, L and Wang, P and Chi, S and Li, Y and Chen, J and Zhang, L and Zhang, J and Ma, Q and Wang, X and Meng, X and Nao, J and Li, X and Lv, Y and Jia, Y and Zhao, Q and Liu, C and Gan, J and Zhu, J and Song, Y and Li, H and Fei, M and Guo, X and Liu, J and Peng, G and Chen, X and Ji, Y},
title = {Lecanemab use in Chinese patients with Alzheimer's disease: a 12-month multicenter real-world study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71702},
doi = {10.1002/alz.71702},
pmid = {42557932},
issn = {1552-5279},
support = {TJYXZDXK-3-014B//Tianjin Key Medical Discipline Construction Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; Female ; Biomarkers/blood ; Male ; Aged ; China ; Treatment Outcome ; Aged, 80 and over ; Amyloid beta-Peptides ; East Asian People ; },
abstract = {INTRODUCTION: We evaluated lecanemab's safety and cognitive outcomes in Chinese patients with Alzheimer's disease (AD) and the utility of blood-based biomarkers (BBMs) for treatment guidance.

METHODS: A multicenter, real-world cohort enrolled 1042 patients receiving lecanemab, with 453, 359, 97 patients followed up at 3, 6, 12 months, respectively. Safety outcomes included amyloid-related imaging abnormalities (ARIA) and infusion-related reactions (IRRs), and the main clinical outcome was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score change.

RESULTS: Of 1,042 patients, ARIA occurred in 7.87%, and IRRs in 16.12%. Discontinuation was 16.51%, mainly due to financial burden. CDR-SB did not change at 12 months overall or in any subgroup. High-accuracy BBMs were the sole AD biomarker assay in 5.28%, with comparable outcomes.

DISCUSSION: Lecanemab exhibited favorable 12-month safety, with no clear evidence of cognitive decline, and BBMs hold potential for treatment guidance. Further studies using a control group are now warranted.},
}

Humans
*Alzheimer Disease/drug therapy/blood/diagnostic imaging
Female
Biomarkers/blood
Male
Aged
China
Treatment Outcome
Aged, 80 and over
Amyloid beta-Peptides
East Asian People

@article {pmid42557952,
year = {2026},
author = {Acharya, A and Thurman, M and Sutar, D and Olasunkanmi, OI and Malik, JR and Dyavar, SR and Végvári, Á and Byrareddy, SN},
title = {In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.},
journal = {Journal of medical virology},
volume = {98},
number = {8},
pages = {e71086},
doi = {10.1002/jmv.71086},
pmid = {42557952},
issn = {1096-9071},
support = {R01DA05284/NH/NIH HHS/United States ; R01DA061678/NH/NIH HHS/United States ; },
mesh = {*Pericytes/virology/metabolism ; *Astrocytes/virology/metabolism ; Humans ; *Signal Transduction ; *HIV Infections/metabolism/complications/virology ; *SARS-CoV-2/physiology ; *Coinfection/virology/metabolism ; *Neurodegenerative Diseases/metabolism/virology ; *COVID-19/metabolism/complications/virology ; Proteomics ; Microglia/virology/metabolism ; Post-Acute COVID-19 Syndrome ; Virus Replication ; Proteome ; },
abstract = {Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.},
}

*Pericytes/virology/metabolism
*Astrocytes/virology/metabolism
Humans
*Signal Transduction
*HIV Infections/metabolism/complications/virology
*SARS-CoV-2/physiology
*Coinfection/virology/metabolism
*Neurodegenerative Diseases/metabolism/virology
*COVID-19/metabolism/complications/virology
Proteomics
Microglia/virology/metabolism
Post-Acute COVID-19 Syndrome
Virus Replication
Proteome

@article {pmid42557955,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Aumont, E and Hosseini, SA and Benedet, AL and Hazrati, LN and Gauthier, S and Zetterberg, H and Vitali, P and Ashton, NJ and Rosa-Neto, P and , },
title = {Predicting continuous amyloid PET levels with CSF and plasma brain-derived p-tau217.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71723},
doi = {10.1002/alz.71723},
pmid = {42557955},
issn = {1552-5279},
support = {//Weston Brain Institute/ ; MOP-11-51-31//Canadian Institutes of Health Research (CIHR)/ ; RFN 152985 159815 162303//Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging (CCNA)/ ; NIRG-12-92090 NIRP-12-259245//the Alzheimer's Association/ ; 34874//the Alzheimer's Association/ ; 33397//the Alzheimer's Association/ ; 2020-VICO-279314//the Fonds de Recherche du Québec - Santé (FRQS); Chercheur Boursier/ ; 2024-VICO-356138//the Fonds de Recherche du Québec - Santé (FRQS); Chercheur Boursier/ ; //the Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; U01 AG024904//Alzheimer's Disease Neuroimaging Initiative (ADNI); National Institutes of Health/ ; //the Fonds de Recherche du Québec - Santé/ ; //Fondation Brain Canada/ ; /ALZ/Alzheimer's Association/United States ; //Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/blood ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; *Brain/metabolism/diagnostic imaging ; Male ; Aged ; Phosphorylation ; },
abstract = {BACKGROUND: Staging amyloid beta (Aβ) burden along a continuous spectrum provides clinically relevant information. Conventional phosphorylated tau (p-tau)217 reliably identifies amyloid positron emission tomography (PET) positivity, but its ability to capture the full Aβ continuum is limited. Recently developed brain-derived (BD) p-tau217 assays enrich for central nervous system tau species and may improve specificity.

METHODS: We tested how closely BD p-tau217 reflected continuous Aβ and how accurately it could classify participants as Aβ positive or negative across different Centiloid (CL) thresholds in 924 participants from the Alzheimer's Disease Neuroimaging Initiative. Conventional and BD cerebrospinal fluid (CSF) and plasma p-tau217 biomarkers were quantified using the Alamar NULISAseq panel.

RESULTS: Across the full cohort, plasma BD p-tau217 demonstrated the strongest continuous association with PET CL (R[2] = 0.63), and the best prediction across the CL spectrum (root mean square error = = 24.5). Prediction was precise in cognitively unimpaired participants at low CL and reasonably accurate in cognitively impaired participants across intermediate-to-high CL.

CONCLUSIONS: Plasma BD p-tau217 best captured the amyloid PET continuum, with BD processing improving discrimination in plasma but not CSF.},
}

Humans
*tau Proteins/cerebrospinal fluid/blood/metabolism
*Positron-Emission Tomography
Biomarkers/cerebrospinal fluid/blood
Female
*Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/blood
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
*Brain/metabolism/diagnostic imaging
Male
Aged
Phosphorylation

@article {pmid42557961,
year = {2026},
author = {Carrigan, M and Birkenbihl, C and Klinger, HM and Langford, O and Coughlan, GT and Seto, M and Brown, JA and Li, A and Cuppels, M and Properzi, M and Chhatwal, J and Price, J and Schultz, A and Rentz, D and Amariglio, R and Krugers, HJ and Ossenkoppele, R and Johnson, K and Sperling, R and Hohman, TJ and Donohue, M and Buckley, RF},
title = {Sex specificity of resistance to caTAUstrophe.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71716},
doi = {10.1002/alz.71716},
pmid = {42557961},
issn = {1552-5279},
support = {WE.08-2024-06//Alzheimer Nederland/ ; WE.03-2021-03//Alzheimer Nederland/ ; K99 AG083063/AG/NIA NIH HHS/United States ; R01AG079142/AG/NIA NIH HHS/United States ; DP2AG082342/AG/NIA NIH HHS/United States ; R01AG073439/AG/NIA NIH HHS/United States ; 949570/ERC_/European Research Council/International ; U24AG074855/AG/NIA NIH HHS/United States ; U01AG082350/AG/NIA NIH HHS/United States ; },
mesh = {Female ; Humans ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Male ; Aged ; *Sex Characteristics ; *Alzheimer Disease/metabolism/pathology ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: As amyloid beta (Aβ) accumulates, tau pathology spreads beyond medial temporal lobe (MTL) into neocortical (NEO) regions, though some older adults resist this progression, or what we call here "caTAUstrophe." Given previous evidence of higher tau levels in women, we tested how tau resistance presented in men and women separately.

METHODS: Employing data from 872 Aβ+ older adults across three cohorts, we trained sex-specific penalized linear regression models in individuals experiencing caTAUstrophe (females: NTrain = 172; males: NTrain = 121) to predict the expected NEO tau levels. We estimate resistance as lower-than-expected NEO tau levels in training-independent individuals (NTest = 579) to assess sex-specific resistance associates.

RESULTS: Relative feature importance in sex-specific expectation models differed in 97.7% of variables (false discovery rate-adjusted p value < 0.001). Age and Aβ burden associated with male resistance, while Clinical Dementia Rating, latent Preclinical Alzheimer's Cognitive Composite, and adjusted hippocampal volume were associates in both sexes.

DISCUSSION: Our study highlights sex-specific biological and clinical factors in the prediction of NEO tau and associates of resistance. Understanding sex-specific resistance pathways informs targeted Alzheimer's interventions.},
}

Female
Humans
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
Male
Aged
*Sex Characteristics
*Alzheimer Disease/metabolism/pathology
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42557982,
year = {2026},
author = {Olayinka, O and Farrell, JJ and Zhu, C and Khurshid, Z and , and Martin, ER and Bush, WS and Pericak-Vance, MA and Wang, LS and Schellenberg, GD and Haines, JL and Lunetta, KL and Zhang, X and Farrer, LA},
title = {Stratification by a polygenic risk score of common variation aids in Alzheimer's disease rare variant discovery.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71710},
doi = {10.1002/alz.71710},
pmid = {42557982},
issn = {1552-5279},
support = {U01 AG024904/NH/NIH HHS/United States ; RF1AG054080/NH/NIH HHS/United States ; U01-AG058654/NH/NIH HHS/United States ; U54-AG052427/NH/NIH HHS/United States ; U19-AG068753/NH/NIH HHS/United States ; U01-AG062602/NH/NIH HHS/United States ; U01-AG 081230/NH/NIH HHS/United States ; U01-AG082665/NH/NIH HHS/United States ; P30-AG072978/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; P01AG026276/NH/NIH HHS/United States ; P30AG066462/NH/NIH HHS/United States ; R01AG064614/NH/NIH HHS/United States ; U01AG052410/NH/NIH HHS/United States ; //Alzheimer's Disease Sequencing Project/ ; //Alzheimer's Disease Genetics Consortium/ ; AG033193/AG/NIA NIH HHS/United States ; AG049607/AG/NIA NIH HHS/United States ; AG033040/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R01AG041797/AG/NIA NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; R01AG15928/AG/NIA NIH HHS/United States ; R01AG20098/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; AI4AD//NIA/ ; //Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)/ ; U01AG057659//Follow Up Study/ ; U01AG062943//Follow Up Study/ ; U54AG052427//Follow Up Study/ ; U01AG058589//Follow Up Study/ ; U01AG058654//Follow Up Study/ ; U01AG058635//Follow Up Study/ ; RF1AG058066//Follow Up Study/ ; RF1AG057519//Follow Up Study/ ; R01AG048927//Follow Up Study/ ; RF1AG054074//Follow Up Study/ ; U01 AG006781//Adult Changes in Thought (ACT)/ ; U19 AG066567//Adult Changes in Thought (ACT)/ ; P30 AG062429//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066468//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062421//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066509//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066514//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066530//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066507//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066444//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066518//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066512//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066462//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072979//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072972//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072976//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072975//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072978//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072977//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066519//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062677//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG079280//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062422//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066511//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072946//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062715//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072973//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066506//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066508//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066515//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072947//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072931//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066546//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068024//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068053//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068077//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068082//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072958//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072959//Alzheimer's Disease Research Centers (ADRC)/ ; R01 AG11101//Alzheimer's Disease Research Centers (ADRC)/ ; RC4 AG039085//Alzheimer's Disease Research Centers (ADRC)/ ; K23 AG030944//Alzheimer's Disease Research Centers (ADRC)/ ; R01 AG019771//Indiana Memory and Aging Study (IMAS)/ ; R01 AG009956//Indiana Memory and Aging Study (IMAS)/ ; P30 AG010133//Indiana Memory and Aging Study (IMAS)/ ; R01 AG032990//Mayo Clinic (MAYO)/ ; U01 AG046139//Mayo Clinic (MAYO)/ ; R01 NS080820//Mayo Clinic (MAYO)/ ; RF1 AG051504//Mayo Clinic (MAYO)/ ; P50 AG016574//Mayo Clinic (MAYO)/ ; NS039764//Mayo Clinic (MAYO)/ ; NS071674//Mayo Clinic (MAYO)/ ; 5RC2HG005605//Mayo Clinic (MAYO)/ ; R01 AG027944//Mayo Clinic (MAYO)/ ; R01 AG028786//Mayo Clinic (MAYO)/ ; R01 AG019085//Mayo Clinic (MAYO)/ ; IIRG09133827//Mayo Clinic (MAYO)/ ; A2011048//Mayo Clinic (MAYO)/ ; R01 AG09029//Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)/ ; R01 AG025259//Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)/ ; U24 AG021886//National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)/ ; U24 AG056270//National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA- LOAD)/ ; //Texas Alzheimer's Research and Care Consortium (TARCC)/ ; //Darrell K Royal Texas Alzheimer's Initiative/ ; R01 AG019757//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG021547//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG027944//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG028786//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; P01 NS026630//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; /ALZ/Alzheimer's Association/United States ; RF1 AG054023//Washington Heights-Inwood Columbia Aging Project (WHICAP)/ ; //University of Washington Families/ ; RF1 AG015473//Columbia University Hispanic Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA)/ ; //University of Toronto (UT)/ ; /WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; /CAPMC/CIHR/Canada ; R01 AG007584//Genetic Differences (GD)/ ; HL105756//National Heart, Lung, and Blood Institute (NHLBI)/ ; RC2HL102419//National Heart, Lung, and Blood Institute (NHLBI)/ ; //CHARGE/ ; //Austrian Stroke Prevention Study (ASPS)/ ; //Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus)/ ; //Atherosclerosis Risk in Communities (ARIC)/ ; //Cardiovascular Health Study (CHS)/ ; //Erasmus Rucphen Family Study (ERF)/ ; //Framingham Heart Study (FHS)/ ; //Rotterdam Study (RS)/ ; //ASPS/ ; P20545-P05//Austrian Science Fond (FWF)/ ; P13180//Austrian Science Fond (FWF)/ ; //Medical University of Graz/ ; //ASPS-Fam/ ; //Austrian Science Fund (FWF)/ ; //Joint Programme - Neurodegenerative Disease Research (JPND)/ ; //BRIDGET/ ; //Austrian Research Promotion agency (FFG)/ ; //Austrian National Bank/ ; N01-HC-25195/HL/NHLBI NIH HHS/United States ; HHSN268201100006C/HL/NHLBI NIH HHS/United States ; HHSN268201100007C/HL/NHLBI NIH HHS/United States ; HHSN268201100008C/HL/NHLBI NIH HHS/United States ; HHSN268201100009C/HL/NHLBI NIH HHS/United States ; HHSN268201100010C/HL/NHLBI NIH HHS/United States ; HHSN268201100011C/HL/NHLBI NIH HHS/United States ; HHSN268201100012C/HL/NHLBI NIH HHS/United States ; U01 2U01HL096812//ARIC/ ; 2U01HL096814//ARIC/ ; 2U01HL096899//ARIC/ ; 2U01HL096902//ARIC/ ; 2U01HL096917//ARIC/ ; R01-HL70825//MRI/ ; HHSN268201200036C//CHS/ ; HHSN268200800007C//CHS/ ; N01HC55222//CHS/ ; N01HC85079//CHS/ ; N01HC85080//CHS/ ; N01HC85081//CHS/ ; N01HC85082//CHS/ ; N01HC85083//CHS/ ; N01HC85086//CHS/ ; U01HL080295//CHS/ ; U01HL130114//CHS/ ; 018947//EUROSPAN (European Special Populations Research Network)/ ; LSHG-CT-2006-01947//EUROSPAN (European Special Populations Research Network)/ ; //European Community's Seventh Framework Programme/ ; //European Commission under the programme/ ; //Erasmus Medical Center and Erasmus University/ ; //Rotterdam, the Netherlands Organization for Health Research and Development/ ; //Research Institute for Diseases in the Elderly (RIDE)/ ; //Ministry of Education, Culture and Science/ ; //Ministry for Health/ ; //Welfare and Sports/ ; //European Commission (DG XII)/ ; //Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)/ ; //Netherlands Consortium for Healthy Aging (NCHA)/ ; R01AG11380//Cache County Study/ ; R01AG031272//Cache County Study/ ; R01AG21136//Cache County Study/ ; RF1AG054052//Cache County Study/ ; P50AG008012//Case Western Reserve University Brain Bank (CWRUBB)/ ; RF1AG058267//Case Western Reserve University Rapid Decline (CWRURD)/ ; NU38CK000480//Case Western Reserve University Rapid Decline (CWRURD)/ ; 3U01AG052410//Cuban American Alzheimer's Disease Initiative (CuAADI)/ ; 5R37AG015473//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; RF1AG015473//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; R56AG051876//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; 2R01AG09029//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; R01AG025259//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; 2R01AG048927//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; U01AG062602//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; 2014-A-004-NET//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG032289//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG048234//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG027944//Hussman Institute for Human Genomics Brain Bank (HIHGBB)/ ; 5R01AG009956//Ibadan Study of Aging (IBADAN)/ ; //Longevity Genes Project (LGP)/ ; R01AG042188//LonGenity/ ; R01AG044829//LonGenity/ ; R01AG046949//LonGenity/ ; R01AG057909//LonGenity/ ; R01AG061155//LonGenity/ ; P30AG038072//LonGenity/ ; R01AG018016//Mexican Health and Aging Study (MHAS)/ ; 2R01AG09029//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; R01AG025259//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; 2R01AG048927//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; R01NS29993//Northern Manhattan Study (NOMAS)/ ; RF1AG054074//Peru Alzheimer's Disease Initiative (PeADI)/ ; GR066133/GR080002//Peru Alzheimer's Disease Initiative (PeADI)/ ; 340755/ERC_/European Research Council/International ; RF1AG054074//Puerto Rican Alzheimer Disease Initiative (PRADI)/ ; U01NS041588//Reasons for Geographic and Racial Differences in Stroke (REGARDS)/ ; U01AG052410//Research in African American Alzheimer Disease Initiative (REAAADI)/ ; P30 AG10161//Religious Orders Study (ROS)/ ; R01 AG15819//Religious Orders Study (ROS)/ ; P30 AG72975//Religious Orders Study (ROS)/ ; R01 AG42210//Religious Orders Study (ROS)/ ; R01 AG017917//RUSH Memory and Aging Project (MAP)/ ; R01 AG060747//RUSH Memory and Aging Project (MAP)/ ; //Miami Brain Endowment Bank (MBB)/ ; U01AG052410//University of Miami/Case Western/North Carolina A&T African American (UM/CASE/NCAT)/ ; R01AG028786//University of Miami/Case Western/North Carolina A&T African American (UM/CASE/NCAT)/ ; R01AG027161//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; R01AG054047//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; R01AG069013//Mexico-Southern California Autosomal Dominant Alzheimer's Disease Consortium/ ; R01AG047649//Center for Cognitive Neuroscience and Aging/ ; R01AG063689//A4 Study/ ; U19AG010483//A4 Study/ ; U24AG057437//A4 Study/ ; //LSACs/ ; U54 HG003273//Human Genome Sequencing Center at the Baylor College of Medicine/ ; U54HG003067//Broad Institute Genome Center/ ; U01AG057659//American Genome Center at the Uniformed Services University of the Health Sciences/ ; U54HG003079//Washington University Genome Institute/ ; //ADSP FUS/ ; //Hussman Institute for Human Genomics (HIHG)/ ; //Center for Genome Technology (CGT)/ ; //National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site/ ; U24AG041689//NIAGADS/ ; /LM/NLM NIH HHS/United States ; //Phenotype Harmonization Consortium/ ; U19AG024904//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; RF1AG058066//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; W81XWH-12-2-0012//Department of Defense/ ; //AbbVie/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir/ ; //Cogstate/ ; //Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc./ ; //NIH/ ; U24AG072122//NACC/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; *Genetic Variation/genetics ; *Multifactorial Inheritance/genetics ; Polymorphism, Single Nucleotide ; Female ; European People ; White People/genetics ; Male ; },
abstract = {INTRODUCTION: We utilized an Alzheimer's disease (AD) polygenic risk score (PRS) to discover associations with novel rare variants (RVs).

METHODS: PRSs for European ancestry (EA) participants of the Alzheimer's Disease Sequencing Project were calculated using summary statistics from a large genome-wide association study. Participants were classified into high (n = 5738) and low (n = 5324) PRS groups based on the median PRS and on the lower and upper 35% of the PRS distribution.

RESULTS: Risk variants were disproportionately enriched in the low-PRS group, while protective ones were disproportionately enriched in the high-PRS group. Genome-wide significant (GWS) associations for increased AD risk were identified with RVs spanning a 3.5-Mb region on chromosome 14. GWS protective variants in ALDH9A1, BICC1, and PAN3 were identified in the upper 35% PRS group.

CONCLUSION: Our findings provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.},
}

Humans
*Alzheimer Disease/genetics
Genetic Risk Score
Genome-Wide Association Study
*Genetic Predisposition to Disease/genetics
*Genetic Variation/genetics
*Multifactorial Inheritance/genetics
Polymorphism, Single Nucleotide
Female
European People
White People/genetics
Male

@article {pmid42558527,
year = {2026},
author = {Li, S and Cao, T and Zhang, Q},
title = {Oxidative stress as a driver of organelle cascade damage in neurological diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1892923},
pmid = {42558527},
issn = {1663-4365},
abstract = {As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.},
}

@article {pmid42558626,
year = {2026},
author = {Chen, J and Zhang, Z},
title = {Advancements in non-pharmaceutical interventions for Alzheimer's disease management: an update review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1855269},
pmid = {42558626},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition that is characterized by an increasing incidence rate due to global population aging, resulting in a significant social and economic burden. Current pharmacological interventions offer only limited relief and are unable to halt neuronal loss and cognitive decline. Therefore, safe and effective non-pharmacological interventions (NPIs) are needed for the management of AD. This review systematically synthesizes literature from the PubMed and Web of Science databases (2020-2025) to evaluate the comparative efficacy of physical activity, dietary interventions, and cognitive stimulation therapy (CST), aiming to establish an evidence-based framework for optimized clinical implementation. Specifically, physical activity (e.g. aerobic exercise and strength training) has been shown to improve cognitive and physical function. Dietary interventions (e.g. the Mediterranean diet, Dietary Approaches to Stop Hypertension and The Mediterranean-DASH diet intervention for neurodegenerative delay diet) have been demonstrated to delay cognitive decline by modulating inflammation, but evidence regarding supplements is weak. Furthermore, CST has been evidenced to enhance patients' cognitive abilities and quality of life. The present review not only summarizes existing literature on the subject, but also explores future research directions, including mechanisms and personalized approaches of these interventions to improve the prognosis of AD patients.},
}

@article {pmid42558652,
year = {2026},
author = {Del Giudice, L and Guida, M and Aletta, MR and Pontieri, P},
title = {Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1882474},
pmid = {42558652},
issn = {1664-2295},
abstract = {Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.},
}

@article {pmid42558846,
year = {2026},
author = {Bhattacharya, A and Manjithaya, R and Chickabasaviah, Y and Alladi, PA},
title = {Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531261462296},
pmid = {42558846},
issn = {0972-7531},
abstract = {BACKGROUND: The brainstem nucleus locus coeruleus (LC) is a rod-shaped, cylindrical, deeply pigmented neuromelanin (NM)-rich cluster of noradrenergic cells placed bilaterally in the dorsolateral tegmentum of the pons. The main neurotransmitter synthesised by these neurons is norepinephrine (NE), which polymerises to NM. Collectively, it regulates a plethora of activities, including vigilance, synaptic plasticity, memory processing, pain, stress responses, selective attention, cognition, sleep, emotion, capillary wall permeability and cerebral blood flow, thereby holding a 'master key' to several processes. Despite being small in dimensions, it is of enormous significance in diverse functions. Degeneration of the LC occurs early and progressively in both Alzheimer's disease (AD) and Parkinson's disease (PD), with diverse impacts, and is linked to neuropsychiatric entities such as depression, anxiety, cognitive impairment, schizophrenia and rapid eye movement sleep disorders, thereby raising considerable interest in normal physiology as well as in disease.

SUMMARY: This review is to better understand the neuroanatomical connections of human LC (master regulator of the central nervous system), pigmentation, cellular types, neurotransmitters/co-transmitters, and its role in ageing and neurodegenerative diseases. Recent and relevant classical research and review articles were referred to from PubMed to prepare a short review of the structure of LC, its projections, NM pigment and neuroprotection. We further examined the details of its cell types, neurotransmitters, co-transmitter functions and its effects in ageing, AD and PD, with emphasis on human studies.

KEY MESSAGE: LC is a vital region that offers neuroprotection, assists in the maintenance of cognitive reserve and enhances resilience and neuronal survival, despite the presence of AD and PD pathology for several decades. Further, it synthesises NE and co-transmitters that regulate attention, sleep-wake cycle, mood, cognition and so on. Maintaining its integrity and function promises potential scope to promote its health with normal ageing and improve clinical strategies in patients with neurodegeneration.},
}

@article {pmid42558896,
year = {2026},
author = {Neal, V and Faria, AV and Zhang, W and Hillis, AE and Stockbridge, MD},
title = {Right hemisphere atrophy rate associates with naming recovery after left hemisphere ischaemic stroke.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag291},
pmid = {42558896},
issn = {2632-1297},
abstract = {Numerous large-scale epidemiological studies investigating the trajectory of brain function after ischaemic stroke have presented data suggesting, on average, a persistent, accelerated decline in cognitive domains, including language, after accounting for the immediate impact of the stroke. We sought to further examine this trend, speculating that the average persistent decline may be a reflection of two subgroups with vastly different prognoses: (i) a minority experiencing decline secondary to neurodegenerative processes such as vascular dementia and Alzheimer's disease and (ii) a majority without marked progressive brain atrophy who typically see improvement. Our team thus investigated atrophy's association with language recovery, hypothesizing that declining naming performance in the year after left hemisphere ischaemic stroke would be correlated to atrophy of the contralesional hemisphere. We postulated that volume loss within the lesioned hemisphere would be less informative due to separate confounding processes related to the stroke itself, such as Wallerian degeneration and encephalomalacia. Participants [n = 72; M (SD) age = 60 (11)] in a longitudinal cohort study of language following left hemisphere ischaemic stroke were included if they completed an MRI both acutely and chronically (either 6 or 12 months post-stroke). Naming performance was assessed using the Boston Naming Test; stroke volumes were extracted from acute imaging; and atrophy was measured as the monthly per cent change in hemispheric volume from baseline to chronic scan for each individual. Pearson's correlations were calculated to determine the relationship between lesion volume and atrophy along with atrophy and change in Boston Naming Test score. Lesion volume negatively correlated with the monthly per cent change in volume of the left (ipsilesional) hemisphere (r = -0.48; P < 0.0001) but did not correlate with rate of right (contralesional) hemisphere volume loss. While there was no clear relationship between atrophy of the left hemisphere and language recovery, we found that volume changes of greater negative magnitude within the right hemisphere (increased atrophy) were associated with worse functional recovery of language (r = 0.38; P = 0.0025). By showing that atrophy of the right hemisphere was not significantly impacted by left hemisphere lesion size, we suggest that accelerated volume loss in the non-lesioned hemisphere after stroke may be indicative of a separate pathology. We then support this claim with behavioural data showing that greater rates of volume loss within the non-lesioned hemisphere were associated with poorer naming recovery. Together, these findings imply that contralesional atrophy after stroke may have negative implications for recovery and could serve as a useful imaging signature for separate neurodegenerative processes.},
}

@article {pmid42558962,
year = {2026},
author = {Corley, DA and Alavi, M and Fireman, BH and Finch, T and Prausnitz, S and Rouillard, S and Lee, K and Hamilton, L and Ansari, M},
title = {Associations of multiple evidence-based care strategies with disease mortality, life expectancy, and disparities in the United States.},
journal = {Health affairs scholar},
volume = {4},
number = {8},
pages = {qxag184},
pmid = {42558962},
issn = {2976-5390},
abstract = {INTRODUCTION: Limited data exist regarding the potential cumulative effects of multiple, integrated, system-level strategies on population-level outcomes and disparities.

METHODS: We evaluated associations between membership within a multi-disease, integrated population health management model with disease-specific mortality, life expectancy, and demographic disparities and relevant comparators. Bias was minimized through use of a large, representative, multicenter community-based setting, multiple comparators (including similar insured status, same-state, comparable comorbidity distributions, and national), demographic adjustments, and causality criteria.

RESULTS: Among 3 944 173 persons demographics-adjusted mortality was significantly lower for 9 of 10 leading causes of death, including the 5 leading preventable conditions (age-, sex-, race-adjusted risk ratios and 95% CIs Kaiser Permanente, Northern California vs United States [US, all])-cancer (0.85; 0.83-0.88), heart disease (0.69; 0.67-0.71), stroke (0.86; 0.82, 0.91), injury (majority overdoses and falls; 0.45; 0.42-0.48), and respiratory disease (0.59; 0.55-0.63)-but not unmodifiable causes (eg, Alzheimer's disease (1.58; 1.51-1.66). Most life-years gained occurred during ages most impacted by disease-management programs: 50-72 years (>0.075 life-year/year). Life expectancy exceeded comparators and was 4.9 years higher than the US average (83.3 vs 78.4 years, 2023). Findings were robust to index years, multiple other comparator populations, and adjusted analyses. Demographic disparities were smaller across major benchmarks.

CONCLUSION: These findings suggest that high uptake of multiple, existing, evidence-based population health strategies may be cumulatively associated with substantially reduced disease-specific mortality, decreased disparities, and increased life expectancy, comparable to values in comparator countries.},
}

@article {pmid42559122,
year = {2026},
author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J},
title = {Multi-organ AI endophenotypes chart the heterogeneity of brain, eye and heart pan-disease.},
journal = {Nature. Mental health},
volume = {4},
number = {2},
pages = {203-230},
pmid = {42559122},
issn = {2731-6076},
abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions. Inspired by pan-cancer and multi-organ research, we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data, curated from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers, called Multi-organ AI Endophenotypes (MAEs), for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.},
}

@article {pmid42559376,
year = {2026},
author = {Niu, S and Liu, X and Xu, R and Zhu, A and Zhu, S and Hu, F and Ding, K and Li, S and Zhu, B and Liang, P and Zhang, S and Xiao, A and Fan, K and Zhang, Z},
title = {Multifunctional nanozyme platforms in central nervous system therapies: from rational design to translational medicine.},
journal = {Theranostics},
volume = {16},
number = {14},
pages = {8385-8426},
pmid = {42559376},
issn = {1838-7640},
mesh = {Humans ; *Central Nervous System Diseases/drug therapy/therapy ; Animals ; *Nanostructures/chemistry/therapeutic use ; Translational Research, Biomedical/methods ; Drug Delivery Systems/methods ; Neuroprotective Agents ; *Enzymes ; },
abstract = {Central nervous system (CNS) disorders-including ischemic stroke, traumatic brain/spinal cord injury, Parkinson's disease, and Alzheimer's disease-have long faced limitations in achieving functional recovery and disease-modifying therapies because of their complex pathophysiological mechanisms. Traditional therapies are often constrained by poor penetration across CNS barriers, limited participation in multiple pathological cascades, and insufficient persistence of therapeutic effects. Nanozymes are a class of nanomaterials with enzyme-like catalytic activity and tunable physicochemical properties. Not only do these nanozymes continuously scavenge reactive oxygen and nitrogen species in pathological environments through stable multi-enzyme synergistic effects by leveraging their abundant active sites, but also serve as multimodal therapeutic delivery platforms to achieve efficient drug delivery, opening up new avenues for neuroprotection and regenerative medicine. This review systematically examines the fundamental characteristics, classification systems, and functional design approaches of nanozymes, along with their potential for combined therapeutic strategies, including synergistic applications with drugs, hydrogels, genes, or cells. Additionally, it summarizes the latest advancements in neuroprotection and repair associated with CNS disorders. The review further analyzes current limitations and challenges related to clinical translation and offers insights into future research directions to enhance scientific knowledge and clinical applications in this significant field.},
}

Humans
*Central Nervous System Diseases/drug therapy/therapy
Animals
*Nanostructures/chemistry/therapeutic use
Translational Research, Biomedical/methods
Drug Delivery Systems/methods
Neuroprotective Agents
*Enzymes

@article {pmid42559503,
year = {2026},
author = {Acevedo-Nieto, J and Martínez, K and Amaya, C},
title = {The Role of Slow Gait Speed in Cognitive Decline among Aging Women: A Systematic Review.},
journal = {HSOA journal of gerontology & geriatric medicine},
volume = {12},
number = {1},
pages = {},
pmid = {42559503},
issn = {2381-8662},
abstract = {UNLABELLED: The prevalence of Alzheimer's disease and related dementias are increasing at an alarming rate, with projections estimating that by 2060, approximately 13.8 million adults aged 65 years and older in the U.S. will be affected by one or both. Among the many symptoms associated with cognitive decline, gait impairment is one that significantly affects functional independence and mobility.

METHODS: A systematic review was conducted to analyze 49 peer-reviewed studies using the Covidence systematic review software and adhering to PRISMA guidelines. The selected articles examined variables related to gait speed, and cognition. Participants were assessed through validated neurocognitive and mobility measures, including the MoCA and Dynamic Gait Index.

RESULTS: A significant negative correlation was identified between usual walking speed and age. This trend was particularly pronounced in women, in whom a significant negative association between MoCA scores and age (P = -0.019) was observed, suggesting an increased susceptibility to cognitive deterioration with advancing age.

CONCLUSION: These findings underline the sex-specific nature of the relationship between gait speed and cognitive function, highlighting increased vulnerability in aging women. The decline in mobility and cognition observed in this population underscores the urgency of developing targeted interventions that integrate physical and cognitive rehabilitation strategies.},
}

@article {pmid42559518,
year = {2026},
author = {Uppalapati, A and Vishnubhotla, A and Pahan, K},
title = {Prospect of Muscle-Building Supplement HMB in Alzheimer's Disease.},
journal = {Journal of clinical & experimental immunology},
volume = {11},
number = {3},
pages = {},
pmid = {42559518},
abstract = {Alzheimer's disease (AD) is the most common progressive and irreversible neurodegenerative disorder in humans that affects memory, thinking and behavior. Impairment in synaptic plasticity is one of the hallmarks in AD, with most of the impairment occurring in the hippocampal region, a key part of the brain for memory and learning. Therefore, the upregulation of hippocampal plasticity is critical to remediate the progression of AD and preserve memory formation and cognitive functions. Recent studies have described β-hydroxy-β-methylbutyrate (HMB), a body building supplement commonly used by athletes, as a candidate molecule for improving hippocampal plasticity. Clinically, AD is characterized by the abnormal accumulation of beta amyloid (Aβ) plaques, coupled with intracellular aggregates of hyperphosphorylated tau protein. In addition to enhancing hippocampal plasticity, HMB has been also demonstrated to lower amyloid plaques in a mouse model of AD. Although liver is rich in peroxisome proliferator-activated receptor alpha (PPARα), recent findings have established the presence of PPARα in hippocampus and other parts of the brain. Interestingly, HMB has been shown to utilize PPARα for lowering plaques and increasing hippocampal plasticity. Here, we discuss these newly described features of HMB with possible implications for the use of HMB supplement in patients with dementia and AD.},
}

@article {pmid42559821,
year = {2026},
author = {Moradi, K and Hadidchi, R and Majbri, A and Hughes, TM and Lu, H and Zhu, Y and Mohammadi, S and Momtazmanesh, S and Mukherjee, P and Abdullah, M and Simonsick, E and Schrack, JA and Goncalves, MD and Coresh, J and Albert, M and Demehri, S},
title = {Temporalis muscle biomarkers from routine brain MRI and risk of dementia in two independent cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71622},
doi = {10.1002/alz.71622},
pmid = {42559821},
issn = {1552-5279},
support = {//National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ ; R01AR079620//National Institutes of Health (NIH)/ ; W81XWH-12-2-0012//DOD ADNI/ ; U01HL096812//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096899//ARIC Neurocognitive Study/ ; U01HL096902//ARIC Neurocognitive Study/ ; U01HL096917//ARIC Neurocognitive Study/ ; U01AG024904/AG/NIA NIH HHS/United States ; R01AR079620/AR/NIAMS NIH HHS/United States ; },
mesh = {Humans ; *Magnetic Resonance Imaging ; Female ; *Dementia/diagnostic imaging ; Male ; *Brain/diagnostic imaging ; Biomarkers ; Aged ; Cohort Studies ; *Muscle, Skeletal/diagnostic imaging/pathology ; Neuroimaging ; Alzheimer Disease/diagnostic imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Skeletal muscle loss is associated with cognitive decline, but whether neuroimaging-derived muscle characteristics predict incident dementia remains unclear.

METHODS: We evaluated associations of deep learning-derived temporalis muscle (TM) cross-sectional area (CSA) and radiomic texture features from baseline T1-weighted magnetic resonance imaging (MRI) with incident dementia in dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 750) and the Atherosclerosis Risk in Communities (ARIC) study (n = 532). TM was segmented using a convolutional neural network trained in ADNI and externally validated in ARIC. Radiomic features were reduced using least absolute shrinkage and selection operator-penalized Cox models to generate a composite score. Multivariable Cox regression adjusted for demographics, apolipoprotein E ε4, baseline cognition, body mass index, and physical performance.

RESULTS: Higher TM radiomic scores were associated with increased dementia risk in ADNI (hazard ratio per SD, 1.32) and ARIC (1.64). Smaller TM CSA predicted dementia in ADNI but not ARIC.

DISCUSSION: TM texture patterns from routine brain MRI are associated with dementia risk, supporting TM phenotyping as a scalable marker of systemic biological vulnerability.},
}

Humans
*Magnetic Resonance Imaging
Female
*Dementia/diagnostic imaging
Male
*Brain/diagnostic imaging
Biomarkers
Aged
Cohort Studies
*Muscle, Skeletal/diagnostic imaging/pathology
Neuroimaging
Alzheimer Disease/diagnostic imaging
Aged, 80 and over

@article {pmid42560011,
year = {2026},
author = {Abrar, F and Martin, DDO},
title = {Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/15548627.2026.2711593},
pmid = {42560011},
issn = {1554-8635},
abstract = {SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.},
}