@article {pmid42680483,
year = {2026},
author = {Kim, SH and Lee, SK},
title = {Lithium: the protective cation singled out by Alzheimer's disease.},
journal = {BMB reports},
volume = {59},
number = {10},
pages = {456-465},
pmid = {42680483},
issn = {1976-670X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Lithium/pharmacology/therapeutic use/metabolism ; Animals ; Glycogen Synthase Kinase 3 beta/metabolism ; Lithium Compounds/pharmacology/therapeutic use ; Phosphoric Monoester Hydrolases/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Lithium is a mood stabilizer that is most prescribed in psychiatry for managing mental disorders. Many findings indicate that lithium is also neuroprotective in various neurodegenerative diseases. In particular, lithium has been of great interest as an affordable but still effective treatment for Alzheimer's disease (AD), due to its diverse neuroprotective actions and mechanistic overlap with key AD pathways, such as A(?) production and tau modification. While the multifaceted activities may result from lithium's inhibitory action on two key enzymes, glycogen synthase kinase-3 beta (GSK-3(?)) and inositol monophosphatase (IMPase), recent findings suggest that selective lithium depletion in neurons mediated by amyloid deposits may be a key pathological trigger in AD and supplementation with lithium orotate, a lithium salt with reduced amyloid binding, may even reverse brain damage and prevent cognitive decline. In this study, we review the neuroprotective properties of lithium, its known mechanisms of action, and discuss its therapeutic potential in AD, a topic that has been debated for decades. [BMB Reports 2026; 59(10): 456-465].},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Lithium/pharmacology/therapeutic use/metabolism
Animals
Glycogen Synthase Kinase 3 beta/metabolism
Lithium Compounds/pharmacology/therapeutic use
Phosphoric Monoester Hydrolases/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42946777,
year = {2026},
author = {Fan, X and Truong, JB and Okada, K and Lin, H and Ori-McKenney, KM and McKenney, RJ},
title = {A pathological phosphorylation pattern enhances tau cooperativity on microtubules and facilitates tau filament assembly.},
journal = {Communications biology},
volume = {9},
number = {1},
pages = {},
pmid = {42946777},
issn = {2399-3642},
support = {25PRE1362890//American Heart Association (American Heart Association, Inc.)/ ; P30AG072972//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {*tau Proteins/metabolism ; Phosphorylation ; *Microtubules/metabolism ; *Neurofibrillary Tangles/metabolism ; Animals ; Humans ; Protein Binding ; },
abstract = {Phosphorylation of the microtubule-associated protein tau plays important roles in both normal physiology and disease. While tau phosphorylation levels are similarly elevated in processes such as fetal development and hibernation and in pathological states like Alzheimer's disease, the pattern of phosphorylation differs between these contexts. Whether distinct phosphorylation patterns differentially impact tau's function on microtubules and its propensity to form neurofibrillary tangles (NFTs) has remained unclear. Here we investigated how differential phosphorylation affects microtubule binding, cooperative tau envelope formation, and NFT-relevant filament assembly. Consistent with prior work, phosphorylation decreases tau's overall microtubule affinity. However, we find that phosphorylation more dramatically impacts cooperativity between tau molecules during envelope formation. Strikingly, the specific pattern of phosphorylation, rather than overall level, strongly promotes tau filament assembly in vitro. These findings provide insights into how tau phosphorylation modulates its physiological microtubule interactions and its pathoconversion into NFTs.},
}

*tau Proteins/metabolism
Phosphorylation
*Microtubules/metabolism
*Neurofibrillary Tangles/metabolism
Animals
Humans
Protein Binding

@article {pmid42946784,
year = {2026},
author = {Tong, J and Li, L and Zhang, D and O'Brien, KS and Lu, Y and Wu, Q and Zhou, T and Zhang, B and Lei, Y and Tang, H and Jing, N and Li, H and Xu, Z and Huang, Y and Hu, Y and Zhou, Y and Lin, F and Jiang, Y and Chu, H and Chen, Y and Wang, F and Bian, J and Xu, H and Wolk, DA and Chen, Y},
title = {FLAT-WHITE: from target trial emulation to federated high-throughput causal machine learning using decentralized real-world data.},
journal = {npj health systems},
volume = {3},
number = {1},
pages = {},
pmid = {42946784},
issn = {3005-1959},
support = {U01TR003709, U24MH136069, U24AG098157, RF1AG077820, R01AG073435, R01LM013519, 1R01LM014344, R01DK128237, R21AI167418, R21EY034179/NH/NIH HHS/United States ; },
abstract = {Randomized clinical trials remain the gold standard for evaluating treatment effects but are often infeasible for rapidly assessing drug repurposing opportunities, particularly in complex conditions such as Alzheimer's disease. Target trial emulation (TTE) provides a principled framework for causal inference with electronic health records and, when coupled with modern machine learning, enables scalable analyses across distributed health systems. We present FLAT-WHITE (Federated Lossless Algorithm for Target Trial Emulation with Overlap Weighting for Healthcare Data Integration via Trusted and Efficient Communication), a novel federated causal machine learning pipeline for high-throughput treatment effect estimation without sharing patient-level data. FLAT-WHITE is a one-shot, lossless algorithm, requiring a single communication round while achieving results equivalent to centralized pooled analyses. With overlap weighting on the propensity score, it robustly addresses heterogeneity in treatment assignment and ensures valid causal inference in decentralized settings. We demonstrate FLAT-WHITE in a Alzheimer's drug repurposing study, scanning 181 candidate drugs using data from four health learning systems encompassing approximately 150,000 patients with mild cognitive impairment. Findings were validated externally in 339,180 patients from the TriNetX global research network. FLAT-WHITE enables rapid, large-scale, and secure evaluation of treatment effects and establishes a foundation for collaborative clinical research across diverse healthcare systems.},
}

@article {pmid42946892,
year = {2026},
author = {Creecy, A and Waning, DL and Khurram, I and Warsame, A and Blosser, RJ and Karnik, SJ and Xu, J and Yamada, C and Smith, DK and Oblak, AL and Fehrenbacher, JC and Movila, A and Kacena, MA and Huot, JR},
title = {Characterization of sex-dependent skeletal muscle alterations in the 3xTg Alzheimer's disease mouse model.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42946892},
issn = {2509-2723},
support = {R01AG064003/AG/NIA NIH HHS/United States ; K022AG068595/AG/NIA NIH HHS/United States ; R37CA299888//Basic Research Laboratory/ ; RSG-24-1258280-01-CDP//American Cancer Society/ ; HF-GRO-23-1199172-46//Hevolution/ ; RX004809//U.S. Department of Veterans Affairs/ ; 1I21BX006307//U.S. Department of Veterans Affairs/ ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic condition with effects beyond the central nervous system. Skeletal muscle dysfunction, including sarcopenia and reduced physical performance, is prevalent in AD patients, yet the underlying mechanisms remain poorly understood. In this study, we characterized skeletal muscle alterations in male and female 3xTg-AD mice at 3, 6, and 12 months of age and compared them to age- and sex-matched B6129 controls. We measured body composition, muscle function, and skeletal muscle parameters including fiber type distribution, cross-sectional area (CSA), and neural cell adhesion molecule (NCAM) expression. Our findings revealed early-onset and progressive impairments of skeletal muscle mass, morphology, and function in 3xTg-AD mice, with sex-specific differences. Male mice exhibited reduced lean mass, muscle weight, and torque generation as early as 3 months and decreased CSA of type IIB and IIX fibers and increased NCAM expression by 12 months, indicating a potential neuromuscular junction deficiency. Female mice in this study generally exhibited a milder phenotype. Together, these results identify skeletal muscle dysfunction as an early and sex-dependent feature of AD pathology in 3xTg-AD mice. Our study underscores the importance of considering systemic effects in AD and highlights skeletal muscle as a potential target for therapeutic intervention aimed at preserving mobility and quality of life in affected individuals.},
}

@article {pmid42946915,
year = {2026},
author = {Challapalli, SSA and Bhattarai, KM and Kamangar, FA and , },
title = {UNICAL: Uncertainty-Aware Multimodal Learning with MRI-Derived Synthetic Amyloid PET for Alzheimer's Disease Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02442-9},
pmid = {42946915},
issn = {2948-2933},
abstract = {Limited availability of amyloid positron emission tomography (PET) motivates imaging-informatics methods that derive complementary molecular-imaging representations from routinely acquired magnetic resonance imaging (MRI). We developed UNICAL, an uncertainty-aware multimodal framework for Alzheimer's disease-spectrum versus cognitively normal classification that combines a self-supervised three-dimensional MRI encoder, Contourlet Wavelet Stationary Radiomics (CoWS-Rad) engineered MRI features, and MRI-derived synthetic 18F-florbetapir (AV45) PET. CoCoLIT generated four stochastic PET realizations per MRI; their mean and voxelwise variance were used for uncertainty gating before probability-anchored transformer fusion. Synthetic PET was validated in 228 paired OASIS-3 MRI-AV45 examinations, achieving a mean per-examination voxelwise Pearson correlation of r = 0.864 and strong cortical-composite SUVR agreement with acquired PET (Pearson r = 0.954). In the OASIS-3 development cohort (813 sessions from 811 participants), participant-grouped five-fold cross-validation repeated across 20 seeds yielded AUROC 0.868 and expected calibration error (ECE) 0.061. The OASIS-3 development endpoint used the manuscript's AD-spectrum reference standard, whereas ADNI3 used AD-versus-CN research-group labels, providing cross-dataset evaluation on a related but non-identical prediction endpoint. Without retraining, feature refitting, threshold optimization, or recalibration, the frozen framework was evaluated in an independent matched ADNI3 cohort of 261 participants (87 AD, 174 CN), achieving AUROC 0.836 (95% CI 0.791-0.876). ECE increased to 0.089 under external transfer, indicating that calibration was more sensitive to domain shift than rank discrimination. Ablation analysis and K-sample sensitivity supported the contributions of uncertainty gating, adaptive weighting, modality dropout, residual correction, and the K = 4 synthesis configuration. UNICAL therefore provides an uncertainty-aware MRI-derived multimodal representation for AD-spectrum classification that retains substantial cross-dataset discrimination while remaining distinct from acquired molecular imaging and not replacing amyloid PET as a clinical biomarker.},
}

@article {pmid42947097,
year = {2026},
author = {Wang, JY and Ansorge, O},
title = {Menopause and Alzheimer's disease: can hormone replacement therapy modify the risk? A narrative review.},
journal = {BMC women's health},
volume = {26},
number = {1},
pages = {},
pmid = {42947097},
issn = {1472-6874},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; Female ; *Menopause ; Risk Factors ; *Hormone Replacement Therapy/adverse effects ; *Estrogen Replacement Therapy ; Women's Health ; },
abstract = {Alzheimer's Disease (AD) prevalence and lifetime risk are higher in women than men. This led to the hypothesis that menopause, with its associated changes in female hormone homoeostasis, may be an AD risk factor modifiable by hormone replacement therapy (HRT). However, HRT is not without its risks to women's health, and any recommendations must rest on sound evidence. Here, we critically review data concerning sex-specific epidemiological and biological parameters that may influence AD development. Recent epidemiological studies suggest that the age-adjusted incidence of AD is not higher in women than men. Whilst there is mechanistic experimental evidence that female sex hormones modulate the metabolism of β-amyloid and tau, the neuropathological hallmarks of AD, no clear conclusions can be drawn from studies conducted in humans. Exposure to HRT may modify the development of AD; however, data are weak and the influence of timing, duration, type of HRT, and ethnic, socioeconomic, educational and genomic factors such as APOE genotype, requires further clarification. Large prospective biobank studies in diverse populations, with long follow-up periods and application of biological consensus criteria for the diagnosis of AD provide opportunities to conclusively clarify the relationship between menopause, HRT therapy and risk for the development of AD. Based on current evidence, HRT cannot be recommended as a generic intervention for the reduction of AD risk in women. Any decision to take HRT must consider the individual circumstances and overall health of a woman.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
Female
*Menopause
Risk Factors
*Hormone Replacement Therapy/adverse effects
*Estrogen Replacement Therapy
Women's Health

@article {pmid42947146,
year = {2026},
author = {Zhang, S and Wang, Q},
title = {Astrocytes and memory: emerging evidence and a paradigm shift.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {},
pmid = {42947146},
issn = {1478-811X},
mesh = {*Astrocytes/metabolism/cytology ; Humans ; Animals ; *Memory/physiology ; },
abstract = {In recent years, with the discovery of astrocytes as components of the tripartite synapse and the development of tools for manipulating astrocyte calcium events, learning and memory are no longer considered the exclusive domain of neurons; activation of astrocytes alone can also trigger memory recall. The mnemonic functions of astrocytes have now been demonstrated in the hippocampus, nucleus accumbens, and amygdala, and are mainly manifested during the memory retrieval phase. On the other hand, cooperation between astrocyte-derived gliotransmitters and memory engram neurons is crucial for the formation and consolidation of both short-term and long-term memory. For example, activation of astrocytic calcium signaling and stimulation by endocannabinoids can induce the release of D-serine, ATP/adenosine, and glutamate, which act on GPCR and thereby influence LTD or LTP. Among these molecules, lactate can also function as a signaling molecule to activate downstream memory processes, potentially involving D-serine- and NMDAR-mediated synaptic plasticity. Similarly, α1, α2, and β-adrenergic receptors, which are predominantly expressed in astrocytes, participate in memory in distinct ways across different brain regions. In addition, this review discusses the mechanisms by which astrocytes, as a medium for memory storage, participate in Alzheimer's disease, addictive behaviors, sleep disorders, depression, and post-traumatic stress disorder, as well as their therapeutic potential. Finally, this review systematically details the challenges and future directions in elucidating the mechanisms by which astrocytes store and process memory at the current stage, which may facilitate the development of novel astrocyte-targeted therapies for cognition-related disorders.},
}

*Astrocytes/metabolism/cytology
Humans
Animals
*Memory/physiology

@article {pmid42947225,
year = {2026},
author = {Beament, M and Wiltshire, K and Belder, CRS and Abel, E and Hart, M and Heslegrave, AJ and Lunn, MP and Rosa-Grilo, M and Swann, O and Schott, JM and Zetterberg, H and Fox, NC and Keshavan, A},
title = {Short-interval variability and test-retest reliability of Alzheimer's disease plasma biomarkers in a clinically heterogenous cohort.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42947225},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Female ; Reproducibility of Results ; Male ; tau Proteins/blood ; Aged ; Amyloid beta-Peptides/blood ; Cohort Studies ; Aged, 80 and over ; Peptide Fragments/blood ; Glial Fibrillary Acidic Protein/blood ; },
abstract = {BACKGROUND: Assessment of short-term within-subject variability and test-retest reliability of Alzheimer's disease (AD)-related plasma biomarkers is important for real-world clinical implementation and interpretation in research studies. In this study we aimed to assess short-term variability and reliability of core AD plasma biomarkers, proposed ratios, and evaluate a broader proteomic panel.

METHODS: Two serial plasma samples were collected from each of the 92 participants enrolled in observational research studies over intervals ranging from 30 minutes to three months. Test-retest reliability and within-subject variability were assessed for 131 biomarkers measured on three immunoassays (Lumipulse G plasma p-tau217; Fujirebio, NULISAseq CNS Disease Panel and NULISAqpcr AD 5-Plex; Alamar Biosciences). We subsequently evaluated the stability of a dual cut-point approach for AD probability diagnostic categorisation and examined whether within-subject variability was associated with inter-sample interval (time between serial blood sampling).

RESULTS: All core AD plasma biomarkers assessed in this study (Aβ42, BD-p-tau181, BD-p-tau217, BD-p-tau231, p-tau181, p-tau217, p-tau231, GFAP and NfL) demonstrated strong correlations (r ≥ 0.79) and high reliability (ICC ≥ 0.84). Within-subject variability was moderate to low for core AD plasma biomarkers. Using a validated dual cut-point approach for plasma p-tau217, most individuals (92%) remained within the same diagnostic category (high/indeterminate/low) across both timepoints, and no individual moved across two boundaries (i.e. from high to low AD probability categorisation or vice versa). For the majority of analytes, within-subject variability was not associated with inter-sample interval after adjustment for age and sex, however, the core AD plasma biomarker, NfL did have a significant association.

CONCLUSIONS: While core AD plasma biomarkers had limited variability and high reliability over short-intervals, other central nervous system (CNS)-relevant biomarkers showed greater variability, which may be relevant for interpretation in association studies and clinical applications.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Female
Reproducibility of Results
Male
tau Proteins/blood
Aged
Amyloid beta-Peptides/blood
Cohort Studies
Aged, 80 and over
Peptide Fragments/blood
Glial Fibrillary Acidic Protein/blood

@article {pmid42947251,
year = {2026},
author = {Peter, DC and McLachlan, M and DiFilippo, AH and Yang, KL and Pasquesi, ME and Barnhart, TE and Engle, JW and Betthauser, TJ and Asthana, S and Johnson, SC and Christian, BT and Bendlin, BB and Otto, M and Oeckl, P},
title = {Plasma β-synuclein associates with hippocampal synaptic density measured with [[11]C]UCB-J PET and plasma tau markers in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71900},
pmid = {42947251},
issn = {1552-5279},
support = {R01 AG062285/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; R01 AG021155/AG/NIA NIH HHS/United States ; F31 AG087651/AG/NIA NIH HHS/United States ; 24-SGP-691 23-PPG-674-2//ALS Association/ALS Finding A Cure/ ; //EU Horizon Europe/ ; //Horizon Europe (EU)/ ; //DZNE Innovation-to-Application/ ; //Cure Alzheimer's Fund/ ; D.7090//Fondation Charcot/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; Positron-Emission Tomography ; Female ; Male ; *tau Proteins/blood ; Aged ; Biomarkers/blood ; *Hippocampus/diagnostic imaging/pathology/metabolism ; *Synapses/pathology/metabolism ; Middle Aged ; *beta-Synuclein/blood ; Glial Fibrillary Acidic Protein/blood ; Neuropsychological Tests ; Cognitive Dysfunction/blood/diagnostic imaging ; Carbon Radioisotopes ; Pyridines ; },
abstract = {INTRODUCTION: Plasma β-synuclein is a promising blood-based synaptic biomarker, but relationships with synaptic density as indicated by [[11]C]UCB-J positron emission tomography (PET), and blood biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and astrocyte activation need further characterization.

METHODS: Middle-aged and older adults with and without cognitive impairment (N = 83 total, 68.7% cognitively unimpaired) underwent blood draw, PET imaging, and neuropsychological testing. Primary analyses focused on relationships between plasma β-synuclein and synaptic density, and associations with related plasma biomarkers (tau phosphorylated at threonine 217 [p-tau217], brain-derived tau [BD-tau], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]).

RESULTS: Plasma β-synuclein levels were higher in cognitively unimpaired and impaired participants with positive amyloid PET. Synaptic density was lower in cognitively impaired participants only. In the full sample, higher plasma β-synuclein levels associated with lower synaptic density in the hippocampus, higher concentrations of plasma tau markers, and higher plasma GFAP.

DISCUSSION: This work further supports utilization of plasma β-synuclein to track synaptic degeneration in AD.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/pathology
Positron-Emission Tomography
Female
Male
*tau Proteins/blood
Aged
Biomarkers/blood
*Hippocampus/diagnostic imaging/pathology/metabolism
*Synapses/pathology/metabolism
Middle Aged
*beta-Synuclein/blood
Glial Fibrillary Acidic Protein/blood
Neuropsychological Tests
Cognitive Dysfunction/blood/diagnostic imaging
Carbon Radioisotopes
Pyridines

@article {pmid42947268,
year = {2026},
author = {Zhao, X and Xu, M and Chen, H and Lei, Z and Yu, Q and Liu, J and Liao, W},
title = {Cost-effectiveness of lecanemab for early Alzheimer's disease in China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71941},
pmid = {42947268},
issn = {1552-5279},
support = {82371186//National Natural Science Foundation of China/ ; //National Key Clinical Specialty (Neurology)/ ; //Key Medical Discipline of Guangzhou (2025-2027)/ ; //Clinical Key Specialties (Clinical Medical Research) of Guangzhou/ ; 2024312093//University Scientific Research Project of Guangzhou Municipal Education Bureau/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; *Cost-Benefit Analysis ; China ; *Cost-Effectiveness Analysis ; Markov Chains ; Female ; Quality-Adjusted Life Years ; Male ; Aged ; },
abstract = {BACKGROUND: Although lecanemab has demonstrated clinical efficacy in early Alzheimer's disease (AD), its cost-effectiveness in China remains uncertain. This study evaluated the long-term cost-effectiveness of lecanemab in Chinese patients from a societal perspective and estimated its value-based price (VBP).

METHODS: A Markov state transition model based on Chinese real-world data was developed to compare the long-term health progression and economic outcomes of lecanemab combined with standard of care (SoC) versus SoC alone.

RESULTS: Compared to SoC alone, the lecanemab combination therapy gained an additional 1.2432 Quality-adjusted life years (QALYs) at an incremental cost of 463,228 Chinese yuan (CNY), resulting in an incremental cost-effectiveness ratio (ICER) of 372,609 CNY/QALY (≈ 52,783 USD/QALY). To achieve cost-effectiveness within the willingness-to-pay threshold, the price of a single vial of lecanemab must be reduced by at least 18.0%.

DISCUSSION: Lecanemab can provide health benefits to Chinese patients with early AD, but it is not cost-effective under the current pricing system.},
}

Humans
*Alzheimer Disease/drug therapy/economics
*Cost-Benefit Analysis
China
*Cost-Effectiveness Analysis
Markov Chains
Female
Quality-Adjusted Life Years
Male
Aged

@article {pmid42947278,
year = {2026},
author = {Wu, W and Liu, H and Liang, Y and Li, H and Zhang, J and Sun, Z and Song, Y and Fei, M and Wu, H and Jiang, M and Fan, S and Zhou, C and Cao, Y and Chen, H and Liu, S},
title = {Caregiver positivity as a psychosocial modifier of lecanemab-related outcomes in Alzheimer's disease: A multicenter longitudinal study in China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71894},
pmid = {42947278},
issn = {1552-5279},
support = {2025017//Tianjin Scientific Research Projects in Key Areas of Traditional Chinese Medicine/ ; TJYXZDXK-3-014B//Tianjin Key Medical Discipline Construction Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; *Caregivers/psychology ; Female ; Male ; Longitudinal Studies ; Aged ; China ; Aged, 80 and over ; Activities of Daily Living ; Middle Aged ; },
abstract = {INTRODUCTION: Real-world modifiers of lecanemab benefit in Alzheimer's disease (AD) remain elusive. We examined associations between caregiver positivity and longitudinal outcomes in AD.

METHODS: This seven-center longitudinal study followed 127 biomarker-supported AD patient-caregiver dyads over 18 months. Mixed-effects, spline, and propensity-score analyses evaluated continuous Positive Aspects of Caregiving (PAC) scores.

RESULTS: Higher baseline PAC scale scores were associated with more favorable 18-month outcomes in cognition (Mini-Mental State Examination (MMSE): β = 0.42, 95% confidence interval [CI]: 0.24-0.59; p < 0.001), daily function (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]: β = 0.68, 95% CI: 0.42-0.93; p < 0.001), disease severity (Clinical Dementia Rating-Sum of Boxes [CDR-SB]: β = -0.26, 95% CI: -0.37 to -0.14; P < 0.001), patient quality of life (Quality of Life in Alzheimer's Disease [QOL-AD]: β = 0.53, 95% CI: 0.34-0.71; p < 0.001), and lower apathy (β = -0.09, 95% CI: -0.16 to -0.03; p = 0.003); these associations remained significant after multiplicity correction (all q's ≤ 0.004). Patient QOL-AD showed the most consistent sensitivity-analysis association. Apathy was associated with caregiver burden and caregiver quality of life, but mediation was not established.

DISCUSSION: Caregiver positivity may stratify lecanemab efficacy in AD, supporting psychosocial assessment in personalized, caregiver-inclusive management pathways.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
*Caregivers/psychology
Female
Male
Longitudinal Studies
Aged
China
Aged, 80 and over
Activities of Daily Living
Middle Aged

@article {pmid42947286,
year = {2026},
author = {Kanekiyo, T and White, LJ and Ye, H and Ren, Y and Ulrich, JD and Raulin, AC and Alnobani, A and Xiong, C and Asmann, YW and Vassilaki, M and Algeciras-Schimnich, A and Peng, J and Amtashar, FS and Schindler, SE and Holtzman, DM and Bu, G and Petersen, RC and Heckman, MG and Han, X},
title = {CSF and plasma lipid profiling predicts risk of cognitive impairment in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71924},
pmid = {42947286},
issn = {1552-5279},
support = {U19 AG069701/NH/NIH HHS/United States ; R01 AG061729/NH/NIH HHS/United States ; R01 AG071226/NH/NIH HHS/United States ; R01 AG057181/NH/NIH HHS/United States ; R01 AG068034/NH/NIH HHS/United States ; R01 AG081203/NH/NIH HHS/United States ; U01 AG006786/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; U19 AG102336/NH/NIH HHS/United States ; U19 AG102336/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Aged ; Male ; Female ; *Lipids/blood/cerebrospinal fluid ; Lipidomics ; Longitudinal Studies ; tau Proteins/cerebrospinal fluid ; Aged, 80 and over ; Lipid Metabolism ; },
abstract = {INTRODUCTION: Age-related cognitive decline and Alzheimer's disease (AD) are strongly influenced by lipid metabolism, yet how central and peripheral lipid profiles relate to disease risk before symptom onset remains unclear.

METHODS: We performed comprehensive shotgun lipidomics in cerebrospinal fluid (CSF) and plasma from cognitively unimpaired older adults, with longitudinal follow-up for Clinical Dementia Rating (CDR) conversion.

RESULTS: CSF lipidomes were primarily associated with age and established CSF AD biomarkers, whereas plasma lipid profiles were strongly influenced by sex. Specific CSF phosphatidylethanolamine subspecies showed robust positive associations with CSF total tau, phosphorylated tau 181, neurogranin, and chitinase-3 like-1. CSF triacylglycerol TAG(C49:6), phosphatidylglycerol PG(18:0-18:1), cholesteryl ester CE(20:3), and phosphatidylethanolamine PE(D16:0-18:1) independently predicted CDR conversion, improving risk prediction. Plasma sphingomyelin subspecies were modestly associated with cognitive decline risk.

DISCUSSION: These findings identify distinct CSF and plasma lipid signatures linked to preclinical cognitive decline and highlight brain lipid metabolism as a promising source of predictive biomarkers and therapeutic targets.},
}

Humans
*Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis
Biomarkers/cerebrospinal fluid/blood
Aged
Male
Female
*Lipids/blood/cerebrospinal fluid
Lipidomics
Longitudinal Studies
tau Proteins/cerebrospinal fluid
Aged, 80 and over
Lipid Metabolism

@article {pmid42947582,
year = {2026},
author = {Fernandez-Bonet, A and Temprano-Sagrera, G and Genius, P and Rodriguez-Fernandez, B and Domingo-Guell, E and Huguet, J and Buongiorno, M and Sánchez-Benavides, G and Cirach, M and Nieuwenhuijsen, M and de Bruijne, M and Evans, TE and Vilor-Tejedor, N},
title = {EXPRESS: Multidomain determinants of perivascular spaces indicate early cerebrovascular vulnerability in individuals at risk of Alzheimer's disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261503069},
doi = {10.1177/0271678X261503069},
pmid = {42947582},
issn = {1559-7016},
abstract = {BACKGROUND: Perivascular spaces (PVS) are MRI-visible markers of cerebrovascular and glymphatic function, but their regional determinants in preclinical Alzheimer's disease (AD), regarding sex and AD biomarkers, remain poorly understood.

METHODS: We studied 1,199 cognitively unimpaired ALFA study participants (aged 54-65 years), genetically enriched for AD risk, with CSF biomarker phenotyping in 296 participants. PVS were automatically quantified in basal ganglia, centrum semiovale, hippocampus, and midbrain on 3T MRI. Counts were modelled using Poisson or negative binomial regression, adjusting for demographics, cardiometabolic, lifestyle, and genetic factors, with effect modification by sex and amyloid/tau (AT) status.

RESULTS: PVS showed marked regional specificity. Centrum semiovale PVS were associated with age, male sex, and cardiometabolic factors, whereas hippocampal and midbrain PVS were more closely related to AD biomarker status and sleep or psychological measures. Men exhibited higher centrum semiovale burden while women showed higher counts in hippocampus, midbrain, and basal ganglia. Associations were stronger in amyloid-positive individuals with concurrent tau pathology. Polygenic scores for lipid and metabolic traits contributed modestly to regional PVS variation.

CONCLUSIONS: PVS burden is associated with multidomain determinants in preclinical AD with regional, sex-specific, and biomarker-dependent patterns, supporting PVS as accessible MRI markers for risk stratification and precision prevention.},
}

@article {pmid42947687,
year = {2026},
author = {Viola, KL and Chromy, BA and Nowar, R and Lambert, MP and Klein, WL},
title = {Safe and efficient intracellular delivery of functional antibodies into cultured neural cells shows a role for Alzheimer's-relevant tau phosphorylation in cell integrity.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1737082},
pmid = {42947687},
issn = {2813-3919},
abstract = {INTRODUCTION: Protein proteoforms generated by post-translational modification are increasingly recognized as important regulators of neuronal function and neurodegenerative disease. However, methods for acutely interrogating specific intracellular proteoforms in living neuronal populations remain limited. We evaluated cationic liposomal delivery (CLD) as a strategy for introducing full-length functional antibodies into living neurons and used this approach to investigate the role of a phosphorylated tau proteoform recognized by the monoclonal antibody PHF-1.

METHODS: Cationic liposomes composed of DOPC+ were complexed with antibodies or molecular probes and applied to cultured neuronal cell lines and primary mouse cortical neurons. Intracellular delivery, cellular localization, viability, and biological activity were assessed using fluorescence microscopy and live-cell imaging.

RESULTS: CLD efficiently delivered full-length antibodies and molecular probes into living neuronal cells and primary neurons without detectable toxicity. Internalized antibodies retained target specificity, producing intracellular staining patterns consistent with the known localization of tau, vinculin, paxillin, and Fyn. Delivery was observed across essentially all cells in treated cultures and remained effective under standard culture conditions. Intracellular delivery of PHF-1 produced a rapid and striking morphological response characterized by neurite retraction and cell-body rounding within hours of treatment. These effects were not observed with heat-inactivated PHF-1, vehicle controls, or other intracellular antibodies, supporting a specific effect of intracellular engagement of PHF-1-reactive tau species.

DISCUSSION: These findings establish CLD as a practical platform for the intracellular delivery of functional full-length antibodies into living neuronal populations. Beyond validating a delivery technology, the study demonstrates that acute intracellular engagement of PHF-1-reactive phosphorylated tau rapidly alters neuronal morphology, suggesting that this tau proteoform contributes to the maintenance of neurite integrity. CLD provides a versatile approach for probing the function of intracellular proteoforms that are difficult to study using conventional genetic or biochemical methods.},
}

@article {pmid42947719,
year = {2026},
author = {H F, T and Jacob, JE},
title = {Computational approaches to deep learning-driven EEG analysis for neurological disease diagnosis: a systematic review.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1778980},
pmid = {42947719},
issn = {1662-5196},
abstract = {Electroencephalography (EEG) is a widely used non-invasive neurophysiological technique for analyzing brain dynamics and diagnosing neurological diseases. However, the non-stationary nature, low signal-to-noise ratio, and inter-subject variability of EEG signals cause significant challenges to traditional analytical approaches. In recent years, deep learning has emerged as a powerful computational tool for EEG analysis, which enables automated feature learning and improved diagnostic accuracy with minimal human-driven feature extraction. This review systematically explains computational approaches in deep learning-driven EEG analysis for the diagnosis of neurological diseases. It includes recent advances in deep learning architectures, such as convolutional neural networks (CNN), recurrent neural networks (RNN), hybrid configurations, Generative Adversarial Networks (GAN), Large Language Models (LLM), autoencoders, and transformer-based models, with a focus on their capacity to model spatial, temporal, and spatiotemporal dynamics in EEG signals. This is applicable in diagnosing major neurological disorders such as Epilepsy, Alzheimer's disease (AD), Encephalopathy, Parkinson's disease (PD), Mild Cognitive Impairment (MCI), sleep disorders, and developmental brain disorders. Furthermore, we discuss essential preprocessing strategies and denoising techniques, showing how removing biological artifacts prevents diagnostic models from confusing noise with actual signs of disease. Key challenges such as limited data availability, lack of model interpretability, inter-subject variability, and difficulty in clinical translation are identified and critically discussed. Finally, key emerging trends and future research directions are identified to support the development of clinical applications of EEG-based disease diagnostic systems.},
}

@article {pmid42947816,
year = {2026},
author = {Dawson, WD and Canty, AJ and Migeot, J and O'Philbin, L and Gelmon, SB},
title = {Editorial: Innovations in dementia policies and services.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {2006454},
pmid = {42947816},
issn = {2813-3919},
}

@article {pmid42947905,
year = {2026},
author = {Majeed, Z and Majeed, J and Ponce, FA and Mahanti, H and Decourt, B and Burke, AD and Sabbagh, MN},
title = {Deep brain stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261441166},
pmid = {42947905},
issn = {2542-4823},
abstract = {Deep brain stimulation (DBS) is a well-established treatment for neurological disorders, but its efficacy and safety in Alzheimer's disease (AD) remain uncertain. This narrative review synthesizes nine clinical trials in patients with mild to severe AD, focusing on stimulation of the fornix, nucleus basalis of Meynert (NBM), and ventral capsule/ventral striatum. Literature was identified through PubMed using the terms "deep brain stimulation" and "Alzheimer's disease," and the results were restricted to clinical trials and case reports in English, with additional references identified through Google Scholar. Across studies, DBS was safe and well tolerated, with few adverse events. Stimulation produced short-term cognitive improvements, most commonly measured by Alzheimer's Disease Assessment Scale cognitive subscale, along with transient reversal of glucose hypometabolism and activation of memory-related networks. One study reported slowed hippocampal atrophy, suggesting neuroplastic effects. In severe AD, DBS targeting both the fornix and NBM yielded transient cognitive gains, with NBM-DBS showing greater benefit for neuropsychiatric symptoms and caregiver burden. Patients with higher baseline cognition and glucose metabolism responded more favorably to DBS. Age-related differences emerged: younger patients (<65 years old), with earlier onset and more aggressive progression, showed less favorable responses to DBS targeting the fornix, whereas older patients (≥65 years old) had comparatively better outcomes. Despite these benefits, DBS does not halt disease progression or reverse AD pathology. Larger, biomarker-stratified, sham-controlled trials with extended follow-up are needed to clarify durability, identify optimal patient subgroups, and determine the most effective stimulation targets.},
}

@article {pmid42947965,
year = {2026},
author = {Han, S and Wang, S and Liu, J and Liu, X and Wang, Q and Meng, C},
title = {Dynamic remodeling of microglial responses in Alzheimer's disease: heterogeneous states, spatiotemporal progression, and immunometabolic dysregulation.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1929282},
pmid = {42947965},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) is characterized by progressive neuroinflammation involving microglia whose functional responses extend far beyond the classical M1/M2 framework and form a dynamically heterogeneous continuum. Here, we review recurrent disease-associated microglia (DAM) states and transcriptional programs, including DAM-associated, interferon-responsive, cytokine-responsive, proliferative, antigen-presentation-associated, and lipid-associated features, emphasizing that these labels do not necessarily represent fixed or mutually exclusive cellular subtypes. Across AD progression, the relative engagement and functional consequences of these programs vary according to Aβ and tau burden, local microenvironment, genetic background, metabolic status, and disease stage. DAM-associated programs may support phagocytosis and plaque containment in some contexts, whereas persistent inflammatory and metabolic stress can increase lipid dysregulation, mitochondrial dysfunction, impaired phagocytic competence, and inflammatory signaling in subsets of microglia. Microglia also exert bidirectional effects on tau pathology. Core AD risk pathways, including TREM2 and APOE, together with immunometabolic remodeling, shape microglial plasticity in a context-dependent manner. We discuss the implications of this dynamic framework for stage- and state-aware therapeutic strategies and highlight the need to integrate single-cell, spatial, and multi-omic approaches to resolve microglial trajectories and functional states in human AD.},
}

@article {pmid42947971,
year = {2026},
author = {Chigriai, M and Kraskovskaya, N and Bolshakova, A and Porozova, NO and Porozov, YB and Pešić, M},
title = {PP2A targeting: balancing anticancer potential and neurological risk.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1945801},
pmid = {42947971},
issn = {2296-634X},
abstract = {Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase that regulates cell-cycle progression, oncogenic signaling, neuronal development, synaptic homeostasis, and protein proteostasis. Its dysregulation contributes to cancer, whereas impaired PP2A activity in the nervous system is linked to neurodevelopmental disorders and neurodegenerative proteinopathies, including tau and α-synuclein pathology. These divergent roles create both opportunities and safety challenges for PP2A-directed therapies. This review examines PP2A as a modular holoenzyme system whose subunit composition determines substrate specificity and context-dependent biological effects. We discuss PP2A dysfunction in cancer, including genetic and regulatory alterations affecting PP2A subunits, assembly, and endogenous inhibitors, and compare therapeutic PP2A activation with transient inhibition. The latter approach is exemplified by LB100, which sensitizes treatment-stressed tumor cells to chemotherapy, radiotherapy, or immunotherapy by disrupting checkpoint adaptation and stress recovery. We further evaluate the neurological implications of systemic phosphatase inhibition, LB100 conversion to the active metabolite endothall, clinical safety and pharmacokinetic data, and the limited brain-tumor penetration of intact LB100. We propose that the clinical utility of PP2A inhibition depends on defining a therapeutic corridor that integrates dosing schedule, parent-drug and metabolite exposure, tumor target engagement, biomarker-informed patient selection, and preservation of PP2A-dependent homeostasis in normal tissues, particularly the nervous system.},
}

@article {pmid42947982,
year = {2026},
author = {Lozano, R and Lin, X and Hagerman, R and Martínez-Cerdeño, V and Pinto, D},
title = {DNA methylation and proteomic profiling of postmortem brain tissue reveals epigenetic dysregulation and inflammatory signaling in fragile X-associated tremor/ataxia syndrome.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1932396},
pmid = {42947982},
issn = {1662-5099},
abstract = {BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a CGG repeat expansion in the premutation range of FMR1. The epigenetic landscape of the FXTAS brain remains largely uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex and targeted proteomic profiling to investigate molecular alterations associated with FXTAS and evaluate convergence on inflammatory signaling.

METHODS: DNA methylation was profiled in postmortem prefrontal cortex from 27 male FXTAS cases and 29 male controls using Illumina MethylationEPIC arrays. Surrogate variable analysis was used to account for latent sources of variation. Differentially methylated positions (DMPs) were defined as well as differentially methylated regions (DMRs). Exploratory functional analyses and comparison with published FXTAS transcriptomic and neurodegenerative-disease methylation datasets. Targeted proteomic profiling using the Olink Inflammation panel was performed in 9 male FXTAS cases and 12 male controls.

RESULTS: We identified 98 DMPs which mapped to 70 genes. Notable DMP-associated genes included CYP2E1, related to oxidative stress; TRAF3, BATF, RCOR1, and MSI2, with roles in immune and NF-κB-related signaling; and genes associated with myelination (LINGO1), synaptic function (SYT3), and zinc homeostasis (SLC39A4). TRAF3, a negative regulator of NF-κB and type I interferon signaling, contained one of the most significant DMPs. Exploratory Reactome analysis highlighted biological themes related to inflammatory resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism, although no pathway remained significant after multiple-testing correction. Transcription-factor motif enrichment and protein-protein interaction analyses identified no significant higher-order regulatory or interaction modules. Seven DMP-associated genes overlapped with differentially expressed genes from an independent FXTAS mouse transcriptomic study, whereas no gene-level overlap was detected with the Alzheimer's, Parkinson's, or Huntington's disease methylation signatures examined. Olink profiling identified 60 significantly altered inflammation-related proteins, 59 of which showed lower abundance in FXTAS, including TLR3, IRAK1, IRAK4, IKBKG/NEMO, and C1QA.

CONCLUSION: These findings identify previously unrecognized DNA methylation alterations in FXTAS prefrontal cortex involving genes related to oxidative stress, myelination, zinc homeostasis, and innate immune/NF-κB signaling. Convergence between methylation changes in immune-regulatory genes, including TRAF3, and a predominantly reduced inflammatory protein signature provides complementary evidence for altered inflammatory signaling in FXTAS.},
}

@article {pmid42947994,
year = {2026},
author = {Islam, K and Hossen, B and Manjar, MTA and Sultana, S},
title = {ConvNeXt-KAN: a Kolmogorov-Arnold Network head for robust multi-class staging of Alzheimer's disease from brain MRI.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1903281},
pmid = {42947994},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which accurate, stage-wise classification from structural magnetic resonance imaging (MRI) can support earlier intervention. Convolutional neural networks (CNNs) dominate this task, but their classifier heads rely on fixed activation functions and linear weights, which constrain the modelling of the subtle, highly non-linear atrophy and texture patterns that separate dementia stages. In addition, the widely used Open Access Series of Imaging Studies (OASIS) collection is severely imbalanced, and two common practices-undersampling every class to the smallest one, and splitting at the image (slice) level-respectively discard most of the data and inflate reported accuracy.

METHODS: We propose ConvNeXt-KAN, a hybrid model that couples a transfer-learned ConvNeXt-Tiny feature extractor with a Kolmogorov-Arnold Network (KAN) classification head whose edges are learnable spline activations implemented efficiently with Gaussian radial basis functions. The model is trained with a robustness-oriented recipe (MixUp and CutMix, label smoothing, decoupled weight decay, a cosine learning-rate schedule with warm-up, and test-time augmentation) and a data strategy that caps abundant classes and oversamples only the training partition, while evaluating on a fixed, balanced, leakage-controlled test set.

RESULTS: On the held-out test set the model attains 94.5% accuracy, a macro-averaged F1 of 0.944, and a mean one-vs.-rest ROC-AUC of 0.991, with an ablation confirming that pre-trained features and expanded data are the main drivers of performance. A head-to-head comparison under a matched protocol shows that the KAN and MLP heads are statistically indistinguishable (McNemar p = 0.52), while the proposed image-space resampling strategy outperforms focal loss, class-balanced cross-entropy and feature-space SMOTE. Evaluated without any fine-tuning on an independent four-class Alzheimer's MRI collection distributed on Kaggle, test-time-augmented accuracy is 61.6% with a macro-averaged F1 of 0.565.

DISCUSSION: The learnable-activation head improves the discrimination of the difficult non-demented vs. very-mild-demented boundary at negligible runtime cost, and the efficient formulation keeps the approach practical in standard deep-learning frameworks. A class-wise analysis of the external evaluation shows that moderate dementia continues to be recognized perfectly while the two clinically intermediate stages absorb most of the domain-shift error. We further quantify the impact of the evaluation protocol and argue that subject-level validation and multi-site external testing are essential before clinical claims.},
}

@article {pmid42948010,
year = {2026},
author = {Gao, Z and Ren, M and Yang, R and Yu, J},
title = {Bipolar disorder and risk of all-cause and specific dementia: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1980508},
pmid = {42948010},
issn = {1663-4365},
abstract = {BACKGROUND: Bipolar disorder (BD) is associated with cognitive impairment and an increased risk of dementia; however, the magnitude of this association and subtype-specific risk patterns remain unclear. This systematic review and meta-analysis quantified the associations between BD and the risks of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD), and explored potential sources of between-study heterogeneity.

METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to September 15, 2026. Eligible cohort and case-control studies reported adjusted effect estimates for the association between BD and dementia. Hazard ratios and odds ratios were converted to risk ratios (RRs) prior to quantitative synthesis. Random- or fixed-effects models were applied according to heterogeneity. Leave-one-out sensitivity analyses, Egger's test for publication bias, and subgroup analyses stratified by follow-up duration, sex, age at BD onset, and study design were conducted.

RESULTS: Eleven studies involving 1,536,508 participants and 90,864 all-cause dementia cases were included. BD was associated with an increased risk of all-cause dementia (RR = 3.55, 95% CI 2.48-5.07; I[2] = 98.7%), AD (RR = 5.08, 95% CI 1.87-13.84; I[2] = 97.2%), and VaD (RR = 4.33, 95% CI 3.06-6.13; I[2] = 71.7%). Estimates for all-cause dementia and VaD were robust in sensitivity analyses, whereas the AD estimate was sensitive to the exclusion of individual studies and should therefore be interpreted cautiously. The association between BD and increased dementia risk was observed across the examined subgroups. Formal tests for subgroup differences showed no statistically significant differences according to sex or age at BD onset.

CONCLUSION: BD is associated with an increased risk of all-cause dementia, AD, and VaD. However, substantial between-study heterogeneity and the limited evidence available for specific dementia subtypes warrant cautious interpretation of the pooled estimates. Further high-quality longitudinal studies are needed to clarify the factors underlying heterogeneity and subtype-specific associations.

https://www.crd.york.ac.uk/prospero/, identifier [CRD420261395626].},
}

@article {pmid42948024,
year = {2026},
author = {Kim, J and Jeong, SY and Lee, SW and Yoon, U and Kang, K},
title = {Altered hippocampal morphology and its association with gait impairment in idiopathic normal-pressure hydrocephalus.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1914240},
pmid = {42948024},
issn = {1664-2295},
mesh = {Humans ; *Hydrocephalus, Normal Pressure/diagnostic imaging/complications/pathology/physiopathology ; *Hippocampus/diagnostic imaging/pathology ; Female ; Male ; Magnetic Resonance Imaging ; Aged ; *Gait Disorders, Neurologic/etiology/diagnostic imaging/pathology/physiopathology ; Positron-Emission Tomography ; Aged, 80 and over ; },
abstract = {UNLABELLED: Background and purpose: This study aimed to characterize structural alterations of the hippocampus associated with idiopathic normal-pressure hydrocephalus (INPH), and to explore their relationship with gait disturbances in affected patients.

METHODS: A total of 48 patients with INPH and 25 β-amyloid-negative healthy controls underwent MRI-based, vertex-wise three-dimensional hippocampal shape analysis. Additionally, all participants received 18F-florbetaben positron emission tomography to assess amyloid status.

RESULTS: Hippocampal shape analysis revealed marked bilateral deformation in the INPH group compared to controls. Both hippocampi exhibited elongation and narrowing, with the middle and posterior regions showing upward curvature, indicating vertical displacement from the hippocampal body to the tail. The normalized hippocampal volume was significantly smaller in INPH patients. No substantial volumetric or morphological differences were observed between amyloid-positive and amyloid-negative individuals within the INPH group. Notably, localized shape deformities correlated with performance on the Timed Up and Go and 10-meter walk tests, more prominently in the right hippocampus. Bilateral inward deformations at the superomedial tail and inferior body of the hippocampus were consistently linked to worse gait performance. Furthermore, smaller right normalized hippocampal volumes were negatively associated with gait test outcomes.

CONCLUSION: These findings indicate that INPH is associated with characteristic hippocampal shape abnormalities. The observed associations between hippocampal morphology and gait disturbances suggest that the hippocampus may contribute to gait and postural control in INPH.},
}

Humans
*Hydrocephalus, Normal Pressure/diagnostic imaging/complications/pathology/physiopathology
*Hippocampus/diagnostic imaging/pathology
Female
Male
Magnetic Resonance Imaging
Aged
*Gait Disorders, Neurologic/etiology/diagnostic imaging/pathology/physiopathology
Positron-Emission Tomography
Aged, 80 and over

@article {pmid42948155,
year = {2026},
author = {Koukoura, A and Antonopoulou, K and Tsolakis, AC and Solomon, A and Tsolaki, M and Froelich, L and Tsolaki, A and Papadaki, E and Vassiliadis, E and Holst, GJ},
title = {Perspectives on plasma biomarkers for point-of-care diagnostics in Alzheimer's disease: Insights into 2D-BioPAD.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437790},
pmid = {42948155},
issn = {2542-4823},
abstract = {We investigated the potential of plasma biomarkers for point-of-care in vitro diagnostics in Alzheimer's disease by collecting insights from 99 stakeholders primarily from Greece, including patients, caregivers, healthcare professionals, and researchers. Data from an online survey was analyzed using descriptive statistics and thematic analysis. Key biomarkers reported by participants included Aβ40, Aβ42, pTau181, pTau217, and neurofilament light chain. While biomarkers were recognized for their value in prognosis, diagnosis, and monitoring, most participants were unfamiliar with point-of-care in vitro diagnostics. Major concerns regarding implementation included cost, reimbursement, and accessibility, underscoring the need for more feasible and context-appropriate diagnostic solutions.},
}

@article {pmid42948157,
year = {2026},
author = {Teng, Z and Hu, M and Zhang, Z and Zhou, M and Yin, P and , },
title = {Heterogeneous progression of AT(N) biomarkers in data-driven subtypes of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1902282},
pmid = {42948157},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) exhibits substantial heterogeneity in brain atrophy patterns and progression rates. Data-driven subtyping based on the Subtype and Stage Inference (SuStaIn) model has identified distinct MRI-derived subtypes, but the longitudinal dynamics of these subtypes within the AT(N) framework remain unknown.

METHODS: This study included 1,576 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with at least two visits. SuStaIn was applied to volumetric measurements of 11 brain regions to identify imaging-based subtypes. Within each subtype, we fitted a Bayesian latent time longitudinal joint mixed-effects model incorporating six biomarkers: amyloid PET (A), CSF p-tau (T), hippocampal volume, cingulate volume, thalamic volume (N), and ADAS-Cog13 (X), with APOE ε4 as a covariate.

RESULTS: The three subtypes exhibited distinctly different longitudinal patterns. Subtype 1 showed early elevation of amyloid, followed by a sharp decline in hippocampal volume, which was tightly coupled with cognitive deterioration. Subtype 2 featured early involvement of cortical regions such as the cingulate cortex, with hippocampal changes occurring at a similar timing to Subtype 1 but accompanied by earlier cortical and thalamic involvement. Subtype 3 exhibited early rapid hippocampal atrophy that later plateaued, and demonstrated the strongest hippocampus-cognition coupling. The association of APOE ε4 with biomarker trajectories was subtype-dependent: its effect estimates were largest for amyloid and p-tau in Subtype 1, whereas in Subtype 3 the effect estimates were significant for nearly all biomarkers, with the largest estimate for cognition.

CONCLUSION: This study demonstrates that AD subtypes defined by spatial atrophy patterns also differ fundamentally in temporal biomarker dynamics and APOE ε4 association, supporting subtype-stratified modeling of disease progression.},
}

@article {pmid42948203,
year = {2026},
author = {Iwasa, K and Omori, N and Ishida, M and Tanaka, T and Nagai, A},
title = {Digital completion time relates more strongly to Alzheimer's disease-type atrophy than to vascular burden in a community cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70526},
pmid = {42948203},
issn = {2352-8729},
abstract = {INTRODUCTION: Slowing on digital cognitive testing may reflect Alzheimer's disease (AD)-type atrophy, small-vessel disease, or both. Single-outcome studies cannot determine whether slowing preferentially reflects one type of brain change or general brain health. We tested whether response-time features from the tablet-based Cognitive Assessment for Dementia, iPad version 2 (CADi2) were more strongly associated with AD-type atrophy than with vascular burden.

METHODS: In 1163 community-dwelling adults undergoing brain-health screening (Izumo cohort, 2019-2025), CADi2 response-time features predicted two primary MRI markers from one framework under repeated nested cross-validation: Alzheimer's disease likelihood score (ADLS; similarity to an AD-type atrophy pattern) and normalized white matter lesion (WML) volume. The primary metric was the incremental observed-predicted correlation (ΔR) over age and sex. Silent brain infarcts, microbleeds, and a composite small vessel disease score were additional vascular outcomes.

RESULTS: CADi2 features improved prediction of ADLS (ΔR = +0.054, 95% confidence interval [CI] +0.010 to +0.095) but not WML (ΔR = -0.006). The improvement reflected completion time, not accuracy. Because predictive headroom differed, we repeated the comparison in residual space. There, the increment correlated about twice as strongly with ADLS as with WML (r = 0.160 vs. 0.080; p = 0.044), although both remained significant. A parallel contrast against the composite vascular score gave Δr = 0.100 (p = 0.008).

DISCUSSION: Digital completion time was preferentially, but not exclusively, associated with AD-type atrophy (neurodegeneration axis) relative to vascular burden. Because ADLS indexes an atrophy pattern rather than amyloid or tau pathology, these cross-sectional findings characterize a structural phenotype.},
}

@article {pmid42948208,
year = {2026},
author = {Li, L and Yu, Y and Fan, J and Zhang, N and Yang, J and Li, H and Zheng, J},
title = {Multifaceted neuroprotection of ginsenosides: Mechanisms, nano-delivery advances, and therapeutic potential in central nervous system disorders.},
journal = {Journal of ginseng research},
volume = {50},
number = {6},
pages = {101149},
pmid = {42948208},
issn = {1226-8453},
abstract = {BACKGROUND: Central nervous system (CNS) diseases remain therapeutic challenges due to complex pathology and poor drug penetration across the blood-brain barrier (BBB). Ginsenosides, the active components of Panax ginseng, possess multi-target neuroprotective properties but exhibit low bioavailability.

PURPOSE: This review synthesizes current evidence on ginsenoside mechanisms and evaluates the role of nanotechnology in enhancing their delivery and efficacy for CNS disorders.

STUDY DESIGN: A systematic search was conducted following PRISMA guidelines across PubMed, Web of Science, CNKI, and Google Scholar (2015-present). Included studies investigated ginsenosides in neurological disease models and nano-formulation strategies.

RESULTS: Ginsenosides modulate neuroinflammation, oxidative stress, apoptosis, and calcium homeostasis through pathways involving NF-κB, Nrf2, and Bcl-2/Bax. Nano-delivery systems-such as liposomes, polymeric nanoparticles, and biomimetic vesicles-significantly improve ginsenoside stability, BBB traversal, and brain-targeted accumulation. Functionalization with ligands (e.g., Angiopep-2) or cell membranes further enhances specificity and therapeutic outcomes in ischemic stroke, glioma, Alzheimer's disease, and spinal cord injury models.

CONCLUSION: Nanotechnology-based delivery systems potently augment the neuroprotective potential of ginsenosides, offering a promising strategy for multi-target CNS therapy. Future efforts should focus on translational safety, scalable production, and clinical validation.},
}

@article {pmid42948220,
year = {2026},
author = {Choe, YM and Kim, JH and Choi, HJ and Suh, GH and Lee, BC and Kim, HS and Kim, JW and Kim, SG and Hwang, J and Yi, D and Kim, JW},
title = {Association of ginseng intake and serum zinc with Alzheimer's disease-related cognition.},
journal = {Journal of ginseng research},
volume = {50},
number = {6},
pages = {101119},
pmid = {42948220},
issn = {1226-8453},
abstract = {OBJECTIVE: Ginseng intake and zinc homeostasis are potential protective factors against Alzheimer's disease (AD), but their interrelationship in cognition remains unclear. This study examined the association of ginseng intake and serum zinc with AD-related cognitive function in older adults.

METHODS: We conducted a cross-sectional study of 160 community-dwelling older adults. Ginseng intake was assessed through structured interviews, and serum zinc levels were measured by inductively coupled plasma-mass spectrometry. Cognitive function, focusing on delayed episodic memory (an early AD-related marker) and non-memory cognition, was assessed using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K) neuropsychological battery. Multiple linear regression analyses were conducted to evaluate independent predictors.

RESULTS: Ginseng intake was significantly associated with higher serum zinc levels (P = 0.002) and better delayed episodic memory (P = 0.005). Higher serum zinc levels were also significantly associated with better delayed episodic memory (P = 0.023) in separate regression models. However, in a simultaneous model including both ginseng and serum zinc, ginseng intake remained a significant independent predictor of delayed episodic memory (P = 0.017), whereas the association between zinc and memory was attenuated.

CONCLUSION: Ginseng intake was associated with better AD-related memory in older adults and may be related to the zinc pathway as an upstream factor. These findings suggest that ginseng may be associated with higher zinc bioavailability while also showing associations with memory that appear independent of zinc homeostasis, supporting its potential value as a nutritional strategy for maintaining cognitive function in early AD.},
}

@article {pmid42948355,
year = {2026},
author = {Li, M and Zhang, Y and Lü, P and Li, J and Zhang, Y and Wang, S and Bai, Y and Wang, Y},
title = {Emerging roles of apolipoprotein E4 in cerebral small vessel disease-related cognitive impairment: mechanistic insights and therapeutic perspectives.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1957032},
pmid = {42948355},
issn = {1662-5161},
abstract = {Cerebral small vessel disease (CSVD) is a major contributor to cognitive decline and vascular cognitive impairment in the elderly. However, the extent to which apolipoprotein E4 (ApoE4) contributes to sporadic, non-amyloid CSVD remains unclear. Previous literature has often inferred CSVD mechanisms from Alzheimer's disease (AD) research, carrying the risk of overstating disease-specific causal relationships. Therefore, this narrative review re-evaluates the relationship between ApoE4 and CSVD using a CSVD-centric hierarchy of evidence. Population-based imaging and epidemiological data suggest that "APOE" ε4 may alter susceptibility to white matter injury and cognitive impairment; however, the effect sizes are generally small or context-dependent, and associations are influenced by factors such as age, hypertension, diabetes, total vascular risk burden, AD pathology, ancestry, sex, and "APOE" gene dosage. Evidence is stronger for cerebral amyloid angiopathy (CAA)-which involves mechanisms distinct from sporadic arteriolosclerotic CSVD-and thus warrants separate discussion. At the mechanistic level, direct evidence regarding CSVD supports endothelial dysfunction, BBB leakage, neurovascular unit (NVU) instability, and white matter injury as core pathological processes. Among the evidence specific to ApoE4, models involving impaired neurovascular regulation and chronic hypoperfusion are the most compelling; conversely, mechanisms such as the cyclophilin A-MMP-9 pathway, TREM2-ApoE signaling, insulin receptor trafficking, reelin-related synaptic effects, endoplasmic reticulum stress, and autophagy currently rely primarily on AD research or preclinical evidence. Two recently proposed specific hypotheses-the brain-heart-kidney axis hypothesis and the microglial lipid droplet model-offer valuable conceptual frameworks but should be viewed as testable theories rather than established mechanisms. To date, no ApoE4-targeted therapies have been proven effective for CSVD-related cognitive impairment future research should prioritize genotype-stratified longitudinal CSVD cohorts, standardized imaging studies, adjustment for Alzheimer's disease (AD) biomarkers, analysis of interactions between vascular risk factors, studies on human white matter tissue, and the development of ApoE4 disease models that integrate chronic hypoperfusion and vascular comorbidities.},
}

@article {pmid42948602,
year = {2026},
author = {Choi, HJ and Choe, YM and Kim, JH and Suh, GH and Lee, BC and Hwang, J and Kim, SG and Kim, HS and Yi, D and Kim, JW},
title = {Panax ginseng in psychiatric disorders: Mechanisms and therapeutic potentials.},
journal = {Journal of ginseng research},
volume = {50},
number = {6},
pages = {101151},
pmid = {42948602},
issn = {1226-8453},
abstract = {Panax ginseng C.A. Meyer is a traditional medicinal herb with a long-standing history as a tonic and adaptogen. Accumulating evidence suggests its therapeutic potential for enhancing mood and cognition, as well as mitigating stress-related psychiatric conditions. This comprehensive review assesses the neuropharmacological mechanisms and potential therapeutic effects of Panax ginseng in psychiatric disorders, based on preclinical and clinical data. Ginseng and its active constituents, particularly ginsenosides, modulate key neurotransmitter systems-including serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid-while exerting neuroprotective, anti-inflammatory, and antioxidant effects. Furthermore, it plays a crucial role in regulating the hypothalamic-pituitary-adrenal axis and stress responses. Preclinical models have shown antidepressant and anxiolytic properties comparable to conventional pharmacotherapies, alongside pro-cognitive and neuroprotective actions. Although clinical evidence remains emerging, existing studies indicate potential benefits for depression, anxiety, and cognitive impairment, specifically improving symptoms in patients with Alzheimer's disease and schizophrenia. Consequently, Panax ginseng may hold promise as an adjunctive therapy for various psychiatric disorders. Its multimodal mechanisms-encompassing monoamine modulation, neurotrophic support, and adaptogenic stress reduction-provide a rationale for its clinical application. Nonetheless, rigorous large-scale clinical trials are essential to confirm efficacy, determine optimal dosing, and ensure safety.},
}

@article {pmid42948702,
year = {2026},
author = {Yin, J and Lv, W and Zhao, W and Ding, Z and Zhu, F and Liu, H and Li, S and Cao, X and Liu, L and Song, K and Gong, Y and Xu, J and Chen, Y and Zhang, Z and Fang, X and Xin, H},
title = {Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {10},
pages = {7037-7053},
pmid = {42948702},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), characterized by amyloid (Aβ) deposition in neurons, is the most serious neurodegenerative disorder, but lacks effective therapeutic drugs in the clinic. Impaired neuronal lysosomal function drives the pathological accumulation of intracellular Aβ. Targeted rehabilitation of lysosomal dysfunction may offer a potential strategy to restore neuronal homeostasis and mitigate AD progression. In this study, we developed a brain-targeted smart lipid nanoparticle (A-PSL@7BIO) to repair lysosomal membrane damage and restore impaired acidification in the brain for AD therapy. The system was composed of Angiopep-2 peptide-conjugated lipid nanoparticles, which were loaded with a Glycogen synthase kinase-3β (GSK-3β) inhibitor 7-bromoindirubin-3'-oxime (7BIO) and incorporated with dipalmitoyl-phosphatidylserine (DPPS) and a reactive oxygen species (ROS) responsive phospholipid. Through Angiopep-2-mediated blood-brain barrier (BBB) transcytosis, the smart lipid nanoparticles could enhance brain biodistribution with subsequent neuronal internalization. Pathologically elevated intracellular ROS levels in AD could induce stimulus-responsive payload release, wherein 7BIO selectively inhibited aberrant GSK-3β hyperphosphorylation to restore the physiological acidic lysosomal environment and DPPS structurally repaired compromised lysosomal membranes, synergistically addressing dual aspects of lysosomal pathology. This smart lipid nanoparticles synergistically restored physiological lysosomal homeostasis, reversed neuronal dysfunction, and ameliorated cognitive deficits in AD models, indicating that A-PSL@7BIO could be used as a potential nanomedicine for AD therapy.},
}

@article {pmid42948713,
year = {2026},
author = {Zhang, Q and Gong, X and Liu, H and Yao, X},
title = {Application of computational methods in the drug discovery and development of Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {10},
pages = {6526-6552},
pmid = {42948713},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive decline. As the most common dementia, AD affects over 50 million individuals worldwide, with 10 million new cases each year. Despite many significant progresses in AD research fields, there is still no effective treatment. Advances in molecular modelling and artificial intelligence (AI) algorithm have facilitated the application of computational methods in AD drug development, offering advantages in terms of efficiency, cost-effectiveness, and resource conservation. These strategies, including molecular docking, molecular dynamics simulation, protein structure prediction, virtual screening, and de novo drug design, have been widely employed in the past decades. Additionally, AI pharmaceutical companies have revolutionized the traditional drug development pipeline such as AD biomarker discovery, accurate diagnosis and precision medicine, etc. This review offers a thorough summary of recent progresses in computational-based methodologies in the study of AD drug development, including the elucidation the pathological mechanism at the molecular level, target identification, target 3D structure prediction, lead compound discovery, de novo molecular generation, multi-target directed ligands, drug repurposing, biomarker discovery, etc., showing promising applications of molecular modelling and AI in the development of AD therapy.},
}

@article {pmid42948724,
year = {2026},
author = {Yao, W and Su, L and Lu, Z and Chen, J and Duan, L and Meng, X and Wan, H and Chen, S and Mi, Y and Ji, A},
title = {Genomic characterization of AP2/ERF transcription factors related to cannabinoids biosynthesis in Cannabis sativa.},
journal = {Chinese herbal medicines},
volume = {18},
number = {4},
pages = {1056-1066},
pmid = {42948724},
issn = {2589-3610},
abstract = {OBJECTIVE: Cannabinoids, secondary metabolites produced by Cannabis sativa (cannabis), have various pharmacological effects, such as anti-inflammatory and analgesic effects, and they can be used in the treatment of Alzheimer's disease. Although the biosynthetic pathway of cannabinoids has been elucidated, relatively few reports about the transcription factors involved in this pathway exist. APETALA2 (AP2)/ethylene-responsive factor (ERF) transcription factor (TF) families play an important role in plant growth and secondary metabolism.

METHODS: APETALA2 (AP2)/ethylene-responsive factor (ERF) transcription factor (TF) family was identified in cannabis plants via phylogenetic analysis, chromosomal distribution, gene structure, conserved motif identification, synteny analysis, alternative splicing event identification, response element prediction, and gene expression analysis.

RESULTS: A total of 111 AP2/ERF members belonging to the APETALA2 subfamily (17 genes), dehydration-responsive element-binding proteins subfamily (39 genes), and ethylene-responsive factor subfamily (53 genes), related to the ABI3/VP1 subfamily (two genes), exist in cannabis. Based on the expression profiles of AP2/ERFs in the genome, quantitative real-time PCR (qRT-PCR) detection and coexpression analysis results, the functional genes of six TFs were clustered with those of other species, and two gene clusters are speculated to be related to cannabinoid biosynthesis. A total of six CsERF proteins were found to be located in the cell nucleus by subcellular localization detection. CsERF02 and CsERF19 exhibited transcriptional activation activity through the AH109 yeast system.

CONCLUSION: CsERF02, CsERF05, CsERF18, CsERF19, CsERF21, CsERF46 and two gene clusters may function in cannabinoid biosynthesis. These results contribute to the characterization of functional AP2/ERF family members in cannabis and lay a foundation for regulating cannabinoid content through metabolic pathways.},
}

@article {pmid42948807,
year = {2026},
author = {Rice, JA and Bouteiller, JC and Khachaturian, AS},
title = {Integrating cure and care in Alzheimer's disease: a systems perspective for precision medicine.},
journal = {Frontiers in molecular medicine},
volume = {6},
number = {},
pages = {1960763},
pmid = {42948807},
issn = {2674-0095},
abstract = {Alzheimer's disease remains a major global health challenge, with limited disease-modifying therapies and a rapidly growing societal burden. Although amyloid and tau remain central to the field, current evidence also implicates neuroinflammation, immune dysregulation, vascular dysfunction, and host-microbe interactions in disease pathogenesis. These developments support a broader systems framework, but simply combining additional disciplines or data modalities does not by itself preserve the dynamic biology or lived experience of disease. Artificial intelligence multi-omics, and digital biomarkers can help identify clinically meaningful patterns only when data and models preserve relevant structure across time, scale, context, and uncertainty. Realizing this potential will require responsible international data sharing, interoperable infrastructure, explicit evidence provenance, and ethical governance grounded in FAIR principles, context-appropriate explainability, and privacy-preserving approaches such as federated learning. Scientific progress should therefore be measured not only by disease modification, but also by patterns of cognition, behavior, function, quality of life, and caregiver burden. This Perspective argues that cure and care are not competing or merely parallel priorities; they are linked outputs of the same continuously learning research and care ecosystem.},
}

@article {pmid42948835,
year = {2026},
author = {Li, S and Huang, L and Guo, Q},
title = {Blood-Based Biomarkers in Alzheimer's Disease: Advances in Detection Technologies and Clinical Applications.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {},
number = {},
pages = {},
pmid = {42948835},
issn = {2475-0360},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder. Irreversible pathological alterations are already present when clinical symptoms emerge. Therefore, early diagnosis and intervention are crucial for improving patient outcomes and reducing the social and healthcare burden. With its advantages of minimal invasiveness, convenience, affordability, and high accessibility, blood-based testing has overcome the limitations of conventional methods, becoming a major focus of research in early AD diagnosis in recent years. Based on the key domestic and international research findings in recent years, this paper systematically reviews the types, mechanisms of action, and relevant detection technologies of blood-based biomarkers for AD.},
}

@article {pmid42948999,
year = {2026},
author = {Mankoo, OK and Priyadarshi, N and Singh, PP and Goyal, B and Singhal, NK and Goyal, D},
title = {Unraveling the synergistic potential of naringenin as an Aβ fibrillation inhibitor with metal chelating and antioxidant properties.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp01611a},
pmid = {42948999},
issn = {1463-9084},
abstract = {Alzheimer's disease (AD) is a fatal, multifaceted degenerative brain disorder characterized by amyloid-β (Aβ) fibrillation leading to the formation of neurotoxic oligomers and fibrils, metal ion dysregulation, and oxidative stress, all of which contribute to its pathophysiology. Naringenin (NAR), a flavonoid isolated from citrus fruits, has been identified as a potential therapeutic agent for AD, due to its ability to cross the blood-brain barrier (BBB) and modulate key pathogenic processes. In this work, the synergistic potential of NAR to modulate Aβ42 fibrillation, disaggregate preformed Aβ42 fibrils, metal-induced Aβ42 fibrillation, and oxidative stress was examined using various biophysical techniques. Notably, NAR effectively inhibits Aβ42 fibrillation (96.6 ± 0.2% inhibition at a 1 : 4 ratio of Aβ42 : NAR), with an IC50 value of 9.62 ± 0.14 µM, and disrupts preformed Aβ42 fibrils by 85.1 ± 1.0%. NAR shows antioxidant properties and thus halts the formation of reactive oxygen species (ROS). Notably, NAR restored 94.1 ± 4.7% of the tyrosine fluorescence at 20 µM concentration, suggesting its potential to extract metal from the Aβ42-Cu[2+] complex and thus mitigate Cu[2+]-induced Aβ42 toxicity. Importantly, at doses up to 100 µM, NAR shows nearly 90% cell viability in PC12 cells, highlighting its safety profile and alleviating the cytotoxicity induced by Aβ42 aggregates. Furthermore, molecular dynamics (MD) simulations highlighted favourable binding of NAR to Aβ42 protofibrils (ΔGfit = -12.85 ± 1.21 kcal mol[-1]), resulting in overall structural deformation of the anti-parallel β-sheet-rich Aβ42 protofibrils. Importantly, NAR-induced lowering in the β-sheet content with an associated rise in the coil content was noted in the Aβ42 protofibrils, consistent with ThT, CD, and TEM assays depicting NAR-mediated disassembly of pre-existing Aβ42 fibrils. The study highlights the potential of NAR as a multifunctional ligand, targeting Aβ42 fibrillation, metal-induced Aβ42 fibrillation, and oxidative stress. Furthermore, MD simulations in this work illuminated the molecular mechanism by which NAR disrupts the Aβ42 protofibril structure, which will provide key insights into the rational design and development of potent therapeutics against the disruption of neurotoxic β-sheet-rich Aβ42 aggregates in AD.},
}

@article {pmid42949022,
year = {2026},
author = {Shah, RC and Borson, S and Luchsinger, JA},
title = {Using the 4Cs of Primary Care to Ensure Timely Diagnosis of Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000759},
pmid = {42949022},
issn = {1546-4156},
support = {//Novo Nordisk, Inc./ ; },
abstract = {BACKGROUND: Disease-modifying treatment is available for patients diagnosed with early symptomatic Alzheimer disease [AD, mild cognitive impairment (MCI), and mild dementia]. Recognition and diagnosis of MCI and dementia occur every day in the primary care setting, but diagnostic challenges and delays are common. Over 90% of MCI cases are missed, and more than half of AD diagnoses occur when the disease is in the moderate or advanced stage, when crises and emergencies are more likely to occur.

DISCUSSION: Diagnostic delays limit opportunities to organize and implement proactive, comprehensive patient care and treatment and to prepare individuals and caregivers for the long-term implications of progressive dementia. With the advent of new diagnostic methods, including blood-based biomarkers, AD can now be diagnosed with greater precision and ease at a lower cost. Given the expected increase in prevalence of AD in the next 2 decades and the growing shortage of geriatricians and memory disorders specialists, the role of the PCP in diagnosing AD will be of even greater importance. However, many PCPs do not feel confident or equipped to recognize and diagnose patients with early symptomatic AD. To empower PCPs as key participants in diagnosis, we propose an approach aligned with the fundamental strengths of primary care, codified in the 4Cs (first contact, comprehensiveness, coordination, and continuity of care).

CONCLUSION: Using the 4Cs framework, PCPs can increase the rate of timely diagnosis of symptomatic AD and be afforded more time to provide comprehensive care, using proactive rather than reactive management strategies throughout the diagnostic process.},
}

@article {pmid42949217,
year = {2026},
author = {Shafiyan, S and Gosselin, N and Léonard, C and Zumbansen, A},
title = {Multimodal Assessment of Emotion in Aging and Dementia: A Laboratory-Based Protocol.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73521},
pmid = {42949217},
issn = {1940-087X},
mesh = {Humans ; *Aging/psychology/physiology ; Aged ; *Dementia/psychology/physiopathology ; *Emotions/physiology ; Female ; Male ; Facial Expression ; },
abstract = {Dementia affects millions worldwide and challenges emotional and social functioning. However, emotional experiences in dementia remain poorly understood. To help better understand this complex phenomenon, the component process model (CPM) was used, which views emotion as a changing process involving appraisal, expression, physiology, motivation, and feeling. It demands a multimodal approach to measure its components. A protocol was developed that combines physiological, facial, vocal, linguistic, and self-report measures, and its feasibility was assessed. The protocol was piloted using iMotions on two older adults with caregiving experience and one with expertise in neuropsychology. Adjustments to instructions, mock tests to familiarize participants with the tasks, and session duration were implemented for a subsequent sample of healthy participants (3 young and 4 older adults) and for 1 older adult diagnosed with dementia due to probable Alzheimer's disease. Participants were screened for impairments in hearing, vision, cognition, and language, as well as psychological distress. The final tasks required watching validated film clips to elicit joy, anger, and sadness. Recorded data according to the CPM included facial movements and voice (expression), electrodermal activity and heart rate (physiology), discourse content, and CoreGRID questionnaire (appraisal; feeling; motivation). Protocol feasibility was assessed by documenting the number of completed tasks, collecting participant feedback via the Post-Study System Usability Questionnaire with comments, and extracting data quality metrics from iMotions for facial expressions and galvanic skin response (percentage of usable data; signal-to-noise ratio). All participants completed the tasks and reported positive feedback on the usability questionnaire. Automated facial expression data were analyzable for all participants, and galvanic skin response recordings were obtained for all participants, with 10 of 11 recordings meeting the predefined signal-to-noise criterion. This protocol was feasible to administer in the tested sample. Further evaluation in larger and more diverse dementia samples is needed.},
}

Humans
*Aging/psychology/physiology
Aged
*Dementia/psychology/physiopathology
*Emotions/physiology
Female
Male
Facial Expression

@article {pmid42949226,
year = {2026},
author = {Yang, S and Grilli, MD and Wootton, RE and van de Weijer, MP and Treur, JL and Klimentidis, YC and Sbarra, DA},
title = {Loneliness as a pathway linking hearing decline to cognitive aging: Longitudinal and genetic evidence.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71950},
pmid = {42949226},
issn = {1552-5279},
support = {R01AG078361-01/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Loneliness/psychology ; *Cognitive Aging/psychology/physiology ; *Hearing Loss/genetics/psychology ; Genome-Wide Association Study ; Longitudinal Studies ; Female ; Male ; Aged ; Europe ; *Cognitive Dysfunction/genetics ; Aging ; },
abstract = {INTRODUCTION: Hearing loss and loneliness are potentially modifiable risk factors for cognitive decline and dementia, but it remains unclear whether loneliness represents a causal pathway linking hearing loss to cognitive aging or whether these associations reflect shared vulnerability.

METHODS: We combined up to 18 years of data from the Survey of Health, Ageing and Retirement in Europe (SHARE; N = 10,375) with summary statistics from eight primary genome-wide association study sources and an independent neuroticism dataset used in sensitivity analyses. Parallel-process latent growth curve models examined level and change associations; additional analyses evaluated hearing-aid moderation, Mendelian randomization, multivariable Mendelian randomization, and colocalization.

RESULTS: At Wave 7, poorer hearing, greater loneliness, and poorer word-recall performance were associated, with a significant indirect association through loneliness. Evidence for coordinated longitudinal mediation was limited, and the primary change-to-change indirect effect was not significant. Current, but not cumulative, hearing-aid use was associated with a weaker concurrent hearing-loneliness association. Genetic analyses provided little evidence for direct or loneliness-mediated causal effects of hearing phenotypes on Alzheimer's disease or all-cause dementia. Results were more consistent with shared liability, including overlap with neuroticism.

DISCUSSION: The findings support late-life associations among hearing difficulty, loneliness, and cognitive performance but provide limited evidence that loneliness is a primary causal pathway linking hearing loss to cognitive aging. Integrating longitudinal and genetic evidence suggests a more complex etiology involving shared liability and supports direct evaluation of hearing care and social connection in intervention studies.},
}

Humans
*Loneliness/psychology
*Cognitive Aging/psychology/physiology
*Hearing Loss/genetics/psychology
Genome-Wide Association Study
Longitudinal Studies
Female
Male
Aged
Europe
*Cognitive Dysfunction/genetics
Aging

@article {pmid42949229,
year = {2026},
author = {Hok-A-Hin, YS and Vermunt, L and de Jong, N and Del Campo Milan, M and Vijverberg, E and Lemstra, AW and Pijnenburg, Y and van Harten, AC and Teunissen, CE},
title = {The Target48 Neurodegeneration panel: A novel tool for profiling protein signatures in neurodegenerative disorders.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
doi = {10.1002/alz.71866},
pmid = {42949229},
issn = {1552-5279},
support = {//Stichting Alzheimer Nederland/ ; //Stichting Steun Alzheimercentrum Amsterdam/ ; //Health∼Holland/ ; RYC2023-043831-I//Ramon y Cajal fellowship/ ; MCIN/AEI/10.13039/501100011033//Ramon y Cajal fellowship/ ; FSE+//Ramon y Cajal fellowship/ ; MCIN/AEI/10.13039/501100011033/FEDER//Ramon y Cajal fellowship/ ; EU//Ramon y Cajal fellowship/ ; PID2023-153312OB-I00//Ramon y Cajal fellowship/ ; //CaixaResearch Institute/ ; 860197//European Commission (Marie Curie International Training Network/ ; 101119596//European Commission (Marie Curie International Training Network/ ; 831434//European Commission (Marie Curie International Training Network/ ; 101034344//European Commission (Marie Curie International Training Network/ ; 22HLT07//European Union's Horizon Europe Research and Innovation Programme/ ; 101156175//European Union's Horizon Europe Research and Innovation Programme/ ; 73305095007//Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands/ ; LSHM20106//Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands/ ; 10510032120003//Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands/ ; //Dutch National Dementia Strategy/ ; },
mesh = {Humans ; Biomarkers/cerebrospinal fluid/blood ; Female ; *Neurodegenerative Diseases/cerebrospinal fluid/blood/diagnosis ; Male ; Aged ; *Alzheimer Disease/cerebrospinal fluid/blood/diagnosis ; Lewy Body Disease/cerebrospinal fluid/blood/diagnosis ; Frontotemporal Dementia/cerebrospinal fluid/blood/diagnosis ; },
abstract = {INTRODUCTION: Novel tools for absolute quantification of established and emerging fluid neuro-biomarkers are required to advance diagnostic studies and improve biological insights.

METHODS: We conducted an extensive analytical and clinical validation of the Olink™ Target 48 Neurodegeneration panel (T48 Neuropanel) in 352 paired cerebrospinal fluid (CSF) and plasma samples from cognitively unimpaired controls (CU), Alzheimer's dementia (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), n = 44 per group. Comparisons with benchmark assays were performed.

RESULTS: Good detectability (CSF: 31 out of 42 assays; plasma: 38 out of 42 assays) and technical performance was observed. Benchmark assays showed good correlations, supporting transformation formula's. Next to emerging biomarkers (MMP10, ITGB2), discriminative performance was excellent in AD: CSF pTau217: area under the curve (AUC) = 1; FTD: plasma neurofilament light chain (NfL): AUC = 0.952; and DLB: CSF dopa decarboxylase (DDC): AUC = 0.901.

DISCUSSION: This analytical and clinical validation of the T48 Neuropanel highlights initial cutoffs and emerging biomarkers to aid clinical studies for the diagnosis, prognosis, and monitoring of neurodegenerative diseases.},
}

Humans
Biomarkers/cerebrospinal fluid/blood
Female
*Neurodegenerative Diseases/cerebrospinal fluid/blood/diagnosis
Male
Aged
*Alzheimer Disease/cerebrospinal fluid/blood/diagnosis
Lewy Body Disease/cerebrospinal fluid/blood/diagnosis
Frontotemporal Dementia/cerebrospinal fluid/blood/diagnosis

@article {pmid42949266,
year = {2026},
author = {Qi, YA and Goldberg, TE and Kim, H and Devanand, DP and Lee, S},
title = {Neuropathological Correlates of Apathy Progression in Alzheimer Disease and Related Dementias: A Longitudinal NACC Cohort Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000754},
pmid = {42949266},
issn = {1546-4156},
abstract = {OBJECTIVE: Apathy is disabling in Alzheimer disease (AD) and related dementias, but its progression across neuropathologies remains unclear. This cohort study examined longitudinal apathy-neuropathology associations.

METHODS: We analyzed 1488 participants from the National Alzheimer's Coordinating Center with autopsy-confirmed neuropathology and at least 2 caregiver-reported Neuropsychiatric Inventory Questionnaire assessments. Generalized linear mixed models tested associations between apathy and AD, Lewy body disease, frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HS), cerebrovascular disease, and cerebral amyloid angiopathy. Time was modeled as years to death, including pathology-by-time interactions. Models were adjusted for age at death, sex, and Neuropsychiatric Inventory Questionnaire total score excluding apathy. Sex-stratified analyses were conducted.

RESULTS: Apathy prevalence increased over time across all pathology groups. FTLD [odds ratio (OR) = 2.11, 95% CI: 1.32-3.39] and HS (OR = 2.23, 95% CI: 1.38-3.60) were consistently associated with higher odds of apathy. No pathology-by-time interaction was significant. Among males, FTLD (OR = 2.58, 95% CI 1.40-4.77), HS (OR = 2.48, 95% CI 1.29-4.77), and Lewy body disease (OR = 1.64, 95% CI 1.03-2.61) were significantly associated with apathy, while only HS (OR = 2.18, 95% CI 1.06-4.47) remained significant in females.

CONCLUSION: Apathy severity varied by neuropathologies but progressed similarly over time. The elevated burden in FTLD and HS, particularly among males, underscores the importance of stratified approaches to early detection and intervention targeting apathy in AD and related dementias.},
}

@article {pmid42949371,
year = {2026},
author = {Watanabe-Nakayama, T and Noguchi-Shinohara, M and Umeda, K and Muramatsu, D and Konno, H and Kodera, N and Ando, T and Ono, K},
title = {Real-Time Single Molecule Imaging Reveals Pathway-Selective Action of Aducanumab on Amyloid-β Aggregation.},
journal = {Nano letters},
volume = {26},
number = {42},
pages = {14560-14568},
doi = {10.1021/acs.nanolett.6c02842},
pmid = {42949371},
issn = {1530-6992},
support = {NA//Kanazawa University/ ; JP19K07965//Japan Society for the Promotion of Science/ ; JP22K07514//Japan Society for the Promotion of Science/ ; NA//Ministry of Education, Culture, Sports, Science and Technology/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Antibodies, Monoclonal, Humanized/pharmacology/chemistry ; Microscopy, Atomic Force/methods ; *Single Molecule Imaging/methods ; Humans ; Protein Aggregates/drug effects ; *Peptide Fragments/chemistry ; *Alzheimer Disease/drug therapy ; Protein Binding ; },
abstract = {Aducanumab is an anti-amyloid-β (Aβ) antibody that binds aggregated Aβ species and has been reported to inhibit secondary nucleation on fibril surfaces. However, how antibody binding influences aggregate dynamics at the molecular level remains incompletely understood. Here, we used high-speed atomic force microscopy (HS-AFM) to directly visualize the interactions between aducanumab and Aβ42 aggregates in real time at single-molecule resolution. Aducanumab extensively decorated oligomers, protofibrils, and fibrils, with fibril binding depending on local surface structure. Consistent with its reported inhibition of secondary nucleation, bulk thioflavin T assays showed slowed aggregation. Nevertheless, in the continued presence of the antibody, protofibril formation proceeded─a pathway distinct from secondary nucleation. These observations reveal a pathway-selective mode of action: extensive surface binding and the suppression of secondary nucleation do not extend to protofibril formation, which proceeds in the continued presence of the antibody.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Antibodies, Monoclonal, Humanized/pharmacology/chemistry
Microscopy, Atomic Force/methods
*Single Molecule Imaging/methods
Humans
Protein Aggregates/drug effects
*Peptide Fragments/chemistry
*Alzheimer Disease/drug therapy
Protein Binding

@article {pmid42949499,
year = {2026},
author = {Poddar, K and Wahi, C},
title = {Deep learning models to detect neurodegenerative diseases across different modalities, datasets, and stages: A systematic review.},
journal = {Technology and health care : official journal of the European Society for Engineering and Medicine},
volume = {},
number = {},
pages = {9287329261502060},
doi = {10.1177/09287329261502060},
pmid = {42949499},
issn = {1878-7401},
abstract = {BackgroundNeurodegenerative diseases like Alzheimer's and Parkinson's pose significant diagnostic challenges because they are incurable. Their symptoms often overlap with those of normal ageing and involve progressive neuronal loss. This makes early prediction, proper diagnosis, and ongoing monitoring crucial at every stage of the disease. Deep learning has become a useful tool for handling different types of data. However, the performance of these models relies heavily on the availability and variety of data, making it important to characterize datasets.ObjectiveThis PRISMA-based systematic review looks at 111 studies from 2019 to April 2026, organized into three clinical stages of neurodegenerative diseases: early prediction, diagnosis, and progression.MethodsEach study is assessed across four dimensions: data type (neuroimaging or non-neuroimaging), datasets (open-access, self-created, or hybrid), deep learning model architecture, and the use of explainable AI.ResultsMRI is the only imaging modality that spans all three stages. Speech is the most common non-neuroimaging method for diagnosis, while gait is used only for diagnosis and progression. The ADNI and PPMI datasets are the most commonly used. Self-created datasets introduce new modalities such as ECG and iPSCs, which are not found in open-access datasets. CNNs are the leading models for neuroimaging tasks, while LSTMs and RNNs capture temporal patterns in longitudinal datasets. Survival models are exclusively used for ALS and LATE. Fewer than 6% of the studies used confirmed XAI. Only 2 of the 111 studies validated their results on an independent external cohort.ConclusionThis review is the only one that covers all three disease stages across multiple neurodegenerative diseases.},
}

@article {pmid42949549,
year = {2026},
author = {Xie, T and Xie, X and Chen, X and Jiang, J and Cheng, H and Li, H and Zhang, X and Liu, M and Wang, X and Wu, B and Zhang, JE},
title = {Resistance-to-care behaviors and associated factors among people with dementia in nursing homes based on latent profile analysis and user personas.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498244},
doi = {10.1177/13872877261498244},
pmid = {42949549},
issn = {1875-8908},
abstract = {BackgroundResistance-to-care behaviors are prevalent among people with Alzheimer's disease and related dementia (ADRD), significantly impeding care delivery and causing distress for residents and care workers. However, knowledge regarding scenario-specific resistance-to-care patterns in Chinese nursing homes remains limited.ObjectiveTo identify latent profiles and personas of resistance-to-care behaviors among people with ADRD in Chinese nursing homes and examine associations with background and interpersonal factors based on the need-driven dementia-compromised behavior model.MethodsThis cross-sectional study recruited 574 people with ADRD from six Chinese nursing homes between March 2023 and March 2024. Data on sociodemographics, care worker-initiated communication, resistance-to-care behaviors, cognitive function, functional independence, depression, and pain were collected. Zero-inflated Poisson mixture models identified latent profiles. Personas were developed as group-level summaries integrating profile-defining resistance-to-care patterns with associated descriptive characteristics. Multivariate logistic regression examined factors associated with profile membership.ResultsFour profiles and personas emerged: stable collaborators (low-resistance profile, 77.0%), mealtime resisters (eating-resistance-dominant profile, 6.6%), bathing defenders (bathing-resistance-dominant profile, 13.8%), and high-resistance care responders (high-resistance profile, 2.6%). Eating- and bathing-resistance-dominant profiles were associated with lower cognitive function and absence of care worker-initiated communication during corresponding activities. The high-resistance profile was associated with greater depression and pain.ConclusionsThis study identified latent resistance-to-care profiles and personas, elucidating relationships between background factors, interpersonal factors, and resistance-to-care behaviors. Findings support a culturally informed, scenario-specific framework for dementia care and highlight the potential relevance of regular cognitive monitoring, culturally adapted communication strategies, and systematic depression and pain management for addressing resistance-to-care behaviors.},
}

@article {pmid42949673,
year = {2026},
author = {Vallejo, MS and Paradas, A and Neira, H},
title = {Beyond reproduction: the emerging role of FSH in postmenopausal aging.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {42},
number = {1},
pages = {2752665},
doi = {10.1080/09513590.2026.2752665},
pmid = {42949673},
issn = {1473-0766},
mesh = {Humans ; Female ; *Follicle Stimulating Hormone/blood/physiology ; *Aging/physiology ; *Postmenopause/physiology/blood ; Animals ; },
abstract = {Follicle-stimulating hormone (FSH) is traditionally regarded as a biochemical marker of menopause and declining ovarian function. However, emerging evidence suggests that its role may extend beyond reproductive physiology. During the menopause transition, FSH concentrations rise progressively, initially due to declining inhibin B and later to loss of ovarian estradiol and inhibin production. Evidence of FSH effects in bone, adipose tissue, the cardiovascular system and brain has raised the possibility of broader physiological actions. Higher FSH levels have been associated with bone loss and hip fracture risk, adverse cardiometabolic and vascular changes, and cognitive decline and Alzheimer's disease. Although these associations do not establish causality, they suggest that FSH may contribute to some consequences of reproductive aging rather than simply reflect ovarian failure. Experimental studies indicate that reducing FSH may benefit bone and adiposity, while preliminary clinical evidence regarding cognition remains inconclusive. Thus, FSH may represent not only a marker of menopause, but also a potential marker of risk and, ultimately, a therapeutic target.},
}

Humans
Female
*Follicle Stimulating Hormone/blood/physiology
*Aging/physiology
*Postmenopause/physiology/blood
Animals

@article {pmid42949878,
year = {2026},
author = {Lewis, TS and Wagner, J and Neher, JJ},
title = {Alzheimer's disease research must connect vascular molecular phenotypes with physiology.},
journal = {PLoS biology},
volume = {24},
number = {10},
pages = {e3004051},
doi = {10.1371/journal.pbio.3004051},
pmid = {42949878},
issn = {1545-7885},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism/genetics ; Humans ; Phenotype ; Animals ; Hemodynamics ; },
abstract = {Molecular profiling studies have mapped vascular alterations in Alzheimer's disease, but have not proven a role for them in pathology. Longitudinal studies are needed to link molecular and structural changes to vascular mechanics, hemodynamics, and tissue perfusion.},
}

*Alzheimer Disease/physiopathology/pathology/metabolism/genetics
Humans
Phenotype
Animals
Hemodynamics

@article {pmid42950073,
year = {2026},
author = {Jing, Z and Liu, S and Song, Q and Tian, S and Zhou, Q},
title = {The Epidemiological Transition of Neurodegenerative Diseases in China: A Multi-Layered Deconstruction Using Global Burden of Disease Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag059},
pmid = {42950073},
issn = {1423-0208},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease and other dementias (ADOD), Parkinson's disease (PD), and motor neuron disease (MND), represent a mounting public health challenge in China amid rapid population aging. A systematic deconstruction of their epidemiological transition using the most recent data remains lacking.

METHODS: Data from the Global Burden of Disease Study 2023 were utilized to examine temporal trends (1990-2023) for ADOD, PD, and MND in China. Age-standardized rates of incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability-adjusted life-years (ASDR) were analyzed. Joinpoint regression was used to identify significant inflection points. Decomposition analysis quantified the contributions of population aging, population growth, and epidemiological change. And bayesian age-period-cohort models projected trends to 2035.

RESULTS: From 1990 to 2023, the ASIR for ADOD (EAPC 0.41; 95% CI 0.33 to 0.49) and PD (EAPC 0.84; 95% CI 0.76 to 0.92) rose significantly. Between 2019 and 2023, multiple indicators across the three diseases demonstrated a consistently synchronous upward trend. This acceleration coincided with the COVID-19 pandemic. Decomposition demonstrated that population aging was the dominant driver. Sex-specific disparities were pronounced. Females bore a higher ADOD burden, whereas males predominated in PD. ASIR and ASPR are expected to rise, while ASMR and ASDR are projected to decline for ADOD and PD. For MND, only the ASPR indicated a brief, peaked rise in the predicted trends.

CONCLUSIONS: In the field of neurodegenerative diseases, China is projected to undergo an epidemiological transition characterized by chronicization. This trend calls for systematic adjustments in healthcare services, long-term care systems, and social support structures. Sex and gender differences further underscore the need for gender-sensitive prevention, clinical management, and care strategies to prevent the further widening of inequalities. Population aging remains a critical factor that cannot be overlooked. Therefore, there is an urgent need to establish a proactive, gender-sensitive framework for system-wide restructuring that incorporates long-term monitoring and oversight.},
}

@article {pmid42950080,
year = {2026},
author = {Gonzales, PNG and Baroña, EGH and Villaraza, SG and Dela Rosa, JC and Joson, MLC and Ampil, ER},
title = {Characterization of Risk Factors Using Lifestyle for Brain Health (LIBRA) Index Scores Among Filipino Patients with Mild Cognitive Impairment and Dementia.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag056},
pmid = {42950080},
issn = {1423-0208},
abstract = {INTRODUCTION: Dementia prevention focuses on modifiable lifestyle risks which can be summarized by the Lifestyle for Brain Health (LIBRA) index. This index has limited evaluation in Southeast Asian clinical samples. This study aims to characterize LIBRA scores in a Filipino clinical population with mild cognitive impairment (MCI) and all cause dementia and assess associations with dementia etiologies and cognitive severity.

METHODS: Cross sectional analysis of patients from the Philippine Neurological Association One Database - Dementia registry. LIBRA was operationalized from nine available modifiable factors. Group comparisons used nonparametric tests and binary logistic regression to estimate odds ratios with 95% confidence intervals.

RESULTS: The study included 552 individuals, including 97 (17.6%) with MCI and 455 (82.4%) with dementia. The mean age was 73.9 ± 11.47 years, and 62.7% were female. Total LIBRA scores did not differ between MCI and dementia (p = 0.855). In unadjusted logistic regression models, physical inactivity showed an association with higher odds of dementia (OR 3.85, 95% CI 1.81-8.18, p < 0.001), while obesity showed an inverse association with dementia (OR 0.61, 95% CI 0.38-0.98, p = 0.040). Compared with Alzheimer's disease (AD), vascular dementia (VaD) (OR 1.28, 95% CI 1.13-1.46, p < 0.001) and mixed AD+VaD (OR 1.33, 95% CI 1.17-1.50, p < 0.001) had significantly higher LIBRA scores. Total LIBRA scores were not associated with cognitive impairment severity in dementia. These associations should be interpreted cautiously given the descriptive cross-sectional design.

CONCLUSION: LIBRA captures modifiable vascular and lifestyle burden which can be associated with vascular-related dementias. The index is more useful for risk stratification and prevention counseling than for cross sectional diagnosis or severity assessment.},
}

@article {pmid42950713,
year = {2026},
author = {Bodke, S and Shelke, P and Bhatt, LK},
title = {The orexinergic-endocannabinoid interface: mechanistic and therapeutic perspectives in Alzheimer's disease, anxiety, and visceral pain.},
journal = {Neuropeptides},
volume = {120},
number = {},
pages = {102665},
doi = {10.1016/j.npep.2026.102665},
pmid = {42950713},
issn = {1532-2785},
abstract = {Orexinergic system is involved in conditions like narcolepsy, eating disorders, central and neuropathic pain where it is directly or indirectly contributing towards the development of symptoms of these conditions. Endocannabinoid system is present throughout the body and acts via cannabinoid (CB) receptors which have their own role in pain modulation, memory processing, movement and balance control. Evidence is growing that the two systems interact, both through receptor-level mechanisms and through orexin-driven synthesis of 2-arachidonoylglycerol (2-AG). CB1-OX1 heteromer formation has been demonstrated in heterologous cell systems, and OX1 antagonism has been reported to potentiate CB2 signalling in microglial models of Alzheimer's disease (AD), although the therapeutic value of orexin antagonism in AD remains unresolved. In rodent fear-extinction paradigms, orexin-A impairs extinction through a 2-AG-dependent mechanism involving microglial CB2 receptors in the basolateral amygdala. In rodent models of visceral pain, CB1 and CB2 antagonists block the visceral hyposensitivity induced by centrally administered orexin, indicating that endocannabinoid signalling is required for this effect. This review summarises the evidence for orexin-endocannabinoid interaction in AD, anxiety and visceral pain, and discusses translational implications, including the absence of approved drugs acting on both systems.},
}

@article {pmid42950793,
year = {2026},
author = {Hung, NV and Hoang, VH and Long, LTB and Linh, VNH and Tien, LQ and Linh, TVT and Bang, LTT and Nguyen, TK and Pham, HTN and Minh, DT and Hien, TTT and Wang, S and Tran, PT},
title = {Discovery of novel pyridine-2-tetrazole derivatives as in vivo memory enhancement agents.},
journal = {Bioorganic chemistry},
volume = {184},
number = {},
pages = {110683},
doi = {10.1016/j.bioorg.2026.110683},
pmid = {42950793},
issn = {1090-2120},
abstract = {Despite the currently incurable nature of Alzheimer's disease (AD), acetylcholinesterase (AChE) inhibitors remain the primary therapeutic strategy for symptom management. In this study, twenty-five novel pyridine-2-tetrazole derivatives were designed, their binding affinities with AChE were predicted using machine learning models, and their drug-likeness were calculated. Following their synthesis, the compounds were evaluated in vitro for AChE inhibitory activity. Based on these findings, lead compounds 11 and 28 were selected for in vivo assessment to determine their effects on cognitive function in trimethyltin (TMT)-induced cognitive impairment mouse models at dosages of 20 mg/kg and 60 mg/kg. Although compound 28 exhibited modest in vitro AChE inhibition, it significantly improved cognitive performance in TMT-induced mice across both dosage groups. This cognitive enhancement was demonstrated through the Object Recognition Test, modified Y-maze, and Passive Avoidance Test. These findings suggest that compound 28 may exert its neuroprotective effects through a different molecular mechanism rather than exclusive AChE inhibition, highlighting its potential as a lead compound for the treatment of cognitive impairment and related neurodegenerative disorders such as AD.},
}

@article {pmid42950904,
year = {2026},
author = {Shang, J and Wang, Y and Wang, W and Dai, F and Liu, J and Li, X and Xie, X and Pang, X},
title = {Dihydrocaffeic acid alleviates APOE4-associated astrocyte dysfunction and cognitive impairment via LRP1/p38 MAPK signaling.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122568},
doi = {10.1016/j.jep.2026.122568},
pmid = {42950904},
issn = {1872-7573},
abstract = {Dihydrocaffeic acid (DHCA) is a phenolic acid produced through the microbial metabolism of plant-derived caffeoylquinic acids. DHCA has been detected in human plasma following oral administration of a standardized aqueous extract of Centella asiatica (L.) Urb., a medicinal plant traditionally used to improve memory and cognitive function. However, whether DHCA exerts neuroprotective effects against APOE4-associated Alzheimer's disease-like pathology remains unclear.

AIM OF THE STUDY: To investigate whether DHCA ameliorates APOE4-associated cognitive deficits and neuropathological abnormalities and to assess the role of astrocytic LRP1/p38 MAPK signaling.

MATERIALS AND METHODS: Twelve-month-old APOE4 mice were administered DHCA once daily for 21 days, with age-matched APOE3 mice and vehicle-treated APOE4 mice serving as controls. Cognitive function, Alzheimer's disease-related neuropathology, neuronal and synaptic integrity, astrocyte phenotypes, and lipid metabolism were evaluated. Mechanistic studies were performed in APOE4-overexpressing U251 cells using siRNA-mediated LRP1 knockdown and pharmacological activation of p38 MAPK.

RESULTS: DHCA improved object recognition and spatial learning and memory, reduced amyloid deposition and tau phosphorylation, restored neuronal and synaptic markers, shifted astrocyte-reactivity markers toward a neuroprotective profile, and restored proteins involved in lipid metabolism. DHCA also increased LRP1 expression and reduced p38 MAPK phosphorylation. LRP1 knockdown or p38 MAPK activation partially reversed these cellular effects.

CONCLUSIONS: DHCA ameliorated APOE4-associated cognitive deficits and neuropathological alterations, at least partly through modulation of LRP1/p38 MAPK-related signaling in the APOE4-overexpressing U251 model, astrocyte reactivity, and lipid metabolism. These findings identify DHCA as a potential neuroprotective metabolite derived from plant polyphenols.},
}

@article {pmid42950967,
year = {2026},
author = {Hu, J and Wang, WX},
title = {Lead-Aggravated Duodenal Barrier Injury Accompanied by Fecal Microbiota Alterations in 5xFAD Mice.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {129434},
doi = {10.1016/j.envpol.2026.129434},
pmid = {42950967},
issn = {1873-6424},
abstract = {Lead (Pb) is a persistent environmental toxicant, yet its effects on intestinal homeostasis in the 5xFAD background remain poorly characterized. Six-month-old 5xFAD mice were exposed to 200 μg/L Pb in drinking water for 8 weeks, with age-matched wild-type and unexposed 5xFAD mice serving as reference groups. We integrated duodenal metal profiling, mucosal architecture assessment, proteomic analysis, and fecal 16S rRNA sequencing to characterize the Pb-associated intestinal responses. Pb exposure increased duodenal Pb burden and reduced Ca, Cu, and Mg concentrations relative to unexposed 5xFAD mice. These elemental changes were accompanied by more pronounced villus shortening, crypt deepening, a lower villus height-to-crypt depth ratio, and loss of AB-PAS-positive goblet cells, suggesting impaired mucosal architecture and mucus-associated protection. Duodenal proteomic screening identified Pb-associated patterns involving epithelial junction organization, cell adhesion, calcium signaling, mineral absorption, complement activation, and mucosal immune pathways. In parallel, Pb-exposed 5xFAD mice showed lower fecal microbial richness and diversity than the unexposed 5xFAD mice, together with reduced abundances of Lachnospiraceae-related commensals and compositional shifts involving taxa associated with inflammatory or barrier-stress responses. Chronic Pb exposure in 5xFAD mice was associated with concurrent changes in duodenal metal homeostasis, mucosal structure, pathway-level proteomic profiles, and distal fecal microbial ecology. The duodenal findings highlight the proximal small intestine as a relevant peripheral site of Pb toxicity.},
}

@article {pmid42950990,
year = {2026},
author = {Yun, Y and Jena, S and Egido-Betancourt, H and Uzoechi, S and Kim, DY and Lee, JM and Nguyen, J},
title = {Engineering human brain microphysiological systems for alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) modeling and drug testing: translational promise, limitations, and future directions.},
journal = {Advanced drug delivery reviews},
volume = {},
number = {},
pages = {115982},
doi = {10.1016/j.addr.2026.115982},
pmid = {42950990},
issn = {1872-8294},
abstract = {This review examines the emerging role of human brain microphysiological systems (HBMPS) in recapitulating diseases and evaluating their translational potential and limitations for Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Both disorders differ in underlying cause, but converge on shared downstream pathophysiology such as tau pathology, neuroinflammation, and blood-brain barrier (BBB) dysfunction. We review the critical pathophysiological features relevant to modeling AD and CTE and introduce HBMPS platforms/validation strategies as potential tools for evaluating therapeutic compounds as well as drug-delivery approaches. We also provide a systematic comparison of the relative advantages and disadvantages of 2D, HBMPS, Xenograft, and animal models and discuss the future potential of HBMPS's drug-testing platform. We further discuss current challenges of HBMPS related to drug testing, engineering extracellular matrix for tissue chips, and BBB penetration in AD and CTE. We suggest future integration of organoid xenografts and AI-assisted frameworks to enhance pathophysiological fidelity/drug predictive capability and to bridge the gap between HBMPS and animal models. In summary, this paper reviews HBMPS technologies as future translation platforms' direction for drug screening and delivery, while providing current limitations and challenges including model validation, reproducibility, and standardized regulatory bases required for preclinical success for HBMPS use. Rather than comparing biological complexity with translational validity, this review applies a decision-oriented framework that distinguishes mechanistic fidelity, comparative candidate ranking, predictive validation, investigational new drug (IND)-supporting use, and replacement of a defined animal test. For each use, we identify quantitative transport, exposure-response, pharmacodynamic, safety, and reproducibility evidence required to support an advance, redesign, or go/stop decision.},
}

@article {pmid42951114,
year = {2026},
author = {Choi, IY and Payne, C and Lee, P and Spaeth, K and Taylor, M and Sullivan, DK},
title = {The Effects of Blueberry Consumption on Cerebral Blood Flow and Brain Glutathione Levels in Older Adults: A Double-Blind Randomized, Placebo-Controlled Trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101613},
doi = {10.1016/j.ajcnut.2026.101613},
pmid = {42951114},
issn = {1938-3207},
abstract = {BACKGROUND: Age-related declines in brain antioxidant capacity and cerebral blood flow (CBF) contribute to cognitive decline and increase the risk of Alzheimer's disease and dementias. Dietary approaches that enhance cerebral antioxidant defenses and CBF may promote brain health during aging. Blueberries are rich in polyphenols with antioxidant properties, and cardiometabolic and endothelial benefits, and may improve both brain glutathione (GSH), a major endogenous antioxidant, and CBF. However, the effects of blueberry intake on brain GSH and CBF have not been well established.

OBJECTIVE: To determine the effects of blueberry consumption on brain GSH and CBF in brain regions vulnerable to aging and neurodegeneration in older adults.

METHODS: In a double-blind, randomized, placebo-controlled trial, older adults aged 65-89 years with low berry intake (≤1 serving/week) consumed freeze-dried whole blueberry powder (hereafter "blueberry") equivalent to one cup of fresh blueberries or a matched placebo powder for three months. Brain GSH and regional CBF were measured using multiple quantum chemical shift imaging and pseudo-continuous arterial spin labeling MRI, respectively.

RESULTS: Sixty participants completed the intervention with adherence exceeding 92% in both groups. Blueberry powder consumption did not alter brain GSH concentrations compared with placebo but significantly increased CBF in the anterior cingulate cortex (P=0.03), a region involved in executive function and cognitive control. Within-group analyses showed increased CBF after blueberry consumption in the anterior cingulate cortex (7%, P=0.03; 95% confidence interval: 1.0%, 14.7%), caudate (7%, P=0.01; 2.9%, 15.8%), and putamen (6%, P=0.04; 0.3%, 13.9%), whereas no significant changes were observed in the placebo group.

CONCLUSIONS: Compared with placebo, blueberry consumption increased CBF in the anterior cingulate cortex, a brain region relevant to age-related cognitive decline. No corresponding brain GSH changes were observed, suggesting that the effects of blueberry polyphenols are more consistent with vascular modulation than alterations in cerebral antioxidant status.

NCT05024916 CLINICAL TRIAL REGISTRY URL: https://clinicaltrials.gov/study/NCT05024916.},
}

@article {pmid42951225,
year = {2026},
author = {Gao, Y and Xu, M and Ou, P and Yang, H and Wang, J and Liu, W and Sun, Y and Du, W and Wang, Y and Liu, T and Xia, H and Fu, L and Shu, N and Yuan, Z and Ma, G},
title = {A multimodal MRI study of DTI-ALPS and cerebral blood flow changes across the Alzheimer's disease continuum.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122322},
doi = {10.1016/j.neuroimage.2026.122322},
pmid = {42951225},
issn = {1095-9572},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by cerebral blood flow (CBF) abnormalities and alterations in the neurofluid-related brain tissue environment, but their evolution along the AD continuum and links to cognitive decline and plasma biomarkers remain unclear. Using multimodal MRI, we quantified the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and CBF alterations and examined their associations with cognitive performance and plasma biomarkers across the AD continuum.

METHODS: This study enrolled 78 healthy controls (HC), 53 subjective cognitive decline (SCD), 40 mild cognitive impairment (MCI), 110 AD. All subjects received MRI and neurocognitive assessments. The DTI-ALPS index was used as a diffusion-based marker of directional water diffusivity within periventricular white matter and the neurofluid-related tissue environment. CBF changes were calculated, and plasma biomarkers associated with neurodegeneration were measured. Partial correlation analysis explored relationships among ALPS index, CBF in cognition-related brain regions, cognitive scores, and plasma biomarkers. Statistical mediation analyses were performed to assess indirect effects involving the ALPS index and plasma biomarkers in the association between regional CBF and cognitive performance.

RESULTS: ALPS index decreased stage-dependently along the AD continuum, significantly lower in MCI and AD versus HC and SCD. HC and SCD showed higher CBF than AD in right middle cingulate and left inferior parietal lobule. CBF in bilateral angular gyri and right superior frontal gyrus positively correlated with MoCA and RAVLT scores. Cognition-related CBF positively correlated with bilateral mean ALPS index, and negatively with NfL and p-tau217. Statistical mediation analyses identified significant indirect effects involving the bilateral mean ALPS index and plasma NfL in the association between regional CBF and cognitive performance.

DISCUSSION: Cerebral hypoperfusion, altered DTI-ALPS measures, and axonal injury were closely associated across the AD continuum, suggesting interrelated neurovascular, neurofluid-related tissue, and neurodegenerative alterations associated with cognitive impairment.},
}

@article {pmid42951263,
year = {2026},
author = {Liu, J and Zhang, C and Li, K and Zhang, C and Si, Q and Wang, M and Liu, J and Zhao, J},
title = {Chronic Polystyrene Microplastic Exposure Worsens Cognitive Dysfunction and Alzheimer's Disease-like Neuropathology in APP/PS1 Mice.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103594},
doi = {10.1016/j.neuro.2026.103594},
pmid = {42951263},
issn = {1872-9711},
abstract = {Microplastics are emerging environmental contaminants with potential neurotoxic effects, but their impact on Alzheimer's disease (AD)-susceptible brains remains unclear. This study examined whether chronic exposure to 1 μm polystyrene microplastics (PS-MPs) aggravates cognitive dysfunction and AD-like neuropathological injury in APP/PS1 mice. Four-week-old male APP/PS1 and C57BL/6 mice were exposed to fluorescent PS-MPs at 100μg/L in drinking water for six months. Spatial learning and memory were evaluated using the Morris water maze. Brain fluorescence signals, neuronal injury, amyloid-reactive staining, glial activation, DNA fragmentation-associated injury, and cGAS-STING pathway markers were examined by in vivo imaging, histology, immunofluorescence, and Western blotting. PS-MPs exposure was associated with enhanced brain-region fluorescence signals and mild pathological changes in C57BL/6 mice. In APP/PS1 mice, PS-MPs exposure further prolonged escape latency, reduced platform crossings and target-quadrant residence time, increased amyloid-reactive staining, decreased NeuN signals, enhanced Iba1 and GFAP immunoreactivity, increased TUNEL-positive signals, and increased cGAS, STING, TBK1, and p-IRF3/IRF3. These findings suggest that chronic PS-MPs exposure aggravates AD-like cognitive and neuropathological abnormalities in APP/PS1 mice and is accompanied by cGAS-STING-related inflammatory signaling.},
}

@article {pmid42951505,
year = {2026},
author = {Zhou, J and Zhang, W and Yang, Y and Jin, Y and Li, X and Wang, Y and Lu, H and Gao, H and Jiang, X},
title = {CCA, a cassane diterpene from Caesalpinia bonduc ameliorates cognition impairment in Alzheimer's disease mice by regulating neuroinflammation and autophagy.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {11},
pages = {1392-1408},
doi = {10.1016/S1875-5364(26)61228-9},
pmid = {42951505},
issn = {1875-5364},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder, with persistent neuroinflammation and impaired autophagy recognized as key contributing factors. CCA is a naturally occurring cassane diterpene compound derived from the seed of Caesalpinia bonduc. Our research is the first to explore the role and mechanism of CCA in treating Alzheimer's disease. We assessed the levels of pro-inflammatory cytokines and autophagy in BV2 cells following lipopolysaccharide (LPS) treatment and anti-neuroinflammatory effects of CCA were evaluated in LPS-induced mice, with the underlying mechanisms explored using transcriptomic. Additionally, we examined the cognitive-enhancing effects of CCA in APP/PS1 mice and investigated Caesalpinia bonduc associated molecular mechanisms through proteomic analysis, immunohistochemistry (IHC) and immunofluorescence (IF) assays. Finally, the molecular target of CCA was validated using molecular dynamics simulations and cellular thermal shift assay (CETSA). CCA can down-regulate the mRNA levels of inflammatory factors in BV2 cells stimulated by LPS, and has good permeability of blood-brain barrier. Furthermore, CCA ameliorated cognitive impairment and neuronal damage in both LPS-induced and APP/PS1 mice. And demonstrated that CCA mitigates neuroinflammation by driving microglial polarization from M1 to M2, a process potentially mediated by the AMPK/NF-κB pathway, thereby reducing tau pathology. Proteomic profiling and IHC revealed that CCA upregulates FOXG1 expression in APP/PS1 mice. Furthermore, the scTenifoldKnk confirmed that AMPK has a significant impact on the regulation of autophagy and inflammation response. Our findings verified that CCA exhibits anti-neuroinflammatory activity by AMPK/NF-κB pathway and activates autophagy via the AMPK-mTOR-FOXG1 signaling axis, which underscores its potential as a novel therapeutic option for the treatment of AD.},
}

@article {pmid42951512,
year = {2026},
author = {Zhang, J and Wang, J and Wei, J and Li, J and He, M and Liu, C},
title = {"Apple tree"-like AuNPs@enzyme microreactor: A reusable microfluidic paper-based analytical device for improved acetylcholinesterase inhibitors screening.},
journal = {Analytica chimica acta},
volume = {1425},
number = {},
pages = {346261},
doi = {10.1016/j.aca.2026.346261},
pmid = {42951512},
issn = {1873-4324},
abstract = {BACKGROUND: Acetylcholinesterase (AChE) inhibitors are key therapeutic agents for neurological disorders such as Alzheimer's disease, yet conventional screening of natural product inhibitors are often time-consuming, instrument-dependent, and limited in reusability. To address this, we developed a simple, colorimetric platform based on a reusable microfluidic paper-based analytical device integrated with Au nanoparticle (AuNPs)-mediated enzyme microreactors, coupled with smartphone-based RGB values (blue (B), green (G), and red (R) channel) analysis for rapid and on-site screening of AChE inhibitors from natural products. The microreactors feature an "apple tree"-like architecture, in which AuNPs serve as the "fruits" enabling high-density oriented enzyme immobilization, enhanced substrate accessibility, and excellent reusability.

RESULTS: AChE was oriented immobilized on concanavalin A-modified AuNPs surface via affinity self-assembly, achieving an 8.6-fold increase in enzyme loading compared to direct adsorption. The immobilized enzyme retained 87.0% of its initial activity after 80 consecutive assays, demonstrating excellent reusability and stability. The method showed superior repeatability with intraday, interday, and batch-to-batch relative standard deviations (RSD) of the colorimetric readouts all below 1.0%. The system enabled visual, quantitative evaluation during bioassay-guided fractionation, substantially reducing unnecessary separation steps. Moreover, half-maximal inhibitory concentration (IC50) values of seven compounds from natural products were determined, correlating well with the reference UV method, confirming the reliability for practical inhibitor screening.

SIGNIFICANCE: This platform offers a cost-effective, reusable, and user-friendly tool for early-stage screening of AChE inhibitors in natural extracts, with potential to accelerate the discovery of lead compounds for neurodegenerative disease therapy while minimizing resource consumption and analytical workload.},
}

@article {pmid42934100,
year = {2026},
author = {Chen, L and Long, Y and Huang, D and Zheng, G and Meng, X},
title = {[Lead exposure aggravates Aβ1-42-induced microglial activation through mitochondrial calcium uniporter-mediated mitochondrial calcium accumulation].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2384-2392},
pmid = {42934100},
issn = {1673-4254},
support = {82473665//National NaturalScience Foundation of China/ ; },
mesh = {*Microglia/drug effects/metabolism ; *Amyloid beta-Peptides ; *Calcium Channels/metabolism ; Animals ; Mice ; *Peptide Fragments ; *Calcium/metabolism ; *Mitochondria/metabolism ; *Lead/toxicity ; Cell Line ; Oxidative Stress ; Nitric Oxide Synthase Type II/metabolism ; Alzheimer Disease ; },
abstract = {OBJECTIVES: To investigate the role of mitochondrial calcium uniporter (MCU) in lead (Pb)‑potentiated microglial activation induced by amyloid β‑protein (1-42) (Aβ1-42) and the regulatory mechanism by which Pb exacerbates Alzheimer disease (AD)-like pathology.

METHODS: Cultured BV2 cells treated with 10 μmol/L Aβ1-42 for 12 h (Aβ1-42 group), 10 μmol/L Pb for 12 h (Pb group), or 10 μmol/L Aβ1-42 for 1 h followed by 10 μmol/L Pb for 12 h (Aβ1-42+Pb group) were examined for changes in intracellular calcium levels using ICP-MS. Morphological changes of the treated cells were observed, and iNOS release and oxidative stress were assessed with immunofluorescence staining. The changes in cellular MCU protein expression was determined with Western blotting, and cell viability was evaluated using CCK-8 assay.

RESULTS: Compared with Aβ1-42-treated cells, the cells with the combined treatment showed significantly elevated mitochondrial Ca²⁺ content and increased MCU protein expression. Downregulation of MCU expression obviously alleviated the reduction of viability of HT22 cells treated with the supernatant from BV2 cells co-treated with Pb and Aβ1-42. The combined treatment with lead and Aβ1-42 caused activation of BV2 cells, manifested by increased cell volume and number of protrusions and intensified fluorescence signals of both Iba1 and iNOS. Downregulation of MCU expression significantly suppressed activation of BV2 cells in the siMCU+Aβ1-42+Pb group, and obviously lowered oxidative stress level, mitochondrial calcium overload, and membrane potential level in the cells.

CONCLUSIONS: Pb exposure exacerbates neuronal injury mediated by Aβ1-42-activated microglia through upregulation of MCU expression, which causes mitochondrial calcium accumulation to trigger oxidative stress.},
}

*Microglia/drug effects/metabolism
*Amyloid beta-Peptides
*Calcium Channels/metabolism
Animals
Mice
*Peptide Fragments
*Calcium/metabolism
*Mitochondria/metabolism
*Lead/toxicity
Cell Line
Oxidative Stress
Nitric Oxide Synthase Type II/metabolism
Alzheimer Disease

@article {pmid42934111,
year = {2026},
author = {Ruan, Y and Cui, C and Li, J and Wang, Y and Wang, X},
title = {[Jiaotaiwan improves lipid metabolism abnormalities in a mouse model of Alzheimer disease by regulating the AMPK signaling pathway].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2509-2517},
pmid = {42934111},
issn = {1673-4254},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; Male ; *Lipid Metabolism/drug effects ; *Signal Transduction/drug effects ; Mice ; *AMP-Activated Protein Kinases/metabolism ; *Drugs, Chinese Herbal/pharmacology ; Mice, Inbred C57BL ; Mice, Transgenic ; Disease Models, Animal ; Brain/metabolism ; PC12 Cells ; },
abstract = {OBJECTIVES: To explore whether Jiaotaiwan ameliorates Alzheimer disease (AD) by regulating lipid metabolism via the AMPK pathway.

METHODS: Twenty 3-month-old male transgenic APP/PS1 mice were randomized equally into two groups for treatment with Jiaotaiwan or normal saline via gavage for 4 weeks, with 10 saline-treated wild-type C57BL/6J mice as the control group. Brain lipid deposition, plasma and brain TC, TG and NEFA levels, and expressions of BACE1, Aβ, p-Tau, ZO-1, occludin, AMPK/p-AMPK, SREBP1, ACC, ATGL, and APOE in the brain tissues were detected. In the in vitro experiment, PC12 cell co-cultured with mature adipocytes were treated with Jiaotaiwan, AICAR, or both, and the intracellular lipid droplets, TG, NEFA, AMPK activity, and ACC expression were measured.

RESULTS: In the AD mouse models, Jiaotaiwan significantly reduced brain lipid deposits, lowered plasma TC and TG levels, increased plasma NEFA level, and decreased brain TG and NEFA expressions without affecting TC expression. Jiaotaiwan treatment also significantly lowered the expressions of cerebral Aβ and p-Tau, increased cerebral occludin expression and p-AMPK/AMPK ratio, and reduced ACC, SREBP1 and APOE expressions without affecting ATGL expression in the mouse models. In the co-cultured cells, Jiaotaiwan obviously alleviated cellular lipid accumulation, lowered cellular TG and NEFA levels, reduced supernatant TG content, and enhanced NEFA release. In both the AD mouse model and co-cultured cell model, Jiaotaiwan significantly lowered Aβ level, increased AMPK activity and p-AMPK/AMPK expression, and lowered the expressions of ACC. Jiaotaiwan combined with AICAR produced a synergistic effect for enhancing p-AMPK/AMPK expressions in the co-cultured cells.

CONCLUSIONS: In the APP/PS1 mouse model of AD, Jiaotaiwan alleviates AD-related lipid deposition and dysregulation by activating AMPK and modulating the downstream lipogenic effectors, providing also protective effects on the blood-brain barrier and neural cells.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy
Male
*Lipid Metabolism/drug effects
*Signal Transduction/drug effects
Mice
*AMP-Activated Protein Kinases/metabolism
*Drugs, Chinese Herbal/pharmacology
Mice, Inbred C57BL
Mice, Transgenic
Disease Models, Animal
Brain/metabolism
PC12 Cells

@article {pmid42934178,
year = {2026},
author = {Liang, J and Cao, H and Ren, X and Sha, N and Han, X and Jiang, L and Liu, B and Zhao, W},
title = {Histone Modifications at the Intersection of Aging, Neuroinflammation and Metabolism in Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {11},
pages = {},
pmid = {42934178},
issn = {1474-9726},
support = {LH2023H073//Natural Science Foundation of Heilongjiang Province/ ; 2026yjscx001//Innovative Research Project for Postgraduate Students of Heilongjiang University of Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *Aging/metabolism ; Animals ; *Histones/metabolism ; *Neuroinflammatory Diseases/metabolism ; *Inflammation/metabolism ; Protein Processing, Post-Translational ; Microglia/metabolism ; },
abstract = {Aging, neuroinflammation and metabolic dysfunction are tightly intertwined in Alzheimer's disease (AD), but how transient pathological signals become persistent cellular states remains poorly understood. Histone post-translational modifications (PTMs) provide a dynamic interface between extracellular stimuli, cellular metabolism and chromatin state. This Review examines how canonical histone modifications and emerging metabolite-derived acylations regulate inflammatory and stress-responsive programmes across microglia, astrocytes and neurons during aging and AD. We discuss how amyloid-β, tau pathology, metabolic dysfunction and innate immune signaling converge on histone-modifying machinery, and how reciprocal interactions between metabolism and chromatin may stabilize disease-associated cell states. Particular attention is given to cellular senescence and neuroimmune memory, while emphasizing the context dependence of individual histone marks across cell types, genomic regions and disease stages. We further evaluate evidence for causality using three criteria: perturbation, persistence and reversibility. This framework distinguishes chromatin states that accompany ongoing pathology from those capable of sustaining pathological cell states beyond their initiating signals. Finally, we consider therapeutic strategies targeting histone-modifying enzymes, chromatin readers and metabolic inputs to restore chromatin plasticity and promote resolution of chronic neuroinflammation.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*Aging/metabolism
Animals
*Histones/metabolism
*Neuroinflammatory Diseases/metabolism
*Inflammation/metabolism
Protein Processing, Post-Translational
Microglia/metabolism

@article {pmid42934374,
year = {2026},
author = {Rao, A and Anwar, M and Rao, AR and Painkra, B and Kiruthika, S and Kumar, S and Yadav, Y and Dey, AB and Dey, S and Chatterjee, P},
title = {Serum neurofilament light protein as a biomarker across the cognitive decline continuum: a cross-sectional study from an Indian cohort.},
journal = {Aging clinical and experimental research},
volume = {38},
number = {1},
pages = {},
pmid = {42934374},
issn = {1720-8319},
mesh = {Humans ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Male ; Aged ; *Cognitive Dysfunction/blood/diagnosis ; India ; Cross-Sectional Studies ; Female ; *Alzheimer Disease/blood/diagnosis ; Case-Control Studies ; ROC Curve ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: The Alzheimer's disease (AD) continuum spans from healthy aging to subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Serum Neurofilament Light Protein (NfL) is a potential non-invasive biomarker for neurodegeneration. This study evaluates serum NfL across the cognitive decline continuum in an Indian cohort.

AIMS: To assess serum NfL as a biomarker for early and progressive neurodegeneration, including its diagnostic utility in SCD, MCI, and AD.

METHODS: This case-control study included 129 participants: 28 cognitively normal older adults (HC), 32 with SCD, 33 with MCI, and 36 with AD. Serum NfL levels were measured using Simoa[®] technology. The association of NfL with cognitive decline was analyzed using a Generalized Linear Model (GLM) adjusted for age and sex, and receiver operating characteristic (ROC) curves assessed diagnostic performance.

RESULTS: Serum NfL median levels progressively increased across groups: HC (21.1 pg/mL), SCD (28.94 pg/mL), MCI (35.5 pg/mL), and AD (48.64 pg/mL). Compared to HC, NfL levels were significantly higher in SCD (adjusted coefficient: 0.59, p = 0.004), MCI (0.72, p = 0.001), and AD (1.13, p < 0.001). ROC analysis showed good discrimination: AUC was 0.795 for SCD vs. HC, 0.908 for MCI vs.HC, and 0.941 for AD vs. HC.

DISCUSSION: The study demonstrates a clear association between rising serum NfL levels and advancing cognitive decline.

CONCLUSIONS: Serum NfL demonstrated potential as a sensitive and non-invasive biomarker for early detection and staging of cognitive decline. The establishment of population-specific cut-offs within an Indian cohort contributes to global efforts toward standardizing blood-based biomarkers for AD.},
}

Humans
*Neurofilament Proteins/blood
Biomarkers/blood
Male
Aged
*Cognitive Dysfunction/blood/diagnosis
India
Cross-Sectional Studies
Female
*Alzheimer Disease/blood/diagnosis
Case-Control Studies
ROC Curve
Middle Aged
Cohort Studies

@article {pmid42934377,
year = {2026},
author = {Wu, Y and Zhang, X and Gao, C and Zhang, Z and Liao, X and Kang, Y},
title = {The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42934377},
issn = {1573-6830},
support = {2024MZFS007//Research Grant of Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education/ ; 82272199//National Natural Science Foundation of China/ ; 2022YFC2504500//Key Technologies Research and Development Program/ ; },
mesh = {Humans ; Animals ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; Inflammation/metabolism/pathology ; },
abstract = {Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.},
}

Humans
Animals
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
*Nervous System Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
*Membrane Proteins/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
STING Protein
Signal Transduction
Inflammation/metabolism/pathology

@article {pmid42934475,
year = {2026},
author = {Lázár, T and Radics, E and Engh, MA and Turkel, C and Tóth, R and Kói, T and Hegyi, P and Kéri, S and Horváth, AA},
title = {How well do dementia risk scores predict dementia? A systematic review and meta-analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42934475},
issn = {2509-2723},
abstract = {In our systematic review and meta-analysis, we aimed to assess the predictive accuracy and clinical applicability of ten dementia risk assessment scores for incident dementia in cohort studies. Three of 10 risk scores had sufficient, comparable data for a meta-analysis. We analyzed the Cardiovascular Risk Factors Ageing and Dementia (CAIDE), Lifestyle for brain health (LIBRA), and Alzheimer's Disease Risk Index (ANU-ADRI) in middle- and older-aged baseline populations with short, medium, and long follow-up durations, starting free from dementia, with or without other health conditions. A total of 29 studies met our inclusion criteria; 13 were included in the meta-analyses. CAIDE performed best, particularly among middle-aged participants at baseline, with longer follow-up periods, yielding pooled areas under the curves (AUCs) of 0.74-0.76. ANU-ADRI showed stable, moderate predictive accuracy with AUCs of approximately 0.65-0.71. The original LIBRA showed the lowest discrimination, with AUCs ranging from 0.51 to 0.60, whereas the modified LIBRA performed better, with AUCs of 0.65-0.67 at short follow-up and a pooled AUC of 0.70 (95% CI 0.66-0.74) at medium follow-up. Dementia risk assessment scales show variable predictive performance across scores, baseline age, and follow-up duration, and may be useful for dementia risk stratification in clinical practice. As a substantial proportion of dementia risk is linked to potentially modifiable factors, identifying high-risk individuals may help guide timely risk-reduction strategies. Further prospective validation is needed across different populations and clinical settings.},
}

@article {pmid42934585,
year = {2026},
author = {Mastaglio, E and Egleston, B and Lee, KT and Fetzer, D and Brown, S and Domchek, SM and Fleisher, L and Yi-Wen, K and Wagner, L and Roberts, S and Cacioppo, C and Christiansen, J and Howe, S and Wood, EM and Weinberg, M and Karpink, K and Selmani, E and Feng, J and John, S and Schweickert, K and McLeod, B and Bradbury, AR},
title = {A Randomized Hybrid Type I Effectiveness-Implementation Study of an eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Cancer (eREACH2): study protocol.},
journal = {BMC cancer},
volume = {26},
number = {1},
pages = {},
pmid = {42934585},
issn = {1471-2407},
support = {U01CA243702/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Genetic Testing/methods ; *Genetic Counseling/methods ; Female ; Telemedicine ; Genetic Predisposition to Disease ; Adult ; Return of Individual Research Results ; *Neoplasms/genetics/diagnosis ; Male ; },
abstract = {BACKGROUND: Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. There are also targeted treatments for some genetic carriers with cancers such as breast and ovarian cancer. Yet, many at-risk patients do not have access to genetic services, leaving many genetic carriers unidentified. The eREACH 2 study (A Randomized Hybrid Type I Effectiveness-Implementation Study of an eReach Delivery Alternative for Cancer Genetic Testing for Hereditary Cancer) evaluates whether an interactive, patient-centered digital alternative for genetic education and disclosure of results is non-inferior compared to the traditional model of pre- and post-test counseling with a genetic counselor.

METHODS: This is a Hybrid Type 1 effectiveness implementation study in which participants are randomized using a 2 × 2 design to test a self-directed, patient-informed, digital intervention to deliver clinical genetic testing versus the traditional pre-test (visit 1) and post-test (visit 2: disclosure) counseling delivered by a genetic counselor. The 4 arms include (A) genetic counselor for visit 1 and visit 2, (B) genetic counselor for visit 1 and digital intervention for visit 2, (C) digital intervention for visit 1 and genetic counselor for visit 2, and (D) digital intervention for both visits. Participants are adults who meet National Comprehensive Cancer Network and/or American Society of Clinical Oncology guidelines for germline genetic testing and are recruited from both community and medical sites across the United States by way of clinician referral as well as patient self-referral. The primary outcomes are non-inferiority in uptake of genetic testing and change in genetic knowledge and general anxiety from baseline to post-disclosure.

DISCUSSION: With many barriers to accessing genetic services, innovative delivery models are needed to address these gaps and increase uptake of genetic services. The eREACH2 study evaluates the effectiveness of an interactive patient-centered digital intervention to deliver clinical genetic testing. We expect this work will inform evidence-based guidelines and the standard-of-care for delivery of genetic testing and is designed to be broadly applicable and easily adaptable for other populations and settings even beyond oncology (e.g. Alzheimer's disease).

TRIAL REGISTRATION: This protocol was registered at clinicaltrials.gov (NCT05427240) on 6/7/2022.},
}

Humans
*Genetic Testing/methods
*Genetic Counseling/methods
Female
Telemedicine
Genetic Predisposition to Disease
Adult
Return of Individual Research Results
*Neoplasms/genetics/diagnosis
Male

@article {pmid42934592,
year = {2026},
author = {Atri, A and Curiale, GG and Aisen, P and Barakos, J and Purcell, D and Bracoud, L and Haeberlein, SB and Grassi, C and Hughes, R and Smirnakis, K},
title = {Spectrum of amyloid-related imaging abnormalities associated with aducanumab treatment: a case series report.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {42934592},
issn = {1471-2377},
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Female ; Magnetic Resonance Imaging ; Male ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; *Brain/diagnostic imaging/drug effects/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) observed on magnetic resonance imaging (MRI) are known adverse events associated with beta-amyloid plaque-lowering monoclonal antibodies. A spectrum of radiographic and clinical presentations of ARIA have been observed. ARIA-E refer to vasogenic edema in the brain parenchyma and/or leptomeningeal/subpial sulcal effusion; ARIA-H refer to hemosiderin deposits including cerebral microhemorrhage and localized superficial siderosis. With clinical availability of anti-amyloid therapies for treatment of early clinical stage Alzheimer's disease, there is an important need for better awareness of ARIA and education among a diversity of clinicians and practice settings.

METHODS: To illustrate the wide spectrum of ARIA, we present the clinical history, course, and MRI findings as well as summarize learnings and implications of 10 ARIA-E cases from the aducanumab phase 3 clinical trials EMERGE and ENGAGE (ClinicalTrials.gov identifiers NCT02484547 and NCT02477800). Monitoring and management of ARIA, including criteria and timing of MRI, and drug dosing actions were defined per protocol and based upon radiographic severity and clinical symptoms associated with ARIA. ARIA were detected by MRI performed at pre-specified intervals or in response to symptoms or for safety follow-up reasons.

RESULTS: The majority of ARIA-E events were asymptomatic. Most ARIA-E events occurred within the first 8 aducanumab doses and generally resolved within 3-4 months whether dosing was continued (i.e. when ARIA-E was asymptomatic and of mild radiographic severity) or whether dosing was suspended or discontinued. Occasionally, ARIA-E were recurrent. ARIA-H (microhemorrhages and superficial siderosis) most commonly occurred concurrently with ARIA-E. However, ARIA-H without ARIA-E, termed isolated ARIA-H, occurred at a similar frequency in aducanumab- and placebo-treated groups. 10% of participants with ARIA in the 10 mg/kg group had accompanying symptoms. When present, symptoms of ARIA most frequently included headache, nausea, fatigue, dizziness, confusional state, and visual disturbance. Serious symptoms associated with ARIA were uncommon (occurring in 0.3% of the participants treated with the 10 mg/kg dose regimen).

CONCLUSIONS: These illustrative cases provide learnings into the nature and factors associated with ARIA that can increase knowledge for clinicians and trialists regarding the varied radiographic and clinical presentations and evolution of ARIA.

TRIAL REGISTRATION: Clinical Trials NCT02484547, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02484547 . Clinical Trials NCT02477800, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02477800 .},
}

Humans
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Female
Magnetic Resonance Imaging
Male
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
*Brain/diagnostic imaging/drug effects/pathology
Middle Aged
Aged, 80 and over

@article {pmid42934641,
year = {2026},
author = {Li, S and Gu, J and Xu, Z and He, C and Yu, C},
title = {Advances in modified anti-Aβ antibodies for the treatment of Alzheimer's disease.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42934641},
issn = {1741-7015},
support = {82460264//the National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy/immunology ; Humans ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Animals ; Antibodies, Bispecific/therapeutic use ; *Antibodies, Monoclonal/therapeutic use ; Blood-Brain Barrier/metabolism ; Immunotherapy/methods ; Immunoconjugates/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder, the treatment of which remains a major clinical challenge. In recent years, significant progress has been made in the immunotherapy of AD. Notably, monoclonal antibodies targeting amyloid-β (Aβ) have already been applied in clinical practice. However, as macromolecular therapeutics, antibodies face substantial challenges in crossing the blood-brain barrier (BBB) efficiently. Systemic administration typically requires high dosages to achieve the therapeutic level of brain exposure, which may trigger adverse events such as amyloid-related imaging abnormalities (ARIA) and thus restrict their widespread clinical application. To resolve this problem, various engineering strategies for modifying anti-Aβ antibodies have been developed. This review summarizes four major modification categories: BBB-penetrating bispecific antibodies (BsAbs), glycosylation engineering, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-based cell therapies (including CAR-macrophages, CAR-T cells, and CAR-astrocytes). We provide an in-depth discussion of their delivery efficiency, targeting capability, and safety, aiming to lay a foundation for developing safer and more effective next-generation anti-Aβ antibody therapeutic strategies.},
}

*Alzheimer Disease/therapy/drug therapy/immunology
Humans
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Animals
Antibodies, Bispecific/therapeutic use
*Antibodies, Monoclonal/therapeutic use
Blood-Brain Barrier/metabolism
Immunotherapy/methods
Immunoconjugates/therapeutic use

@article {pmid42934778,
year = {2026},
author = {Shitrit, A and Khattib, A and Khatib, S},
title = {Cannabis flower extracts as a multi-target agent in Alzheimer's disease: Inhibition of AChE, BChE, and BACE1 with cell-protective effects in a PC12 cell model.},
journal = {Journal of cannabis research},
volume = {8},
number = {1},
pages = {},
pmid = {42934778},
issn = {2522-5782},
support = {2022//Jewish Colonization Association (JCA) in Israel/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline. Despite extensive research, its multifactorial nature continues to challenge the development of effective therapies. Current treatments, including anticholinergic agents and amyloid β-targeted drugs, alleviate symptoms but fail to halt disease progression and often produce side effects. Therefore, novel multi-target strategies are urgently needed. Cannabis (Cannabis sativa L.) has long been recognized for its medicinal properties, yet its potential in AD therapy has only recently gained attention. Previous studies have mainly focused on single cannabinoids or endocannabinoid system modulation. In this study, we investigated whole cannabis flower extracts, rich in diverse active compounds, for their ability to inhibit key AD-related enzymes: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE1), using spectrophotometric assays. Fractionation of one extract further identified components with potent inhibitory activity against both BChE and BACE1. Additionally, the extracts were evaluated for their cell-protective potential in PC12 cells exposed to hydrogen peroxide (H2O2) and amyloid β (Aβ1-42), mimicking AD-like oxidative stress conditions. Cannabis extracts showed stronger inhibition of cholinergic enzymes compared to Galantamine, with efficacy depending on extract composition. Importantly, this study is among the first to reveal significant BACE1 inhibition by cannabis extracts. Moreover, the extracts enhanced PC12 cell viability under oxidative stress, indicating cell-protective effects. Overall, these findings suggest that multi-component cannabis extracts may interact with several AD-related molecular targets in vitro and may serve as promising leads for further mechanistic and preclinical investigation.},
}

@article {pmid42934801,
year = {2026},
author = {Chen, Y and Tang, F and Li, X},
title = {MSC-derived extracellular vesicle-associated miRNAs in CNS diseases: mechanisms of microglial polarization and therapeutic implications.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {42934801},
issn = {1757-6512},
support = {2025ZNSFSC0674//Natural Science Foundation of Sichuan Province/ ; 82071353//National Natural Science Foundation of China/ ; 2021YFS0029 and 2020YFS0104//Key R&D Projects of the Science and Technology Department of Sichuan Province/ ; },
mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Extracellular Vesicles/metabolism/genetics ; *Mesenchymal Stem Cells/metabolism ; *Central Nervous System Diseases/therapy/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; },
abstract = {Microglia-mediated neuroinflammation contributes to the pathogenesis of many central nervous system (CNS) diseases. After injury or infection, microglia can adopt pro-inflammatory programs that amplify neuronal damage. By contrast, reparative microglial states support inflammatory resolution, tissue repair and regeneration. Strategies that redirect harmful microglial activation toward reparative programs therefore have therapeutic relevance. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), particularly small EV-enriched preparations, are increasingly studied as low-immunogenicity carriers of regulatory cargo. EV-associated microRNAs (miRNAs) are among the major payloads implicated in immunomodulation. This review synthesizes how MSC-EV-associated miRNAs regulate microglial polarization and neuroinflammation through TLR/NF-κB, MAPK, JAK/STAT, PI3K/Akt and Wnt/β-catenin signaling. We discuss evidence from ischemic stroke, traumatic brain injury, spinal cord injury, Alzheimer's disease and sepsis-associated encephalopathy, and highlight EV terminology, donor source, species context and translational comparability as key barriers for future development.},
}

Humans
*MicroRNAs/metabolism/genetics
*Extracellular Vesicles/metabolism/genetics
*Mesenchymal Stem Cells/metabolism
*Central Nervous System Diseases/therapy/genetics/metabolism/pathology
*Microglia/metabolism/pathology
Animals

@article {pmid42934846,
year = {2026},
author = {Tang, L and Chen, X and Zhang, L and Fan, L and Chen, N and Li, C and Cai, Z and Chen, G and Chen, H and Ye, M and Zheng, H and Li, Q and Ke, Z and Hu, Z and Cao, M and Yang, D and Xu, S and Xie, C and Li, X and Xu, X and Yu, M and Lian, X and Hu, H and Li, H and Cai, X and Chen, H and Xu, W and Cui, G and Zhao, Y and Dong, J and Zhang, L and Zhu, X and Zhao, H and Xu, Y},
title = {Real-world clinical, biomarker, and imaging outcomes of lecanemab in Alzheimer's disease: a multicenter longitudinal cohort study in Jiangsu, China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42934846},
issn = {1552-5279},
support = {2022ZD0211800//STI2030-Major Projects/ ; 82130036 82471454 U25A2064//National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; ZKX23026//Nanjing Key Medical Science and Technology Development Project/ ; //the Nanjing Key Medical Science and Technology Development Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/blood ; Female ; Biomarkers/blood ; Male ; Longitudinal Studies ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; China ; Aged ; Peptide Fragments/blood ; Cognitive Dysfunction/drug therapy ; Cohort Studies ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Real-world data on lecanemab's efficacy and the longitudinal dynamics of plasma biomarkers are scarce in Chinese patients with Alzheimer's disease (AD).

METHODS: In this multicenter cohort study, 181 AD patients received biweekly lecanemab. Disease-stage-specific Clinical Dementia Rating-Sum of Boxes meaningful within-patient change defined response at Months 3, 6, and 12. We used penalized models, receiver operating characteristic analysis, attrition comparisons, and exploratory Month 3 plasma biomarker analysis.

RESULTS: Cognitive response emerged at Month 6 and intensified by Month 12, largely restricted to mild cognitive impairment and mild dementia due to AD. Repeated five-fold cross-validated areas under the curve across the follow-up timepoints were 0.560, 0.747, and 0.773, with apolipoprotein E ε4 positivity and more severe cognitive impairment linked to lower response odds. Plasma phosphorylated tau 217 (p-tau217) and amyloid beta (Aβ) 42/40 altered as early as Month 3. Month 3 Aβ42/40 showed modest exploratory discrimination. The incidence of amyloid-related imaging abnormalities was 7.2%, all asymptomatic.

DISCUSSION: Lecanemab is effective and safe in AD over 6 to 12 months. Early biomarker changes (p-tau217, Aβ42/40) precede clinical improvement, serving as scalable response indicators.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/blood
Female
Biomarkers/blood
Male
Longitudinal Studies
Amyloid beta-Peptides/blood
tau Proteins/blood
China
Aged
Peptide Fragments/blood
Cognitive Dysfunction/drug therapy
Cohort Studies
Positron-Emission Tomography
Magnetic Resonance Imaging

@article {pmid42934953,
year = {2026},
author = {Peshoff, MM and Hambardzumyan, D and Wu, LJ},
title = {TREM2: friend or foe in glioma?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag369},
pmid = {42934953},
issn = {1460-2156},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a neuroimmune signaling hub involved in key cellular processes including microglial phagocytosis, chemotaxis, and inflammation. Dysregulation of TREM2 has been implicated in a variety of diseases, most notably in the innate immune response to neurodegenerative disorders and cancer. The TREM2 pathway plays a significant role in governing microglia phenotypic transitions in Alzheimer's disease, as well as in regulating tumor-associated macrophages' ability to modulate cytotoxic activity. However, TREM2's role can be dependent on experimental parameters and disease contexts. Due to its intricate involvement in related disorders and the myeloid-dominated microenvironment in brain tumors, TREM2 has emerged as a vital player to better understand neuroimmune contributions to central nervous system malignancies. This review critically evaluates TREM2's controversial function in gliomas, analyzes experimental and biological variables that may underlie divergent findings, and outlines important considerations for future investigations.},
}

@article {pmid42935028,
year = {2026},
author = {Khuman, YM and Kapadiya, YM and Maru, JJ},
title = {Synthetic Insights on Donepezil: An Anti-Alzheimer Drug.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {10},
pages = {},
doi = {10.1002/ardp.70364},
pmid = {42935028},
issn = {1521-4184},
mesh = {*Donepezil/chemical synthesis/pharmacology/chemistry/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Nootropic Agents/chemical synthesis/pharmacology ; Animals ; Molecular Structure ; },
abstract = {Alzheimer's disease is a severe condition that poses significant global health concerns to international health agencies and remains a major threat to public health. As there is no cure for Alzheimer's disease, various anti-Alzheimer's medications are used to manage its symptoms. Donepezil is one of the most highly marketed drugs, known for its positive effects on cognition, function, behaviour and overall patient condition, making it a standout treatment option. Various synthetic methods have been developed to produce more efficient pathways that minimise by-products and maximise yield. This review summarises the reported literature on various synthetic routes for producing Donepezil. We have also made an effort to highlight the advantages and limitations of prior literature, which may lead to potential improvements for future research. This work will serve as a foundation for upcoming researchers, ultimately benefiting the well-being of Alzheimer's patients and human society as a whole.},
}

*Donepezil/chemical synthesis/pharmacology/chemistry/therapeutic use
Humans
*Alzheimer Disease/drug therapy
*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
*Nootropic Agents/chemical synthesis/pharmacology
Animals
Molecular Structure

@article {pmid42935251,
year = {2026},
author = {Haricharan, PB and El-Amier, N and Nicolau, B and Feine, J and de Souza, RF},
title = {Is There Evidence That Dental Care Modifies Cognitive Decline? Insights from a Scoping Review.},
journal = {JDR clinical and translational research},
volume = {},
number = {},
pages = {23800844261491617},
doi = {10.1177/23800844261491617},
pmid = {42935251},
issn = {2380-0852},
abstract = {BACKGROUND: Emerging research suggests that poor oral health, manifested as tooth loss, periodontal disease, or edentulism, may contribute to cognitive impairment and dementia in older adults. However, the role of dental care interventions in modifying this risk remains unclear.

OBJECTIVE: To systematically map and evaluate the evidence on whether dental care utilization and specific dental interventions are associated with cognitive function or cognitive decline in middle-aged and elderly populations.

METHODS: A scoping review was conducted using PRISMA-ScR guidelines. Four databases (MEDLINE, Embase, CINAHL, and PsycINFO) were searched from inception to April 11, 2025. Eligible studies examined the association between dental care and cognitive outcomes in adults aged 45 y or older with tooth loss or other oral conditions. Dental care exposures were grouped into 4 domains: dental care utilization, removable prosthodontic rehabilitation, fixed prosthodontic rehabilitation, and periodontal therapy.

RESULTS: Fifty-three studies were included. Most studies on dental care utilization found that regular dental visits were associated with lower dementia risk, although some showed null associations. Removable prosthodontic rehabilitation, especially with well-fitting or implant-supported dentures, was associated with improved cognitive function, likely mediated by chewing efficiency and nutrition. Fixed prosthodontic rehabilitation, such as implants and crowns, was consistently linked to better cognitive scores. Periodontal therapy showed the most consistent benefit, reducing systemic inflammation and dementia risk. However, evidence remains predominantly observational and marked by substantial heterogeneity across study designs, definitions of dental exposures, and cognitive outcome measures.

CONCLUSION: Maintaining oral health via regular dental care appears to support cognitive resilience in middle-aged and older adults. However, standardized methodologies and prospective studies are needed to clarify causal pathways and inform clinical guidelines.Knowledge Transfer Statement:This scoping review maps the current evidence on whether dental care utilization and common oral health interventions are associated with cognitive outcomes in adults. The findings may guide future translational research and integrated care pathways to reduce cognitive decline through optimized dental care.},
}

@article {pmid42935328,
year = {2026},
author = {Klimov, NA and Orlov, DS and Grishina, TV and Leonova, LE and Shamova, OV},
title = {[Prospects of application of peptide preparations in therapy of Alzheimer's disease.].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {39},
number = {4},
pages = {502-511},
doi = {10.34922/AE.2026.39.4.002},
pmid = {42935328},
issn = {1561-9125},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology ; *Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Peptides/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a serious kind of pathology that mainly affects older adults and significantly reduces the quality of their life. Despite decades of research, the pathogenesis of AD, the causes and the trigger mechanism of its occurrence remain the subject of debate. This review examines hypotheses of the pathogenesis of AD, including the involvement of amyloid-β peptide and hyperphosphorylated tau protein fragments in neuroinflammation and neurodegeneration. It also discusses potential therapies for AD based on peptides that target various aspects of the disease's pathogenesis.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology
*Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Peptides/pharmacology

@article {pmid42935350,
year = {2026},
author = {van de Veen, D and Smeets, B and Peetoom, K and de Vugt, M and Bakker, C and Koopmans, R},
title = {The influence of caregivers' lived experiences in decision-making processes on care transitions in young-onset dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498377},
doi = {10.1177/13872877261498377},
pmid = {42935350},
issn = {1875-8908},
abstract = {BackgroundCaregivers of people with young-onset dementia (YOD) hold diverse perspectives on the caregiving trajectory, reflecting the heterogeneity of underlying etiologies and the life stages of these people, who are often in the midst of employment, child-rearing, and other social responsibilities. Post-diagnostic care and services are often suboptimal and caregivers tend to be hesitant to initiate formal care and support services. We refer to movements of persons between different levels of care or physical locations as care transitions.ObjectiveTo improve caregiver support, this study aimed to provide insights into caregivers' perspectives on the decision-making process regarding care transitions and associated barriers and facilitators.MethodsSeventeen interviews with six caregivers of people with YOD were analyzed. Inductive content analysis was used to generate codes, followed by constant comparative analysis to create categories and themes describing caregivers' experiences.ResultsBarriers and facilitators influencing the decision-making process related to the initiation of care transitions were identified at two themes: individual and contextual level. Six categories and 23 sub-categories emerged. Individual-level categories included the character traits of the caregiver, the caregiver's need for support, impacts on the quality of the caregiver's relationship, and the burden experienced by the caregiver. Contextual-level categories included the social environment and the caregivers' experiences with healthcare professionals.ConclusionsCaregivers' decision-making regarding care transitions is shaped by thinking processes, character traits and contextual aspects. Healthcare professionals should strengthen collaboration and communication with caregivers. Acknowledging grief and supporting caregivers'sense of control are essential to providing adequate support.},
}

@article {pmid42935558,
year = {2026},
author = {Sattari, N and Dave, A and Chen, IY and Lui, KK and Chappel-Farley, MG and Berisha, DE and Sprecher, KE and Riedner, BA and Jones, S and Bendlin, BB and Mander, BA and Benca, RM},
title = {Sex differences in sleep and memory relationships in older adults at risk for Alzheimer's disease.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1930177},
pmid = {42935558},
issn = {1664-2392},
mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics ; Female ; Male ; Aged ; *Memory/physiology ; Polysomnography ; *Sleep/physiology ; *Sex Characteristics ; Apolipoprotein E4/genetics ; Electroencephalography ; Risk Factors ; Aged, 80 and over ; Sex Factors ; Sleep Stages ; },
abstract = {INTRODUCTION: Biological sex is an important modifier of aging and Alzheimer's disease risk, yet the sleep-related mechanisms through which sex and genetic risk interact to influence memory remain poorly understood. We examined whether associations among non-rapid eye movement sleep physiology, overnight memory retention, and apolipoprotein E ϵ4 (APOE ϵ4) status, a genetic risk factor for Alzheimer's disease, differed by sex in cognitively unimpaired older adults enriched for Alzheimer's disease risk.

METHODS: Eighty participants completed overnight polysomnography with high-density electroencephalography, and 65 also completed an evening encoding/immediate recall and morning delayed recall word-pair memory task.

RESULTS: Overnight memory retention did not differ by sex. However, exploratory analyses of the proportional overnight retention measure suggested a sex × APOE ϵ4 interaction, such that female APOE ϵ4 carriers may exhibit reduced overnight forgetting relative to female non-carriers and male carriers. Although counterintuitive, this pattern may reflect compensatory or resilience-related sleep-memory mechanisms in cognitively unimpaired women at genetic risk for Alzheimer's disease rather than a protective effect of APOE ϵ4 itself. Women spent more time in N3 sleep and had higher non-rapid eye movement delta and slow sigma power than men. Sleep-memory associations also differed by sex: greater N2 duration was more strongly associated with better overnight retention in men, whereas greater frontal slow sigma power and fronto-central fast sigma power were positively associated with retention in women. Exploratory APOE-stratified analyses suggested sex-specific differences in sleep stage-memory relationships, with more positive N2-memory associations in male than female APOE ϵ4 carriers and more positive N3-memory associations in female than male carriers; both differences remained significant after FDR correction. TFCE-corrected analyses further identified positive associations between NREM delta and sigma activity and overnight memory retention in female APOE ϵ4 carriers.

DISCUSSION: These findings highlight sex-specific patterns in NREM sleep physiology and sleep-memory relationships in cognitively unimpaired older adults at risk for Alzheimer's disease. More broadly, the results suggest that sex and APOE ϵ4 status may jointly shape the neurophysiological pathways linking sleep and memory, underscoring the importance of considering sex as a biological variable when studying sleep, cognitive aging, and Alzheimer's disease vulnerability.},
}

Humans
*Alzheimer Disease/physiopathology/genetics
Female
Male
Aged
*Memory/physiology
Polysomnography
*Sleep/physiology
*Sex Characteristics
Apolipoprotein E4/genetics
Electroencephalography
Risk Factors
Aged, 80 and over
Sex Factors
Sleep Stages

@article {pmid42935632,
year = {2026},
author = {Bae, YJ and Daily, JW and Park, S},
title = {Gut Microbiota as a Mechanistic Nexus between Type 2 Diabetes and Alzheimer's Disease: Insulin Resistance, Neuroinflammation, and Functional Food Strategies.},
journal = {Preventive nutrition and food science},
volume = {31},
number = {5},
pages = {},
pmid = {42935632},
issn = {2287-1098},
abstract = {Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share substantial pathological overlap, including brain-specific insulin resistance driven by impaired insulin receptor substrate-1/phosphoinositide 3-kinase/protein kinase B signaling, glycogen synthase kinase-3β dysregulation, tau hyperphosphorylation, and amyloid-β accumulation. Brain-insulin resistance is a key mechanistic link between peripheral metabolic dysfunction and neurodegeneration, although the upstream regulatory pathways remain incompletely defined. Gastrointestinal depletion of butyrate-producing microbial taxa and enrichment of pro-inflammatory genera have been independently documented in T2DM and AD. Gut microbiota dysbiosis propagates insulin resistance through at least five pathways: short-chain fatty acid depletion, lipopolysaccharide (LPS)-mediated endotoxemia, bile acid dysregulation, tryptophan-kynurenine imbalance, and vagus nerve disruption. Critically, LPS translocation and kynurenine-driven neurotoxicity propagate AD-relevant neuroinflammation independently of peripheral metabolic dysfunction, implicating a bidirectional gut-brain mechanism. These risks are amplified in Asian populations, who exhibit a lower pancreatic β-cell mass and attenuated insulin secretion that confer disproportionate vulnerability to glucotoxic cycling and its neurological complications. Such a population-specific dimension remains largely absent from reviews. Against this backdrop, traditional Asian fermented foods (chungkookjang, kimchi, and natto) and plant-derived functional ingredients (Eucommia ulmoides, gooseberry, and black garlic) have a preclinical capacity to restore microbial balance, attenuate insulin resistance, and exert neuroprotection. This review integrates these strands into a unified mechanistic and translational framework, positioning gut microbiota modulation through culturally grounded dietary strategies as a tractable approach to reducing the converging burdens of T2DM and AD in Asians.},
}

@article {pmid42935657,
year = {2026},
author = {Hussain, A and Bokhari, SAI},
title = {Mechanistic insights of Artemisia-derived therapeutics in Alzheimer's disease (AD): from crude botanical extracts to artemisinin and derivatives.},
journal = {3 Biotech},
volume = {16},
number = {11},
pages = {479},
pmid = {42935657},
issn = {2190-572X},
abstract = {Alzheimer's disease (AD) is characterized by several pathological processes including amyloid-β (Aβ) accumulation, Tau hyperphosphorylation, oxidative stress, synaptic dysfunction, neuroinflammation, mitochondrial impairment and loss in neuronal stability. This review assessed the reported neuroprotective potential of crude extracts of different Artemisia species and artemisinin with its derivatives in AD. It focuses on targets, mechanisms, observational markers and functional effects validated by Artemisia extracts and compounds like artemisinin, artemisinin B, artemether, artesunate and dihydroartemisinin in experimental AD models. A comprehensive review of studies was conducted including in vitro, in vivo and in silico research on Artemisia extracts and derivatives focusing on their effects on various pathological processes related to brain. Results showed crude extracts from 17 Artemisia species, which have been reported with considerable neuroprotective effects. Artemisinin and derivatives deliver neuroprotection via targeted mechanisms and effecting observational markers with varying functional outcomes. However, differences in AD models, administration routes, doses, extract composition and outcomes limit direct efficacy comparisons. Hence, direct comparisons of efficacy among Artemisia extracts, artemisinin and its derivatives should be interpreted cautiously. Future inquiries should highlight standardized preparations, brain exposure and pharmacokinetics, mechanistic validation, long-term safety and well-designed comparative and clinical trials to evaluate their potential for AD treatment.},
}

@article {pmid42935659,
year = {2026},
author = {Timsina, J and Chen, Y and Liu, M and Mu, R and Gong, K and Budde, J and Wang, G and Li, Y and Schindler, SE and Morris, JC and Holtzman, DM and Bateman, RJ and Hohman, TJ and Cruchaga, C},
title = {Symmetric Centipolar Normalized Score (SCeNS): A standardization framework for fluid marker cross-comparability in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70516},
pmid = {42935659},
issn = {2352-8729},
abstract = {INTRODUCTION: Multiple platforms measure Alzheimer's disease fluid biomarkers, such as amyloid beta (Aβ) and p-tau, leading to heterogeneous data. Existing harmonization methods are difficult to interpret as they still provide specific cut-offs and biomarker values are not commaptible between different biomarkers.

METHODS: We propose a standardization approach, Symmetric Centipolar Normalized Score (SCeNS), which uses Gaussian mixture model-derived cutoffs to rescale biomarker z-scores onto a -100 to 100 scale, with a constant cut-off to derive biomarker status, that can be applied to fluid as well as imaging biomakers. The sign (plus or minus) reflects sample's biomarker status. We present the calculation steps and demonstrate how SCeNS enables direct comparison across cohorts, platforms, and tissue types. We also demonstrate a use case of the approach using real-world data from individuals treated with lecanemab.

RESULTS: SCeNS were calucated using cerebrospinal and plasma AD biomarkers measured in mutliple platforms, demostrating that the SCeNS methods provide a consistent and easy to understand biomarker level. We applied the SCeNS method to the lecanmab-treated cohort, where we demostrated the SCeNS previde easy to interpert biomkaer changes as p-tau217 showed highest unit of change, while p-tau181 had highest conversion (7.57%) to biomarker negative.

DISCUSSION: SCeNS provides a simple, interpretable biomarker metric across platforms.},
}

@article {pmid42935768,
year = {2026},
author = {Tian, J and Huang, W and Wen, Y and Liang, Y},
title = {Application of large language models in early screening of Alzheimer's disease: a scoping review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1906641},
pmid = {42935768},
issn = {1663-4365},
abstract = {OBJECTIVE: To systematically map the current applications of large language models (LLMs) in the early screening of Alzheimer's disease (AD) and to provide evidence to inform future research and nursing practice.

METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodological framework. A comprehensive search was performed in PubMed, Web of Science, Embase, Cochrane Library, ProQuest, and Scopus from database inception to April 20, 2026. Eligible studies were screened, selected, and synthesized according to predefined inclusion criteria.

RESULTS: A total of 25 studies were included. The LLMs applied in these studies mainly consisted of general-purpose generative models, multimodal models, and medical-specific models. Data sources primarily included public databases, along with real-world clinical data and simulated data. LLMs were mainly applied for cognitive impairment identification, data augmentation, automated cognitive assessment, and clinical decision support, with cognitive impairment identification being the predominant application direction. Several studies employed prompting strategies including zero-shot prompting, few-shot prompting, chain-of-thought prompting, and agent-based prompting. Multimodal integration and agent-based collaborative reasoning have emerged as important research directions in recent years.

CONCLUSION: Large language models provide a novel technological approach for early AD screening and demonstrate potential for supporting cognitive assessment and risk identification. Future research should strengthen real-world studies, multicenter validation, and the development of model safety and ethical governance frameworks to facilitate the standardized application of LLMs in early AD screening.},
}

@article {pmid42935792,
year = {2026},
author = {Puri, BK and Preyer, R and Lee, GS and Monaghan, L and Schwarzbach, A},
title = {Prefrontal Planning Latency Associated With Age and Serological Evidence of Microbial Exposure.},
journal = {Chronic diseases and translational medicine},
volume = {},
number = {},
pages = {},
pmid = {42935792},
issn = {2589-0514},
abstract = {BACKGROUND: It has been hypothesized that certain cognitive disorders characterized by frontal executive dysfunction, such as Alzheimer's disease (a neurodegenerative conformational proteinopathy involving amyloid-β and tau), may be associated with prior exposure to infectious agents. This study aimed to test the hypothesis that serological markers of microbial exposure are associated with frontal lobe activity in humans.

METHODS: Executive planning latency was measured in 53 adult participants in this cross-sectional study. A venous blood sample was collected from each participant. Assays for the serological markers of bacterial and viral exposure were performed in a blinded manner.

RESULTS: Generalized linear modeling (likelihood ratio χ [2] = 27.76, df = 5, p = 0.0001) included five statistically significant independent variables. Among these, age (|t| = 4.360, p = 0.0001), Borrelia burgdorferi lymphocyte function-associated antigen-1 (| t | = 3.260, p = 0.002), and Ehrlichia chaffeensis and Anaplasma phagocytophilum assays (| t | = 3.138, p = 0.003) were highly significant.

CONCLUSION: This study supports the hypothesis that frontal lobe executive function, as indexed by prefrontal cortical planning latency, is associated with serological evidence of exposure to several bacterial genera, particularly Borrelia and Ehrlichia/Anaplasma, as well as with age.},
}

@article {pmid42935795,
year = {2027},
author = {Oliveira, GM and Nunes, BP and Lam, K and Lima-Costa, MF and Torres, JL and Macinko, J and Moreira, BS and Avelino-Silva, TJ and Gonçalves, VAD and Fortes-Filho, SQ and de Castro, TF and Batista, SRR and Ferriolli, E and Aliberti, MJR},
title = {Primary care effectiveness, multimorbidity, and hospital use in public and private health-care systems in Brazil: a cross-sectional analysis of data from the 2019-2021 Brazilian longitudinal study of aging.},
journal = {Lancet regional health. Americas},
volume = {66},
number = {},
pages = {101680},
pmid = {42935795},
issn = {2667-193X},
abstract = {BACKGROUND: Whether patient-reported experiences in primary care modify the association between multimorbidity and emergency department (ED) visits and hospitalizations remains unclear. We examined these associations across public and private health system sectors among Brazilians aged ≥50 years.

METHODS: This cross-sectional study used nationally representative data from the 2019-2021 Brazilian Longitudinal Study of Aging. Multimorbidity was defined as the presence of ≥2 of 13 chronic conditions. A 12-item patient-reported primary care effectiveness index captured access, continuity, communication, and coordination with participants' usual source of healthcare. Primary outcomes were ED visits and hospitalizations in the past 12 months. Poisson regression models estimated associations with the outcomes, and assessed interactions among multimorbidity, primary care effectiveness, and health system sectors.

FINDINGS: Among 9058 participants (mean age = 66.3 ± 9.9 years; females = 55.3%; White race/ethnicity = 46.4%), 38.0% had multimorbidity. Overall, 12.5% reported an ED visit and 6.0% ≥ 1 hospitalization in the past 12 months. Multimorbidity was associated with approximately twice the prevalence of ED visits and three times the prevalence of hospitalizations. Primary care effectiveness modified these associations across health system sectors (three-way interaction p = 0.04 for ED visits and p < 0.001 for hospitalization). In the public system, higher primary care effectiveness attenuated the association between multimorbidity and hospitalization (interaction prevalence ratio [PR] = 0.74, 95% confidence interval [CI] = 0.63-0.87). In contrast, in the private system, higher primary care effectiveness strengthened the associations of multimorbidity with ED visits (interaction PR = 1.40, 95% CI = 1.18-1.66) and hospitalization (interaction PR = 1.75, 95% CI = 1.22-2.50).

INTERPRETATION: Associations between multimorbidity and healthcare use varied according to patient-reported primary care experiences and health system sector.

FUNDING: The Brazilian National Council for Scientific and Technological Development, the Alzheimer's Association, and the National Institute on Aging.},
}

@article {pmid42935819,
year = {2026},
author = {Zhao, H and Qin, B and Zou, Z and Wen, P},
title = {Explainable machine learning for identifying high-risk Alzheimer's disease and key health characteristics among community-dwelling adults.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1943300},
pmid = {42935819},
issn = {2296-2565},
mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; Male ; Female ; *Machine Learning ; Aged ; *Independent Living/statistics & numerical data ; Random Forest ; Middle Aged ; Risk Assessment/methods ; Risk Factors ; Health Surveys ; Aged, 80 and over ; Predictive Learning Models ; },
abstract = {OBJECTIVE: To develop an interpretable machine learning model to identify individuals with AD8-defined high-risk status for Alzheimer's disease among community-dwelling adults, identify key health characteristics and their association patterns with high-risk status, and to inform community-based cognitive health promotion.

METHODS: Based on health survey data from 6,267 community-dwelling adults, AD8-defined high-risk status for Alzheimer's disease was assessed using the Alzheimer's Disease Screening Scale (AD8). LASSO logistic regression, random forest, and decision tree models were constructed, and SHapley Additive exPlanations (SHAP) was used to analyze the importance of key health characteristics and their association patterns.

RESULTS: A total of 6,267 community-dwelling adults were included, of whom 1,454 (23.2%) were classified into the AD8-defined high-risk group. The random forest model showed the highest discriminative performance among the three models. SHAP analysis indicated that fruit intake, age, snoring, mean grip strength, and sleep duration were important health characteristics associated with AD8-defined high-risk status for Alzheimer's disease. SHAP dependence plots further revealed a graded negative association between fruit intake and high-risk status, a U-shaped association for sleep duration, a U-shaped association for mean grip strength, and a positive graded association between snoring frequency and high-risk status.

CONCLUSIONS: Random forest combined with SHAP identified key health characteristics associated with AD8-defined high-risk status among community-dwelling adults and revealed non-linear association patterns involving health behaviors and physical function. These findings may provide useful information for community-based risk stratification and targeted cognitive health promotion.},
}

Humans
*Alzheimer Disease/diagnosis/epidemiology
Male
Female
*Machine Learning
Aged
*Independent Living/statistics & numerical data
Random Forest
Middle Aged
Risk Assessment/methods
Risk Factors
Health Surveys
Aged, 80 and over
Predictive Learning Models

@article {pmid42936480,
year = {2026},
author = {Ding, JA and Samvelian, D and Ying, Z and Diamante, G and Ahn, IS and Palafox-Sanchez, V and Wang, SS and Gomez-Pinilla, F and Yang, X},
title = {Hippocampal and hypothalamic cell-type specific mechanisms underlying nutritional and metabolic modulation of Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117920},
pmid = {42936480},
issn = {2589-0042},
abstract = {To understand the potential of modulating metabolism for therapeutic development for Alzheimer's disease (AD), we investigated the effects of high fructose consumption as a potential risk, and docosahexaenoic acid (DHA) and nicotinamide riboside (NR) as potentially beneficial, on cell type-specific transcriptomic responses in the hippocampus and hypothalamus of the 5xFAD mouse model. Fructose increased the expression of C3, encoding complement component 3, in ependymal cells and inflammatory genes in microglia, which were normalized by DHA and NR. NR and DHA reversed Aβ-associated transcriptional signatures across cell types, but the effects were modified by fructose. DHA and NR treatments reversed the AD-associated decrease in hippocampal oligodendrocytes, with DHA further reducing hippocampal microglia and increasing hypothalamic astrocytes, and NR further increasing hippocampal neuronal proportions. Our study supports the impact of metabolic regulation of AD-associated cell types and pathways and provides molecular support for utilizing nutritional modulators for AD intervention.},
}

@article {pmid42936906,
year = {2026},
author = {Valentim, C and Denecke, J and Frerich, S and Betthauser, TJ and Li, Y and Ahmadi, R and Franzmeier, N and , and Malik, R and Ewers, M},
title = {Pathway-specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {},
pmid = {42936906},
issn = {1552-5279},
support = {//European Union's Horizon/ ; 01KU2203//Bundesministerium für Bildung und Forschung/ ; 2525FSB005//Bundesministerium für Gesundheit/ ; 570971002//Deutsche Forschungsgesellschaft/ ; /ALZ/Alzheimer's Association/United States ; //Joachim Herz Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology ; Female ; Positron-Emission Tomography ; Genetic Risk Score ; *tau Proteins/metabolism ; Genome-Wide Association Study ; Male ; Aged ; Polymorphism, Single Nucleotide ; Brain/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; Cross-Sectional Studies ; Aged, 80 and over ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) identified multiple genetic variants associated with Alzheimer's disease (AD) risk, yet the biological pathways linking these to amyloid and tau pathology remain unclear.

METHODS: We conducted a meta-analysis of recent GWASs to identify independent genome-wide significant single nucleotide polymorphisms which were mapped via gene-set enrichment to derive pathway-specific polygenic risk scores (pPRSs). Analyses included 441 amyloid-positive participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 224 with longitudinal tau positron emission tomography [PET]) and 250 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study (113 with longitudinal tau PET). Robust linear regressions tested cross-sectional and longitudinal pPRS-by-amyloid chronicity interactions on tau PET.

RESULTS: Four pPRSs were identified including adaptive immune response, leukocyte activation, transport, and intracellular signaling. Only the transport pPRS strengthened amyloid-tau coupling cross-sectionally across all Braak stages in ADNI (p < 0.05) and at Braak I in A4 (p < 0.05), with stronger effects observed in females; in ADNI, these associations persisted longitudinally only at the higher Braak stages.

DISCUSSION: Genetic variation in transport pathways modulates amyloid-driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology
Female
Positron-Emission Tomography
Genetic Risk Score
*tau Proteins/metabolism
Genome-Wide Association Study
Male
Aged
Polymorphism, Single Nucleotide
Brain/metabolism/diagnostic imaging
*Amyloid beta-Peptides/metabolism
Cross-Sectional Studies
Aged, 80 and over
Genetic Predisposition to Disease

@article {pmid42937271,
year = {2026},
author = {Wang, D and Zhao, Z and Ding, Y},
title = {Relaxin-2 protects synaptic integrity via hippocampal NLRP3-mTOR-autophagy pathways in an age-dependent Alzheimer-like model.},
journal = {Acta pharmaceutica (Zagreb, Croatia)},
volume = {},
number = {},
pages = {},
doi = {10.2478/acph-2026-0023},
pmid = {42937271},
issn = {1846-9558},
abstract = {Alzheimer disease (AD) is associated with age-related synaptic degeneration, neuroinflammation, and impaired autophagy. The present study aimed to investigate the age-dependent neuroprotective effects of relaxin-2 (RLN2) in amyloid-beta 1-42 (Aβ1 - 42)-induced AD-like pathology and hypothesised that RLN2 would provide greater therapeutic benefit in young than aged mice. Young (3-4 months) and aged (12-14 months) mice were intracerebrally (i.c.) injected with amyloid-β (Aβ1 - 42) to develop an AD-like phenotype and treated with RLN2 or a control. Western blot analysis of hippocampal tissues was performed to assess the expression levels of ionised calcium-binding adaptor molecule 1 (Iba1) (microglial activation marker), NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components, and mechanistic target of rapamycin (mTOR) pathway activity. Neuroinflammation was determined by interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α), while synaptic integrity was assessed by synaptophysin and PSD-95. The Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests were used to measure cognitive and memory performance. Neuroinflammation markers IL-1β and TNF-α were significantly elevated in Aβ1 - 42-injected mice, with aged mice showing a greater increase than young mice. RLN2 treatment markedly reduced IL-1β and TNF-α levels in young mice, whereas the reduction was limited in aged mice. RLN2 treatment had a significant inhibitory effect on hippocampal NLRP3 signalling, reduced mTOR signalling, modulated autophagy-related protein expression, preserved synaptic proteins, and improved cognitive and memory performance (decrease in the MWM escape latency and increase in the NOR discrimination index). RLN2 was not effective in the aged mice, and there was persistent inflammatory activation, impaired autophagy, minimal improvement in synaptic recovery, and a moderate improvement in cognition. These findings suggest that RLN2 could be a potential therapeutic candidate for early-stage AD by targeting neuroinflammation, mTOR-mediated autophagy-related dysregulation, and synaptic loss, while also potentially providing a basis for age-based stratification of treatment responsiveness; however, further studies are required to determine its utility as a biomarker of treatment response or disease progression. Overall, RLN2 exerted neuro-protective effects in i.c. Aβ1 - 42-induced AD-like pathology in an age-dependent manner.},
}

@article {pmid42937433,
year = {2026},
author = {Choi, A and Haystead, A and D'Cunha, R and Hsu, J and Zhu, M and Johnson, KG and Whitson, H and Grewal, DS and Fekrat, S},
title = {Longitudinal Multimodal Retinal Imaging in Cognitively Normal Apolipoprotein E4 Carriers and Noncarriers.},
journal = {Translational vision science & technology},
volume = {15},
number = {10},
pages = {45},
doi = {10.1167/tvst.15.10.45},
pmid = {42937433},
issn = {2164-2591},
mesh = {Humans ; Female ; Tomography, Optical Coherence/methods ; *Apolipoprotein E4/genetics ; Male ; *Multimodal Imaging/methods ; Heterozygote ; *Cognition/physiology ; *Retina/diagnostic imaging ; Middle Aged ; Longitudinal Studies ; Aged ; Retinal Vessels/diagnostic imaging ; Retinal Ganglion Cells/pathology ; Follow-Up Studies ; },
abstract = {PURPOSE: To evaluate longitudinal retinal structural and microvascular changes in cognitively normal apolipoprotein E (APOE) ε4 carriers compared with noncarriers.

METHODS: Cognitively normal adults with known APOE genotype underwent multimodal retinal imaging at baseline and follow-up visits. Optical coherence tomography (OCT) metrics included macular central subfield thickness (CST), ganglion cell-inner plexiform layer (GC-IPL) thickness, and retinal nerve fiber layer (RNFL) thickness. OCT angiography (OCTA) parameters included vessel and perfusion density across 3-mm and 6-mm circles and rings, peripapillary capillary perfusion density (CPD), and capillary flux index (CFI). Annual rates of change were estimated using linear mixed-effects models adjusted for age and sex. A subgroup analysis was performed in participants with ≥5-year follow-up.

RESULTS: This study analyzed 871 eyes from 439 participants (230 APOE ε4 noncarriers and 209 carriers). Baseline retinal parameters did not differ significantly between groups. Carriers demonstrated nominally slower annual RNFL decline (β = 0.334; P = 0.023) and attenuated peripapillary CPD decline (β = 0.0010; P = 0.014) versus noncarriers; neither survived false discovery rate (FDR) correction (P = 0.18). In the ≥5-year subgroup (n = 58), carriers demonstrated nominally higher peripapillary CPD than noncarriers (P = 0.011; FDR-adjusted P = 0.17), although rates of change did not differ significantly between groups.

CONCLUSIONS: Cognitively normal APOE ε4 carriers demonstrated nominally slower peripapillary CPD and RNFL decline over longitudinal follow-up, with carriers maintaining higher CPD at ≥5 years despite comparable baseline imaging.

TRANSLATIONAL RELEVANCE: Longitudinal peripapillary and RNFL changes may reflect early retinal findings associated with APOE ε4 carrier status prior to cognitive decline, supporting further investigation of longitudinal retinal imaging as a potential noninvasive biomarker in preclinical Alzheimer's disease.},
}

Humans
Female
Tomography, Optical Coherence/methods
*Apolipoprotein E4/genetics
Male
*Multimodal Imaging/methods
Heterozygote
*Cognition/physiology
*Retina/diagnostic imaging
Middle Aged
Longitudinal Studies
Aged
Retinal Vessels/diagnostic imaging
Retinal Ganglion Cells/pathology
Follow-Up Studies

@article {pmid42937842,
year = {2026},
author = {Peng, L and Li, Q and Li, Z and Bai, G and Tian, Y and Zhou, S},
title = {Blood-Brain Barrier-Permeable Macrocyclic Chimeras (BmTACs) for Targeted Protein Degradation in the Aging Brain.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {38},
pages = {41137-41150},
doi = {10.1021/jacs.6c11943},
pmid = {42937842},
issn = {1520-5126},
support = {2682025ZTPY051//Fundamental Research Funds for the Central Universities/ ; 2023JDRC0028//Department of Science and Technology of Sichuan Province/ ; 2024NSFTD0002//Department of Science and Technology of Sichuan Province/ ; 52495011//National Natural Science Foundation of China (NSFC)/ ; 52633003//National Natural Science Foundation of China (NSFC)/ ; U22A20161//National Natural Science Foundation of China (NSFC)/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Proteolysis/drug effects ; *Macrocyclic Compounds/chemistry/metabolism/pharmacology ; *Aging/metabolism ; Mice ; *Brain/metabolism ; Humans ; Death-Associated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Proteolysis Targeting Chimera ; },
abstract = {Targeted protein degradation has emerged as a transformative therapeutic strategy, yet its application to neurodegenerative diseases remains fundamentally constrained by the blood-brain barrier (BBB) and lesion specificity. Critically, the BBB undergoes age-dependent functional remodeling, further exacerbating the difficulty of therapeutic intervention. Here we report BBB-permeable macrocyclic chimeras (BmTACs), a modular degradation platform for selective elimination of activated death-associated protein kinase 1 (DAPK1) in the aging brain. BmTACs harness a macrocyclic peptide shuttle that exploits age-upregulated caveolae-mediated transcytosis in brain endothelial cells to achieve efficient BBB traversal and neuron-targeting. A reactive oxygen species (ROS)-responsive caging group on the von Hippel-Lindau ligand enables conditional PROTAC activation exclusively within the high-ROS microenvironment of Alzheimer's disease lesions, minimizing off-target degradation. Systemic administration of BmTACs in aged APP/PS1 mice achieved potent degradation of activated DAPK1, attenuated amyloid-β deposition and Tau hyperphosphorylation, and improved cognition. This work establishes a modular, senescence-adapted paradigm for targeted protein degradation in the aging central nervous system.},
}

Animals
*Blood-Brain Barrier/metabolism
*Proteolysis/drug effects
*Macrocyclic Compounds/chemistry/metabolism/pharmacology
*Aging/metabolism
Mice
*Brain/metabolism
Humans
Death-Associated Protein Kinases/metabolism
Reactive Oxygen Species/metabolism
Proteolysis Targeting Chimera

@article {pmid42938023,
year = {2026},
author = {Ghosh, S and Siddharth, KS and Wagalgave, SM and George, SJ},
title = {Bio-Inspired Chain Capping Selectively Inhibits Elongation to Direct Secondary Pathways in Supramolecular Polymers.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {37},
pages = {40120-40130},
doi = {10.1021/jacs.6c12274},
pmid = {42938023},
issn = {1520-5126},
support = {NA//Council of Scientific and Industrial Research, India/ ; ANRF/2025/02766//Science and Engineering Research Board/ ; NA//Jawaharlal Nehru Centre for Advanced Scientific Research/ ; },
mesh = {*Polymers/chemistry/chemical synthesis ; Polymerization ; *Amyloid beta-Peptides/chemistry/metabolism ; Macromolecular Substances/chemistry/chemical synthesis ; },
abstract = {Amyloid β aggregation in Alzheimer's disease proceeds via fibril elongation and toxic oligomer generation through secondary nucleation. In biology, molecular chaperones selectively modulate these competing pathways to control aggregate formation and toxicity. Replicating such pathway selectivity in synthetic supramolecular polymerization─differentiating elongation from secondary nucleation─remains a major challenge. Here, we introduce a unique bioinspired small-molecule based inhibition strategy that achieves selective modulation of these pathways in seeded supramolecular polymerization. The rationally designed capper selectively binds fibril ends, suppressing elongation via the end-capping mechanism while preserving fibril surfaces for secondary nucleation. This redirects monomer flux from elongation to surface-catalyzed nucleation, dramatically enhancing branching and yielding hierarchical superstructures. In contrast to conventional seeded polymerization, which yields linear architectures dominated by elongation, this tunable kinetic switch establishes a synthetic analogue of chaperone-mediated regulation, providing a general framework for programming pathway selection in supramolecular polymerization to access complex hierarchical materials.},
}

*Polymers/chemistry/chemical synthesis
Polymerization
*Amyloid beta-Peptides/chemistry/metabolism
Macromolecular Substances/chemistry/chemical synthesis

@article {pmid42938161,
year = {2026},
author = {Santa, NA and Daza-Santacoloma, G and Serna, WS},
title = {Predicting MCI-to-Alzheimer's Conversion: A Systematic Benchmark of Classical, Machine Learning, and Deep Survival Models.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {20},
pages = {},
pmid = {42938161},
issn = {2075-4418},
support = {790-2023//Technological University of Pereira/ ; },
abstract = {Background/Objectives: Predicting time-to-conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is a critical clinical challenge. Most survival analyses rely on static baseline variables, ignoring the temporal dynamics of serial neuroimaging. We benchmark seven survival model families using a novel temporal MRI descriptor pipeline on ADNI. Methods: A cohort of 661 MCI patients (250 conversion events, 37.8%, median follow-up 42.0 months) was constructed from ADNI. FreeSurfer volumetrics of six brain regions were summarised into three time-based descriptors each (atrophy rate, trajectory variability σ, and time-weighted cumulative mean μ) under strict anti-leakage constraints, yielding 18 neuroimaging features which, combined with six clinical variables (age, sex, education, MMSE, ADAS-13, and APOE-ε4), form a 24-dimensional covariate vector. Cox PH, Weibull AFT, Exponential, RSF, GBST, DeepSurv, and DeepHit were evaluated under stratified 5-fold cross-validation and assessed on an independent OASIS-3 cohort (n=78) as an exploratory analysis. Results: All seven models achieved C-index 0.853-0.863 (Δ=0.010), with Cox PH reaching 0.863±0.027 using only routine structural MRI. Time-dependent AUC ranged from 0.856 (12 months) to 0.938 (48 months). Risk stratification by quartile yielded highly separated Kaplan-Meier curves (log-rank p<0.001). On OASIS-3 (n=78, exploratory), classical models showed preliminary cross-cohort consistency (Weibull AFT 0.760±0.063, RSF 0.759±0.049), while deep learning degraded substantially (DeepSurv 0.551±0.116); these results are hypothesis-generating and should not be interpreted as confirmatory given the small per-fold sample size (EPV ≈ 1). Conclusions: The temporal MRI descriptor pipeline achieves a C-index of 0.863 using only routine structural MRI, without PET or CSF biomarkers, demonstrating strong discriminative performance on ADNI MCI-to-AD conversion. The narrow performance band (Δ=0.010) suggests that, within this feature-engineering paradigm, no clear performance separation was observed among the evaluated model architectures; this convergence may reflect feature-level rather than architecture-level constraints, although the underlying cause cannot be established from discriminative performance alone. Classical models showed more stable cross-cohort behaviour under data-scarce conditions; prospective validation on larger cohorts with full covariate parity is required before clinical translation can be considered.},
}

@article {pmid42938304,
year = {2026},
author = {Yamada, H and Yanaizu, M and Iwai, N and Kato, M and Suzuki, H and Wakai, M and Araki, M and Kino, Y},
title = {Identification of RNA-Binding Proteins Regulating the Alternative Splicing of TREM2 Exon 4.},
journal = {Genes},
volume = {17},
number = {10},
pages = {},
pmid = {42938304},
issn = {2073-4425},
support = {19K07982//Japan Society for the Promotion of Science/ ; 20K07876//Japan Society for the Promotion of Science/ ; 23K14763//Japan Society for the Promotion of Science/ ; },
mesh = {*Membrane Glycoproteins/genetics/metabolism ; Humans ; *Receptors, Immunologic/genetics/metabolism ; *Alternative Splicing/genetics ; Exons ; HEK293 Cells ; *RNA-Binding Proteins/genetics/metabolism ; *Alzheimer Disease/genetics ; CELF Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Most AD cases are sporadic, with both environmental and genetic factors contributing to disease onset and progression. TREM2, an AD susceptibility gene, encodes a receptor protein expressed on the plasma membrane of microglia and macrophages. In addition to membrane-bound TREM2, soluble TREM2 (sTREM2) is also present in the brain. sTREM2 can be generated through two distinct mechanisms: proteolytic shedding of membrane-bound TREM2 and alternative splicing of TREM2 exon 4. Because the mechanisms regulating the latter pathway remain unclear, we investigated the molecular mechanisms underlying TREM2 exon 4 alternative splicing, with a particular focus on RNA-binding proteins (RBPs).

METHODS: We designed guide RNAs (gRNAs) targeting sequences within exon 4. The gRNAs and an exon 4 splicing reporter were transfected into HEK293-based cells with inducible dCasRx expression to identify regions containing cis-regulatory elements involved in exon 4 splicing. RBPs interacting with the candidate region were subsequently identified by RNA pulldown followed by LC-MS/MS analysis.

RESULTS: We identified regions within exon 4 containing putative cis-regulatory elements involved in its alternative splicing and found that CELF1, CELF2, and DDX41 interact with RNA containing one of these regions. Knockdown experiments indicated that these RBPs differentially regulate exon 4 splicing.

CONCLUSIONS: Our findings suggest that TREM2 exon 4 alternative splicing is regulated by multiple cis-regulatory elements and RBPs, including CELF1, CELF2, and DDX41. Together with our previous identification of CELF1 and CELF2 as regulators of TREM2 exon 3 splicing, these findings suggest that CELF1 and CELF2 play complex roles in the regulation of TREM2 alternative splicing.},
}

*Membrane Glycoproteins/genetics/metabolism
Humans
*Receptors, Immunologic/genetics/metabolism
*Alternative Splicing/genetics
Exons
HEK293 Cells
*RNA-Binding Proteins/genetics/metabolism
*Alzheimer Disease/genetics
CELF Proteins/genetics/metabolism
Nerve Tissue Proteins/genetics/metabolism

@article {pmid42938334,
year = {2026},
author = {Tian, X and Xue, X},
title = {Associations of Blood Lipid Traits with Cognitive-Related Outcomes and Their Sensitivity to APOE-Region Instrumental Variables: A Mendelian Randomization and Colocalization Study.},
journal = {Genes},
volume = {17},
number = {10},
pages = {},
pmid = {42938334},
issn = {2073-4425},
support = {2025-JYB-JBGS-007//Fundamental Research Funds for the Central Universities/ ; 2021-ZXFZJJ-044//University-Level Vertical Scientific Research Development Fund/ ; 2024-HXFZJJ-008//Horizontal Scientific Research Development Fund/ ; },
mesh = {Humans ; Mendelian Randomization Analysis ; *Apolipoproteins E/genetics ; *Lipids/blood/genetics ; Cholesterol, HDL/blood/genetics ; *Cognition ; *Alzheimer Disease/genetics/blood ; Female ; *Dementia/genetics/blood ; Male ; Phenotype ; },
abstract = {Background: Neurodegenerative, cognitive, and cerebrovascular outcomes are central to brain health. Previous studies have linked blood lipid traits to these outcomes, but associations differ across lipid components and outcome types. However, the contribution of APOE remains unclear. We compared these patterns, quantified their dependence on APOE, and identified shared signals outside the region. Methods: We used two-sample Mendelian randomization to examine associations between four blood lipid traits from the Global Lipids Genetics Consortium and seven cognitive-related outcomes from FinnGen R11, followed by regional colocalization analysis. We stratified instruments into APOE and non-APOE regions and compared region-specific estimates. Robust non-APOE signals supported by colocalization were further assessed using UK Biobank BIG40 imaging-derived phenotypes. Results: Genetically predicted high-density lipoprotein cholesterol (HDL-C) was inversely associated with the FinnGen composite endpoint of stroke excluding SAH and with cerebrovascular sequelae. Total cholesterol (TC) was positively associated with Alzheimer disease (AD) and dementia.Colocalization supported shared regional signals for TC-AD near TSBP1/TSBP1-AS1, LDL-C-AD within the extended HLA region, and HDL-C-stroke excluding SAH near ILRUN. Estimates for AD, dementia, and memory loss were sensitive to APOE-region exclusion, whereas the HDL-C-stroke estimate was materially unchanged. In separate exploratory analyses of 13 BIG40 imaging phenotypes, HDL-C colocalized with left lateral and right medial orbitofrontal gray-white matter intensity contrast. Conclusions: Lipid-related genetic effects differ across brain outcomes. AD and dementia estimates were sensitive to APOE-region instruments, whereas the HDL-C-associated signal for the composite stroke endpoint persisted after their exclusion. Exploratory imaging results nominate orbitofrontal intensity contrast as an HDL-C correlate.},
}

Humans
Mendelian Randomization Analysis
*Apolipoproteins E/genetics
*Lipids/blood/genetics
Cholesterol, HDL/blood/genetics
*Cognition
*Alzheimer Disease/genetics/blood
Female
*Dementia/genetics/blood
Male
Phenotype

@article {pmid42938377,
year = {2026},
author = {Zhong, S and Xie, G and Zhang, Z},
title = {Multi-Cohort Transcriptomic Integration Identifies Overlapping Immune and Antigen-Presentation Features in Alzheimer's Disease and Hashimoto's Thyroiditis.},
journal = {Genes},
volume = {17},
number = {10},
pages = {},
pmid = {42938377},
issn = {2073-4425},
support = {82371191//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Hashimoto Disease/genetics/immunology/pathology ; *Alzheimer Disease/genetics/immunology/pathology ; *Transcriptome/genetics ; *Antigen Presentation/genetics ; Female ; Male ; Thyroid Gland/immunology/metabolism ; Cohort Studies ; Gene Expression Profiling ; Brain/immunology/metabolism ; },
abstract = {BACKGROUND: Thyroid disorders and Alzheimer's disease (AD) have been linked epidemiologically, but whether AD brain tissue and thyroid tissue affected by Hashimoto's thyroiditis (HT) share molecular features remains unclear.

METHODS: Differential expression was estimated in AD (GSE122063) and HT (GSE138198) discovery cohorts using limma, with donor-level blocking and adjustment for age, sex and post-mortem interval where available. Shared genes were tested against chance within the genes measured in both cohorts, separately for each direction of change; characterized by enrichment analysis; related to marker-based cell-state scores; and evaluated in two AD cohorts, three thyroid cohorts including one with concurrently collected normal thyroid (GSE165724), and a single-nucleus AD dataset (GSE138852).

RESULTS: The discovery analyses identified 3593 AD- and 3806 HT-associated genes. The overlap was direction-specific: genes upregulated in both diseases exceeded chance (117 vs. 83.2 expected; p = 8.9 × 10[-5]), whereas the other direction combinations did not. Co-upregulated genes were enriched for MHC class II antigen presentation (FDR = 0.004), complement (FDR = 0.002), microglial activation (FDR = 0.017) and T-cell activation (FDR = 1.7 × 10[-4]), and recurred in two independent thyroid datasets and the within-study LT+ versus LT- comparison, with less consistent, region-dependent recurrence in AD cohorts. This shared component tracked immune cell-state signals-glial/myeloid activation in AD and lymphocytic infiltration in HT. Fourteen co-upregulated genes, including ITGAX, CD22 and BST2, met prespecified recurrence and detectability criteria.

CONCLUSIONS: AD brain tissue and thyroid tissue affected by HT exhibit a co-upregulated immune and antigen-presentation transcriptional program that reflects immune activation in both tissues. These overlapping features are associative and do not establish a causal relationship between AD and HT.},
}

Humans
*Hashimoto Disease/genetics/immunology/pathology
*Alzheimer Disease/genetics/immunology/pathology
*Transcriptome/genetics
*Antigen Presentation/genetics
Female
Male
Thyroid Gland/immunology/metabolism
Cohort Studies
Gene Expression Profiling
Brain/immunology/metabolism

@article {pmid42938969,
year = {2026},
author = {Nguyen, T and Woods, C and Liu, J and Wang, C and Lin, AL and Cheng, J},
title = {APOEFormer: A Multimodal AI Model for APOE4 Carrier Status Prediction and Phenotype Characterization in Alzheimer's Disease.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {42938969},
issn = {2306-5354},
support = {//University of Missouri/ ; },
abstract = {The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the most common form of dementia. APOE4 carriers exhibit cerebrovascular and metabolic dysfunction, structural brain alterations, and gut microbiome changes decades before the onset of clinical symptoms. Better understanding of the early manifestation of these physiological changes is critical for development of timely AD interventions and risk reduction protocols. Multi-modal datasets encompassing a wide range of APOE ε4 and AD associated biomarkers provide a valuable opportunity to gain insight into the APOE4 phenotype; however, these datasets often present analytical challenges due to small sample sizes and high heterogeneity. Here, we propose a two-stage multimodal AI model (APOEFormer) that integrates blood metabolites, brain vascular and structural MRI, microbiome profiles, and other clinical and demographic data to predict APOE4 allele status. In the first stage, modality-specific encoders are used to generate initial representations of input data modalities, which are aligned in a shared latent space via self-supervised contrastive learning during pretraining. The contrastive learning objective encourages learning of informative and consistent representations across modalities through leveraging cross-modality relationships. In the second stage, the pretrained representations are used as inputs to a multimodal transformer that integrates information across modalities to predict a key AD-risk genetic variant (APOE4). Across 10 repeated experimental runs with different train-validation-test splits, APOEFormer predicts whether an individual carries an APOE4 allele with an average prediction accuracy of 75%, demonstrating robust performance under limited sample sizes. Post hoc perturbation analysis of the predictive model revealed valuable insights into the driving components of the APOE4 phenotype-including key blood biomarkers and brain regions strongly associated with APOE4.},
}

@article {pmid42939079,
year = {2026},
author = {Cantillo-Negrete, J and Rodríguez-García, ME and Carrillo-Mora, P and Méndez-Gómez, DD and Carino-Escobar, RI},
title = {Brain-Computer Interfaces for Cognitive Rehabilitation: A Narrative Review.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {42939079},
issn = {2306-5354},
abstract = {Cognitive diseases/disorders are a major cause of disability affecting millions of people worldwide due to pathologies or conditions such as Alzheimer's disease, Parkinson's disease, vascular cognitive impairment, and attention deficit/hyperactivity disorder. The effects of these diseases/disorders can range from subjective cognitive complaints to mild cognitive impairment and even dementia that can affect multiple cognitive domains, causing disability and alterations in daily functioning and quality of life. Cognitive training has been researched as a potential therapeutic option for treating cognitive disability. In particular, cognitive training delivered using brain-computer interfaces (BCIs) represents a promising technology for cognitive rehabilitation. For this reason, this work presents a narrative review aimed at bridging the clinical aspects of cognition performance and the technical features of BCI systems. Additionally, it reports on the current advances of BCIs for cognitive rehabilitation in the pathologies/conditions that are the main contributors of cognitive impairment globally. Specifically, Alzheimer's disease, Parkinson's disease, mild cognitive impairment, cerebrovascular diseases, and attention-deficit/hyperactivity disorder were included in the review; other pathologies that can also cause cognitive impairment such as multiple sclerosis, traumatic brain injury, brain tumors, infectious diseases, and psychiatric conditions such as schizophrenia or autism spectrum disorder, or drug or toxin-related causes were outside the scope of the present review. Across the literature, studies have reported that BCI cognitive training can improve cognition performance for mild cognitive impairment, stroke, and attention-deficit/hyperactivity disorder, showcasing its feasibility as a complementary therapy. However, the amount of evidence is still scarce, with few reported randomized controlled clinical trials and all of the applications comprising non-invasive systems using electroencephalography, while invasive or other non-invasive approaches remain largely unassessed. Therefore, further research regarding the design of BCIs for targeting specific cognitive domains is necessary to allow for the future introduction of these types of systems into clinical rehabilitation environments, rather than only demonstrating their feasibility, as has been mainly done to date.},
}

@article {pmid42939080,
year = {2026},
author = {Omidi, S and Bacsu, JR and Absher, JR and Babaieasl, F and Kooshiar, H and Imani, SM and Ebrahimi, N and Smith, ML and Rahemi, Z},
title = {Generative Artificial Intelligence in Health Research and Care: A Narrative Review of Applications and Implications for Alzheimer's Disease and Related Dementia.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {42939080},
issn = {2306-5354},
support = {Grant K01AG081485/AG/NIA NIH HHS/United States ; Grant 24AARG-D-1242910/ALZ/Alzheimer's Association/United States ; //Clemson University/ ; },
abstract = {The advent of generative artificial intelligence (AI), particularly large language models (LLMs) and deep generative networks, is transforming the landscape of Alzheimer's disease and related dementia (ADRD) research and care. This narrative review aims to synthesize current applications of generative AI in ADRD research and care, highlight ethical and implementation challenges, and propose strategies for responsible integration into clinical practice. We conducted a narrative review of literature, regulatory documents, program reports, and relevant sources published between 2016 and 2026, with a specific focus on cognitive screening, synthetic data generation, digital twin modeling, and caregiver support. Techniques discussed include generative adversarial networks (GANs), variational autoencoders (VAEs), diffusion models, multimodal transformers, and LLM-powered chatbots. Generative AI enables applications such as virtual patient companions, remote cognitive assessments via conversational agents, multimodal image-to-text tools, synthetic data augmentation, disease progression simulation, and improved caregiver communication. Challenges include model explainability, clinical validation, regulatory compliance, privacy, data bias, hallucination risk, patient autonomy, and global disparities. Responsible development requires transparent reporting, stakeholder co-design, rigorous clinical and economic validation, and continuous post-deployment monitoring to support fairness and effectiveness in real-world settings.},
}

@article {pmid42939267,
year = {2026},
author = {Gatto, RG and Youssef, H and Uruk, G and Carlos, AF and Reichard, RR and Lowe, VJ and Whitwell, JL and Josephs, KA},
title = {Pilot Multimodal Imaging Assessment of Neuropathological Iron Deposition and Molecular PET in Frontotemporal Lobar Degeneration.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939267},
issn = {2076-3425},
support = {5RF1NS112153-26/NH/NIH HHS/United States ; 5R01DC012519-26/NH/NIH HHS/United States ; 5R01NS089757-25/NH/NIH HHS/United States ; },
abstract = {BACKGROUND/OBJECTIVES: The role of iron in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) has been debated. However, the effects of iron on protein burden in these diseases remain poorly elucidated. We hypothesized that there is an association between iron deposition and tau and beta-amyloid deposition in deep grey matter (GM) regions in FTLD.

METHODS: Neuropathological samples were collected from two control subjects and 10 disease subjects. This included 12 subjects, with several pathological subgroups represented by only one or two cases. Of the 10 disease subjects, one had low-level AD neuropathology (L-AD), and one had high-level AD neuropathology (H-AD), whereas the remaining eight subjects had FTLD-tau pathology, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and Pick's disease (PiD). Neuropathological samples were stained for iron with Prussian blue (PB) and ferritin, tau, and beta-amyloid in the basal ganglia (BG). All 12 subjects had also undergone diffusion MRI, amyloid-PET (PiB-PET), and Tau-PET (flortaucipir) before death. Diffusion tensor imaging mean diffusivity (MD) from BG was examined in each subject. Spearman's rank correlations between imaging and histology were calculated.

RESULTS: Increased BG iron was observed in PSP subjects. Prussian blue and ferritin measures were associated with higher tau- and β-amyloid pathological burden. Tau-PET uptake correlated with iron in the BG.

CONCLUSIONS: The results of this exploratory study suggest associations between iron burden and tau- and β-amyloid-related measures within basal ganglia regions that may help to explain increased PET signals in AD and FTLD-Tau. Our findings should be considered to be hypothesis-generating and require validation. These preliminary findings require validation in larger cohorts.},
}

@article {pmid42939269,
year = {2026},
author = {Dong, H and Wang, W and Zeng, W and Zou, Q and Lu, W and Chen, C and Yao, J and Li, Y},
title = {Acupuncture in Aging-Related Brain Diseases: From Mitochondrial Homeostasis to Clinical Signals.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939269},
issn = {2076-3425},
support = {82405582//National Natural Science Foundation of China/ ; GZB20240087 and 2024M750285//China Postdoctoral Science Foundation/ ; },
abstract = {Mitochondria play a key role in maintaining cellular homeostasis through energy metabolism, ROS regulation, calcium handling, and apoptosis control. Mitochondrial dysfunction contributes to neurological vulnerability in the aging brain, where neuronal energy demand, axonal transport, synaptic activity, and neurovascular repair depend on mitochondrial integrity. Animal studies in chronic brain disease and acute brain-injury models have examined acupuncture-related changes in phenotypic outcomes and mitochondrial measures, including behavioral, physiological, and molecular readouts. Their findings span mitochondrial ultrastructure, biogenesis, dynamics, mitophagy, and downstream signaling. Clinical studies have examined acupuncture in Parkinson's disease, stroke, and Alzheimer's disease. Animal studies report acupuncture-related changes in mitochondrial structure and indices of quality control alongside improvements in neurological, behavioral, or injury-related outcomes. These mitochondrial changes may influence oxidative stress, calcium regulation, apoptosis, mitochondrial transport, and intercellular mitochondrial support. Clinical studies mainly report symptom and functional outcomes, while a small number of imaging studies also describe changes in cerebral glucose metabolism or neural activity. These preliminary clinical and metabolic signals may inform further investigation into whether mitochondrial processes are associated with clinical responses to acupuncture. Current experimental work also has important limitations: most studies focus on a limited set of mitochondrial quality-control markers, while the mitochondrial unfolded protein response, axonal mitochondrial trafficking, and dynamic mitochondrial transfer are rarely assessed. Future clinical studies should pair neurological outcomes with feasible measures of mitochondrial function and energy metabolism. Tracking these measures over time may help clarify how changes in mitochondrial function and energy metabolism during acupuncture treatment relate to functional recovery.},
}

@article {pmid42939317,
year = {2026},
author = {Kumar, P},
title = {Editorial: Advances in Memory and Cognitive Decline Associated with Aging and Alzheimer's Disease.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939317},
issn = {2076-3425},
abstract = {Alzheimer's disease is a progressive neurodegenerative disease in the elderly population [...].},
}

@article {pmid42939320,
year = {2026},
author = {Macoir, J},
title = {Numerical Cognition in Neurodegenerative Disorders: A Systematic Review of Patterns of Preservation and Impairment.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939320},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Numerical cognition comprises multiple processes supporting the representation, comprehension, production, and manipulation of numerical information. Although numerical impairments have been described in neurodegenerative diseases, findings remain fragmented across disorders and numerical domains. This systematic review aimed to characterize patterns of preserved and impaired core numerical abilities across neurodegenerative disorders and to examine their implications for cognitive models and clinical assessment.

METHODS: PubMed, Web of Science, and PsycINFO were systematically searched for original empirical studies in English or French examining core numerical cognition in adults with neurodegenerative disorders or mild cognitive impairment. Reference lists were additionally screened. Methodological quality was appraised using design-specific Joanna Briggs Institute critical appraisal tools. Forty-seven studies published between 1989 and 2026 met the eligibility criteria. Findings were synthesized qualitatively because of substantial heterogeneity in study designs, clinical populations, and numerical measures.

RESULTS: Numerical profiles varied considerably across disorders, individuals, and disease stages, but several broad patterns emerged. Basic number comprehension and magnitude processing were often relatively preserved, whereas greater vulnerability was observed for processes requiring transformation, retrieval, or manipulation of numerical information. Arithmetic fact knowledge showed variable preservation, including dissociations between stored knowledge and its retrieval. Calculation procedures and complex calculation were among the most consistently affected abilities. Evidence was strongest for Alzheimer's disease and semantic variant primary progressive aphasia and remained limited for several other neurodegenerative disorders.

CONCLUSIONS: Numerical cognition is differentially affected across neurodegenerative diseases, supporting its multicomponent organization. These findings suggest the potential value of multidomain assessment rather than reliance on isolated calculation tasks. However, methodological heterogeneity, variation in methodological strength across studies, and the limited evidence available for several disorders reduce confidence in the generalizability of these patterns and currently preclude defining reliable disease-specific numerical signatures.

REGISTRATION: OSF, 10.17605/OSF.IO/DU2Y9.

FUNDING: None.},
}