@article {pmid42709250,
year = {2026},
author = {Yang, W and Lu, Y},
title = {Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42709250},
issn = {1590-3478},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *alpha-Synuclein/metabolism ; Animals ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/metabolism ; *Protein Aggregation, Pathological/metabolism/therapy ; },
abstract = {BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD).

OBJECTIVE: This review examines cross-disease protein interactions and their implications for diagnosis and treatment.

METHODS: We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies.

RESULTS: Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91% of individuals over 80 years harbor multiple neuropathologies. Co-pathology accelerates cognitive decline and complicates biomarker interpretation. Anti-amyloid immunotherapies lecanemab and donanemab demonstrate 27-35% slowing of cognitive decline, while anti-tau antibodies targeting N-terminal epitopes have uniformly failed, prompting investigation of combination approaches.

CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
*alpha-Synuclein/metabolism
Animals
*DNA-Binding Proteins/metabolism
*Alzheimer Disease/metabolism
*Protein Aggregation, Pathological/metabolism/therapy

@article {pmid42709336,
year = {2026},
author = {Colosimo, C},
title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42709336},
issn = {1179-1918},
abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.},
}

@article {pmid42709495,
year = {2026},
author = {Yang, X and Xu, X and Liu, Y and Shi, L and He, F},
title = {Roles of smoke exposure and inflammatory biomarkers in cognitive function among older adults: Findings from two prospective cohort studies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482025},
doi = {10.1177/13872877261482025},
pmid = {42709495},
issn = {1875-8908},
abstract = {BackgroundMany studies have established associations between smoke exposure and both accelerated cognitive decline and systemic inflammation. However, their interrelationship remains unclear.ObjectiveThis study aims to provide novel insights into the tripartite relationships linking smoke exposure, inflammatory biomarkers, and cognitive function among older adults.MethodsThis study analyzed data from 2503 participants in the National Health and Nutrition Examination Survey (NHANES, 2011-2014) and 3263 participants in the China Health and Retirement Longitudinal Study (CHARLS, 2011-2012). Serum cotinine was mainly used to assess smoke exposure in NHANES, while self-reported smoking status was used in CHARLS. Cognitive function was assessed using standard cognitive tests in NHANES and CHARLS. Inflammatory biomarkers included NLR, SII, leukocyte, neutrophil and lymphocyte in NHANES and leukocyte in CHARLS. Linear regression, nonlinear threshold effect models, and mediation analysis examined associations and mediating effects.ResultsHigher cotinine was associated with lower cognitive scores in NHANES (β = -0.219, p < 0.001). In CHARLS, current smokers exhibited lower cognitive scores than never-smokers (β = -0.090, p = 0.004). Neutrophil and leukocyte showed linear relationship with cognitive function in NHANES, while other inflammatory indicators showed significant nonlinear threshold effects. Mediation analysis revealed that neutrophil and leukocyte partially mediated 7.39% and 9.75% of the smoke-cognitive decline association.ConclusionsSmoking is related to cognitive decline in older adults from two national cohorts, with neutrophil and leukocyte partly mediating this link in the U.S. cohort. Interventions for smoking cessation and inflammation reduction may help mitigate cognitive decline.},
}

@article {pmid42709503,
year = {2026},
author = {Xu, L and Wei, L and Li, R and Hu, Y},
title = {A Bayesian network meta-analysis of specific exercise modalities for depressive symptoms in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485578},
doi = {10.1177/13872877261485578},
pmid = {42709503},
issn = {1875-8908},
abstract = {BackgroundPatients with mild cognitive impairment (MCI) frequently experience depressive symptoms, which are linked to accelerated cognitive decline, poorer quality of life, and an increased risk of progression to Alzheimer's disease. Exercise is considered a promising non-pharmacological strategy for mood improvement and brain health; however, the specific effects of different exercise modalities remain insufficiently defined.ObjectiveTo compare the relative efficacy of specific exercise interventions on depressive symptoms in patients with MCI.MethodsRandomized controlled trials (RCTs) evaluating the effects of exercise interventions on depressive symptoms in patients with MCI were systematically searched. Standardized mean differences (SMD) were calculated to pool outcomes across different depression scales. A Bayesian network meta-analysis was conducted to integrate direct and indirect evidence, and interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Network consistency and model fit were also assessed.ResultsA total of 19 RCTs involving nine exercise modalities were included. Compared with the control group, dance exercise demonstrated a statistically significant improvement in depressive symptoms (SMD = -0.51, 95% credible intervals: -0.84 to -0.16), representing a moderate effect size, and showed a relatively high-ranking probability (SUCRA = 80.71%). Overall heterogeneity was moderate, and local inconsistency was observed in some comparisons.ConclusionsExercise interventions may contribute to the alleviation of depressive symptoms in patients with MCI, with dance exercise showing relatively greater therapeutic potential. However, these findings should be interpreted with caution in light of evidence inconsistency, and further high-quality studies are warranted to substantiate these results.},
}

@article {pmid42709508,
year = {2026},
author = {Ruitenberg, MFL and Carmona Osorio, PD and King, JB and Hoffman, JM and Duff, K and Koppelmans, V},
title = {Motor sequence learning and learning to learn across the Alzheimer's disease continuum: Associations with biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485584},
doi = {10.1177/13872877261485584},
pmid = {42709508},
issn = {1875-8908},
abstract = {BackgroundWhile amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) are primarily associated with cognitive impairments, motor dysfunction has also consistently been observed. Less is known, however, about the acquisition of new motor sequences along the AD continuum.ObjectiveThis study examined motor sequence learning in individuals with aMCI and AD dementia compared to cognitively normal individuals (CNI), and to what extent such learning is related to AD biomarkers.MethodsA total of 28 individuals with AD dementia, 33 with aMCI, and 52 CNI performed a computerized task that assessed general motor performance and motor sequence learning abilities. Participants also completed a neuropsychological test battery to assess their cognitive abilities. APOE genotyping was used to determine the presence of ɛ4 alleles, amyloid PET imaging to quantify amyloid deposition, and structural MRI scanning to obtain hippocampal volume.ResultsWhile individuals with aMCI or AD dementia generally performed slower and less consistent than CNI, motor sequence learning occurred regardless of cognitive status. The rate of initial learning was slower in individuals with aMCI or AD dementia than in CNI. No significant associations between motor learning and AD biomarkers were observed. A combination of motor and cognitive measures best predicted amyloid burden, whereas a model with cognitive measures only best predicted hippocampal volume and APOE allele count.ConclusionsOverall, individuals with aMCI and AD dementia showed relatively preserved motor sequence learning abilities, despite some decrements in the initial rate of learning. Combining measures of motor and cognitive functioning may enhance the prediction of amyloid burden. Future studies should use more complex sequential movements and further explore the value of integrating motor measures in AD/aMCI assessment and monitoring.},
}

@article {pmid42709512,
year = {2026},
author = {Li, OY and Turnbull, A and Vankee-Lin, F},
title = {Stage-dependent associations of glial fibrillary acidic protein and chitinase-3-like protein 1 with white matter network integrity in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485599},
doi = {10.1177/13872877261485599},
pmid = {42709512},
issn = {1875-8908},
abstract = {BackgroundAstrocytes become reactive in Alzheimer's disease (AD), and fluid markers of this response, including glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40), increase across the AD continuum. However, it remains unclear whether astrocytic biomarker levels relate to preserved versus disrupted white matter (WM) integrity, and whether these relationships vary by amyloid-β (Aβ) burden and apolipoprotein E (APOE) ε4 status.ObjectiveTo examine associations of GFAP and YKL-40 with WM integrity, AD pathology, and memory across Aβ and APOE ε4 contexts.MethodsWe analyzed 52 dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with longitudinal diffusion tensor imaging and baseline cerebrospinal fluid (CSF) biomarkers. WM integrity was assessed using network-level stability and mean diffusivity within medial temporal lobe-associated networks. Baseline CSF GFAP, YKL-40, Aβ1-42, phosphorylated tau (p-tau181), APOE ε4 status, and episodic memory were examined. Findings were evaluated in an independent Stanford Alzheimer's Disease Research Center sample with plasma GFAP.ResultsGFAP showed context-dependent associations with WM integrity and AD pathology. In Aβ-negative and APOE ε4-negative individuals, higher GFAP was associated with greater WM stability, lower mean diffusivity. In Aβ-positive and APOE ε4-positive individuals, higher GFAP was associated with higher p-tau18 rather than WM integrity. Higher YKL-40 was associated with reduced WM stability. In the validation cohort, APOE ε4 status moderated the association between plasma GFAP and WM integrity.ConclusionsAstrocytic biomarkers demonstrated relationships with WM integrity and AD pathology. GFAP appeared to reflect context-dependent astrocytic responses, whereas YKL-40 was consistently associated with WM disruption.},
}

@article {pmid42709642,
year = {2026},
author = {Kim, DY and Yoon, J and Kim, S and Park, J and Kim, JH and Yoo, H and Kim, J and Kim, K and Woo, HG and Woo, S and Yon, DK},
title = {Decoding the drivers of Alzheimer's disease and other dementias mortality in Asia, 1990-2023: a Global Burden of Diseases Study 2023.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag033},
pmid = {42709642},
issn = {1423-0208},
abstract = {BACKGROUND: Despite the burden of Alzheimer's disease and other dementias (ADOD) in Asia, evidence on patterns of mortality attributable to risk factors remains limited.

METHODS: We used data from the Global Burden of Diseases Study (GBD) 2023 to examine mortality from ADOD attributable to GBD-quantified risk factors in Asia from 1990 to 2023. Analyses included 34 countries and territories. These were grouped into five regions according to the GBD classification: Central Asia, East Asia, South Asia, Southeast Asia, and the high-income Asia Pacific. ADOD was defined as dementia characterized by progressive cognitive decline with functional impairment. ADOD mortality attributable to air pollution, tobacco use, high fasting plasma glucose(FPG), and high body mass index was assessed among adults aged ≥70 years using the GBD comparative risk assessment framework. The Das Gupta decomposition method was applied to quantify the contributions of population growth, population aging, and epidemiological change. Uncertainty was reported as 95% uncertainty intervals (UIs) derived from 250 posterior draws.

RESULTS: In 2023, ADOD mortality rates in Asia showed marked variation, with the highest burden in high-income Asia Pacific (661.10 [95% UI, 189.78-1504.67] per 100,000 population) and the lowest in Central Asia (273.00 [65.15-695.77]). From 1990 to 2023, the burden attributable to high FPG increased across all regions. High-income Asia Pacific remained the highest, increasing from 75.60 (95% UI, 17.97-204.39) per 100,000 population to 139.21 (32.10-323.57). Air pollution remained a major driver, while tobacco-attributable burden in 2023 remained concentrated in East Asia (16.86 [95% UI, 3.38-41.27] per 100,000 population). The burden increased steeply with age and differed by sex, with higher burdens from air pollution and high FPG in females and from tobacco in males. Decomposition analyses showed varying contributions of population growth, population aging, and epidemiological change to changes in attributable mortality. The Maldives showed the largest increases for air pollution, high FPG, and tobacco.

CONCLUSIONS: The substantial heterogeneity in risk-attributable ADOD mortality across regions, age groups, and sexes supports risk- and region-specific prevention priorities across Asia. Dementia prevention should be aligned with local cardiometabolic, tobacco, and air-pollution risk profiles, while future studies should assess whether reducing these exposures translates into lower ADOD mortality.},
}

@article {pmid42709650,
year = {2026},
author = {Honjo, Y and Kawasaki, I and Nagai, K and Yuri, T and Nakai, H and Harada, S and Tamaru, Y and Suganuma, I and Ogawa, N},
title = {Longitudinal Association between Day Service Use and Regular Memory Clinic Attendance in Alzheimer's Disease: A 3-Year Retrospective Observation of Completers.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag006},
pmid = {42709650},
issn = {1421-9824},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a common progressive cognitive disease. Day services (DS) are provided through the Japanese public nursing care system. This study examined the association between DS utilization and regular memory clinic attendance among patients with AD.

METHODS: We retrospectively analyzed the association between DS utilization and duration of regular memory clinic attendance in 302 patients with AD during a 3-year period. The patients were divided into 4 groups according to attendance duration. We examined the association between DS utilization and attendance duration. Next, we evaluated the 3-year efficacy of anti-AD drugs alongside non-pharmacological therapies. Cognitive function was assessed using the Revised Hasegawa Dementia Scale (HDS-R) and the Mini-Mental State Examination (MMSE) scores. Behavioral and psychological symptoms of dementia in AD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q).

RESULTS: In bivariate analysis, attendance duration was significantly associated with age, number of family members, DS utilization, and first-visit scores for the NPI-Q, HDS-R, and MMSE. In Cox regression, DS non-utilization showed no significant association with regular attendance, though it trended toward higher dropout risk (HR = 1.25, 95% CI: 0.69-2.25, p = 0.44). HDS-R and MMSE scores declined significantly over time across all groups, consistent with the typical disease course.

CONCLUSIONS: DS non-utilization warrants investigation in larger cohorts as a potential marker of attrition risk. While this association does not imply direct causality due to potential residual confounding, monitoring DS engagement might assist clinicians in identifying patients at higher risk of clinic dropout.},
}

@article {pmid42709657,
year = {2026},
author = {Jung, J and Lee, H and Park, S},
title = {Rhinitis, sinusitis, and risk of dementia: A systematic review and meta-analysis.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag032},
pmid = {42709657},
issn = {1423-0208},
abstract = {INTRODUCTION: This study aimed to systematically review epidemiological evidence on the association between rhinitis or sinusitis and the risk of dementia.

METHODS: This review followed PRISMA 2020 guidelines and a protocol registered in PROSPERO (CRD420251181185). A comprehensive search was conducted in Medline, EMBASE, CINAHL, and Web of Science databases for literature published up to October 2025. The search strategy incorporated the terms of 'rhinitis' OR 'sinusitis' AND 'dementia' OR 'Alzheimer'. We included cohort, case-control, and Mendelian randomization studies that reported the risk of dementia among adults diagnosed with rhinitis or sinusitis. Three PECO questions were defined to guide data synthesis and the assessment of certainty of evidence using the GRADE approach. Hazard ratios (HRs) or odds ratios (ORs) were pooled using a random‑effects model in the meta‑analysis. Risk of bias was evaluated for each study design.

RESULTS: A total of eight articles met the inclusion criteria, all of which were suitable for meta‑analysis. Among the included articles, one article included both a cohort and a case‑control design, resulting in a total of nine study units in the final analysis. Three cohort studies showed an association between rhinitis or sinusitis and all-cause dementia (HR 1.10, 95% CI: 1.09-1.11). However, rhinitis or sinusitis was not significantly associated with Alzheimer's disease in either cohort or case-control analyses. There was no evidence of a relationship between allergic rhinitis and Alzheimer's disease in either cohort or Mendelian randomization analyses. Certainty of evidence ranged from low to very low. Most studies were judged to have a low risk of bias.

CONCLUSION: Rhinitis or sinusitis was associated with a modestly increased risk of all-cause dementia in the cohort analysis, but inconsistency and imprecision across studies limit causal inference. Therefore, large-scale observational or Mendelian randomization studies that include diverse populations and encompass both chronic rhinitis and sinusitis are needed. Mechanistic studies are also needed to elucidate whether type 2 immune responses may contribute to neurodegeneration.},
}

@article {pmid42709795,
year = {2026},
author = {Du, X and Liu, N and Zhang, T and Yang, C and Luo, H},
title = {Size-tailored nanoparticle-antibody conjugates overcome hepatic sequestration in Alzheimer's disease treatment.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {37},
pages = {e2603034123},
doi = {10.1073/pnas.2603034123},
pmid = {42709795},
issn = {1091-6490},
support = {0214187096//Huazhong University of Science and Technology (HUST)/ ; XJ2400008870//Hainan University (HU)/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/therapy/metabolism/immunology ; *Nanoparticles/chemistry ; Amyloid beta-Peptides/metabolism/immunology ; *Liver/metabolism/drug effects ; Silicon Dioxide/chemistry ; Mice ; *Antibodies, Monoclonal/chemistry ; Particle Size ; Mice, Transgenic ; Polyethylene Glycols/chemistry ; Brain/metabolism ; Humans ; *Immunoconjugates/chemistry ; },
abstract = {Antibody-based immunotherapy targeting amyloid-β (Aβ) is a promising approach for Alzheimer's disease (AD). However, its efficacy is limited by rapid hepatic sequestration, complement activation, and liver dysfunction. In this study, we synthesized low-immunogenic 450-nm functionalized mesoporous silica nanoparticles (PEG-MSN-1F12) by conjugating the anti-Aβ42 monoclonal antibody 1F12 to polyethylene glycol-modified mesoporous silica nanoparticles to address these challenges. In APP/PS1 mice, intravenous PEG-MSN-1F12 administration markedly enhanced peripheral Aβ clearance, promoted intestinal excretion, reshaped gut microbiota, and alleviated intestinal inflammation, thus reducing AD-associated hepatic burden. Peripheral Aβ removal further led to decreased brain Aβ deposition, attenuated microglial activation, and improved cognition. These findings highlight that the use of particle size-engineered antibody-nanoparticle conjugates is a safe and effective strategy to overcome hepatic sequestration, augment Aβ clearance, and improve AD outcomes.},
}

Animals
*Alzheimer Disease/drug therapy/therapy/metabolism/immunology
*Nanoparticles/chemistry
Amyloid beta-Peptides/metabolism/immunology
*Liver/metabolism/drug effects
Silicon Dioxide/chemistry
Mice
*Antibodies, Monoclonal/chemistry
Particle Size
Mice, Transgenic
Polyethylene Glycols/chemistry
Brain/metabolism
Humans
*Immunoconjugates/chemistry

@article {pmid42709841,
year = {2026},
author = {Xiong, C and Nie, Y and Luo, J and Lu, R and Wolk, D and Shaw, LM and Gleason, CE and Johnson, SC and Agboola, F and Morris, JC and Schindler, SE},
title = {Sample size determination for a prospective bridging study to harmonize retrospective data from multiple studies-Application to a biofluid biomarker study of Alzheimer's disease.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261468023},
doi = {10.1177/09622802261468023},
pmid = {42709841},
issn = {1477-0334},
abstract = {Biomarkers measured from biofluid samples and imaging scans are important to aid diagnosis of diseases and track their progression over time, especially in neurodegenerative diseases such as Alzheimer's disease (AD). Combining retrospectively obtained biomarker data across multiple studies can increase statistical power, but existing biomarker data may be generated using different assay platforms, scanner types, or processing protocols by different studies, which may significantly affect the measurements of biomarkers and hence render it necessary to harmonize the data across the studies. An optimal way of biomarker data harmonization is to re-analyze all the biofluid samples or imaging scans together on a single platform in a central reference lab, but this is often not practical because of the substantial cost involved as well as the limited amount of biofluid samples available. A more practical solution is to prospectively design a bridging study by re-measuring a subset of biofluid samples or imaging scans from the studies in a reference lab to evaluate how biomarker values may be harmonized across studies. An important design question for such a bridging study is the size of the retrospectively collected biofluid samples or imaging scans that will be re-measured. We aim to address this question by conceptualizing a latent but true biomarker that underlies the observed versions of the biomarker measured across retrospective studies and proposing methods to determine the sample size of a bridging study for estimating the biological correlation of the true biomarker with a standard and validated clinical outcome. We also report bridging data of several analytes from cerebrospinal fluid (CSF) in a multi-center biomarker study of AD and demonstrate that a small proportion of the CSF samples may be sufficient to design a future bridging study for estimating the correlations of CSF biomarkers with a cognitive and functional outcome.},
}

@article {pmid42709901,
year = {2026},
author = {},
title = {In brief: Subcutaneous lecanemab (Leqembi Iqlik) for initial treatment of Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1763},
pages = {151},
doi = {10.58347/tml.2026.1763c},
pmid = {42709901},
issn = {1523-2859},
}

@article {pmid42709903,
year = {2026},
author = {},
title = {Comparison table: Amyloid beta-directed antibodies for Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1763},
pages = {e151},
doi = {10.58347/tml.2026.1763e},
pmid = {42709903},
issn = {1523-2859},
}

@article {pmid42710414,
year = {2026},
author = {Charavner, EL and Fillatreau, S and El Behi, M},
title = {Is there a role for B cells in Alzheimer's disease?.},
journal = {Cellular immunology},
volume = {428-429},
number = {},
pages = {105154},
doi = {10.1016/j.cellimm.2026.105154},
pmid = {42710414},
issn = {1090-2163},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder associated with dementia, progressive neuronal loss, extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau deposition. Currently, no curative therapies are available for this condition. Beyond these features, AD pathogenesis is associated with neuroinflammation, which is thought to be primarily driven by microglial cells, and has evolved as an important contributor to AD pathogenesis over the past decade. Although microglia cells play a central role in neuroinflammation, they are also a highly heterogeneous population existing in distinct transcriptional states that can be either beneficial or detrimental to disease progression. Importantly, microglial activation and the ensuing neuroinflammatory milieu do not operate independently of the systemic immune system. The longstanding view of the brain as an immune-privileged organ has been fundamentally revised, with increasing evidence demonstrating that the crosstalk between brain-resident and circulating peripheral immune cells plays a pivotal role in AD pathogenesis. Peripheral immune cells, recruited in the central nervous system in response to Aβ and tau pathology, actively modulate the neuroinflammatory environment. While CD4[+] and CD8[+] T cells have been extensively investigated in this context, the contribution of B cells to AD remains poorly understood. Here, we comprehensively review the phenotypic and functional alterations of B cells in AD, integrating evidence from experimental models and human studies, to evaluate whether B cells constitute an underappreciated component of the adaptive immune response in AD and whether they represent a compelling immunotherapeutic target. We also highlight key unresolved questions and propose future research directions to guide the field towards a deeper mechanistic understanding of B cell biology in AD.},
}

@article {pmid42710551,
year = {2026},
author = {Kosa, AC and Lopez-Gutierrez, L and Ando, K and Doeraene, E and Aydin, E and Lasri, H and Wathelet-Depauw, A and Pieters, K and Van Morckhoven, D and Dubois, C and Hupkens, E and Jespers, P and Dewachter, L and Stamatopoulos, B and Brion, JP and Leroy, K},
title = {Effect of tau silencing on tau pathology propagation, a treatment efficient at the earliest stages of the disease?.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107598},
doi = {10.1016/j.nbd.2026.107598},
pmid = {42710551},
issn = {1095-953X},
abstract = {Cognitive decline in Alzheimer's disease (AD) correlates more strongly with tau pathology than with amyloid plaques, switching the therapeutic focus towards targeting tau pathology. Tau silencing therapies present an increasing interest as potential therapeutical approaches to treat AD due to their efficiency in reducing pathological tau burden. However, the effects of tau silencing on tau pathology formation and spreading, as well as on cognitive deficits, have not been investigated in AD or AD preclinical models expressing WT tau. In this study, we investigated the effects of Tau siRNA on tau pathology propagation in a mouse model of AD expressing 6 human WT tau isoforms, in which tau pathology formation and spreading has been initiated by intracerebral injection of pathological tau from a human AD brain. Specifically, we examined whether tau silencing affects tau pathology progression when started either simultaneously with the induction of tau pathology or subsequent to the onset of tau lesions, thereby mimicking the clinical scenario in which AD patients are typically diagnosed. Three months after tau pathology was induced, spatial learning and tau pathology were assessed. Cognitive performance was rescued, and tau pathology development was reduced when tau silencing started simultaneously with the induction of tau lesions. Nevertheless, Tau siRNA was ineffective on both cognitive performance and tau pathology propagation when administered after some development of tau pathology. Our results indicate that tau silencing therapy should be administered in early stages of the disease to achieve therapeutic efficacy on the development of tau pathology in AD.},
}

@article {pmid42710552,
year = {2026},
author = {Huang, Y and Xie, X and Fernaine, M and Li, Z and Wang, X and Wang, J},
title = {Subregion-specific input organization of prefrontal-projecting basal forebrain cholinergic neurons and weakened striatal-NBM inhibitory transmission in 5xFAD mice.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107600},
doi = {10.1016/j.nbd.2026.107600},
pmid = {42710552},
issn = {1095-953X},
abstract = {Basal forebrain cholinergic neurons regulate cortical activity and cognition and are vulnerable in Alzheimer's disease (AD). However, the upstream circuits controlling projection-defined basal forebrain cholinergic populations remain incompletely understood. Here, we used projection-specific rabies-mediated monosynaptic tracing to map whole-brain inputs to medial prefrontal cortex (mPFC)-projecting cholinergic neurons in the nucleus basalis of Meynert (NBM) and horizontal limb of the diagonal band of Broca (HDB). mPFC-projecting NBM and HDB cholinergic neurons received broad but distinct input patterns. NBM cholinergic neurons received prominent striatal input, including input from D1-expressing medium spiny neurons, whereas HDB cholinergic neurons showed proportionally weaker striatal input and broader non-striatal contributions. Optogenetic electrophysiology confirmed that striatal inputs formed monosynaptic GABAergic inhibitory synapses onto NBM cholinergic neurons. This inhibitory transmission was weakened in 5xFAD mice, indicating impairment of a striatal-NBM inhibitory circuit in an AD mouse model. Together, these findings reveal subregion-specific input organization of mPFC-projecting basal forebrain cholinergic neurons and identify an amyloid-associated vulnerability of the striatal-NBM circuit.},
}

@article {pmid42710608,
year = {2026},
author = {Liu, S and Ren, L and Liu, L and Chen, LL and Zhang, Y and Wang, P and Xie, GJ},
title = {Du-Shu-Wan alleviates Tau protein phosphorylation in Alzheimer's disease by regulating MAPK/JNK signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122380},
doi = {10.1016/j.jep.2026.122380},
pmid = {42710608},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is one of the leading causes of cognitive impairment and dementia among the elderly and has become an urgent public health challenge due to population ageing. Du-Shu-Wan (DSW) is an ancient Chinese herbal medicine that aims to enhance memory and soothe the spirit, and has long been applied for forgetfulness and cognitive decline. At present, there is still no systematic research on the pharmacological basis of DSW and its specific molecular mechanisms for alleviating AD.

AIM OF THE STUDY: The researchers aimed to investigate the mechanisms by which DSW attenuates AD-related pathological changes in animal models and in vitro cultured cells.

MATERIALS AND METHODS: The chemical composition of DSW was characterized using UPLC-Q-TOF-MS. Subsequently, HE staining, Nissl staining, and silver staining were employed to evaluate the effects of DSW on neuronal damage in an AD rat model induced by intracerebral injection of Aβ1-42 into the lateral ventricle. Potential mechanisms of action were investigated through network pharmacology, molecular docking, and transcriptomics. Finally, the results of the in vivo experiments were validated in an HT22 cell model.

RESULTS: This study reports the identification of 101 compounds from DSW for the first time. After a four-week course of DSW treatment, AD model rats exhibited significantly improved cognitive function, along with decreased neuronal injury and reduced neurofibrillary tangle pathology. A comprehensive analysis suggests that DSW enhanced cognitive function, an effect associated with inhibition of the MAPK/JNK pathway and reduction in the level of phosphorylated Tau at Ser422 sites. Additionally, in vitro experiments further showed that the protective effect of DSW-containing serum against Aβ1-42-induced neurotoxicity was associated with reduced JNK activation, and this reversal was obviously compromised by a JNK activator.

CONCLUSIONS: According to this study, DSW may enhance cognitive function in AD rats, an effect that is associated with reduced JNK pathway activity and reduced tau protein hyperphosphorylation at Ser422.},
}

@article {pmid42710609,
year = {2026},
author = {Zheng, J and Tan, Q and Liu, G and Xie, R and Wang, Q and Liang, Y},
title = {Bushen-Yizhi formula promotes neurogenesis and ameliorates cognitive impairment by activating ST8Sia Ⅱ/Ⅳ-PSA-NCAM pathway in ibotenic acid induced mice.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122356},
doi = {10.1016/j.jep.2026.122356},
pmid = {42710609},
issn = {1872-7573},
abstract = {Bushen-Yizhi formula (BSYZ), a traditional Chinese herbal prescription, has been widely used to treat kidney deficiency syndrome and alleviate cognitive impairment associated with Alzheimer's disease (AD). Loss of polysialylation of the neural cell adhesion molecule (PSA-NCAM) is closely associated with cognitive dysfunction. However, whether BSYZ regulates PSA-NCAM polysialylation and the underlying mechanisms remain unclear.

AIM OF THE STUDY: This study aimed to investigate whether BSYZ promotes hippocampal neurogenesis and ameliorates cognitive impairment through activation of the ST8Sia II/IV-PSA-NCAM pathway.

METHODS: An AD-like mouse model was established by bilateral ibotenic acid (IBO) injections into the basal nuclei of C57BL/6 mice. Animals were randomly assigned to five groups: control, model, low- BSYZ (1.46 g/kg), high-dose BSYZ (5.84 g/kg), and donepezil (3 mg/kg). Cognitive function was evaluated using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Hippocampal PSA-NCAM expression was assessed by immunofluorescence staining and further investigated using proteomic analysis combined with network pharmacology. PSA-NCAM-associated polysialic acid levels were quantified by hydrochloric acid hydrolysis followed by 4,5-methylenedioxy-1,2-phenylenediamine dihydrochloride (DMB) derivatization coupled with mass spectrometry. The mRNA and protein expression levels of α-2,8-sialyltransferase II and IV (ST8Sia II/IV) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. Hippocampal neurogenesis was evaluated by immunofluorescence double-labeling. The bioactive compounds targeting ST8Sia II/IV were identified using HPLC-Q-TOF MS/MS, followed by molecular docking and molecular dynamics simulations to predict their binding affinities.

RESULTS: The IBO-induced mouse model exhibited significant cognitive deficits, confirming successful model establishment. Behavioral assessments demonstrated that both low- and high-dose BSYZ significantly improved learning and memory performance. Proteomic analysis and immunofluorescence staining revealed that BSYZ markedly increased hippocampal PSA-NCAM expression (**P < 0.01, n = 5). Quantitative analysis further showed that PSA-NCAM-associated polysialic acid levels increased by 78% (*P < 0.05, n = 5) and 102% (**P < 0.01, n = 5) following low- and high-dose BSYZ treatment. BSYZ significantly increased the number of PSA-NCAM[+]/DCX[+] cells in the hippocampal dentate gyrus (*P < 0.05), accompanied by significant increases in Nestin[+]/BrdU[+] (*P < 0.05), DCX[+]/BrdU[+] (**P < 0.01), and NeuN[+]/BrdU[+] (**P < 0.01) double-positive cells, indicating enhanced neurogenesis and neuronal maturation. Furthermore, BSYZ significantly upregulated both the mRNA and protein expression of ST8Sia II (**P < 0.01) and ST8Sia IV (**P < 0.01) in the hippocampus. HPLC-Q-TOF MS/MS, molecular docking, and molecular dynamics simulations identified isoimperatorin as a major active constituent of BSYZ with strong binding affinity toward both ST8Sia II/IV, exhibiting docking energies of -8.7 and -7.6 kcal/mol, respectively (n = 3, RSD < 2%).

CONCLUSIONS: Our study demonstrates BSYZ promotes hippocampal neurogenesis to ameliorate cognitive impairment by activating ST8Sia II/IV-PSA-NCAM pathway. These findings provide mechanistic evidence supporting the therapeutic potential of BSYZ for AD treatment.},
}

@article {pmid42710667,
year = {2026},
author = {Zhang, J and Zhu, Y and Zhang, Q and Dai, Y and Liu, H and Shi, J and Jiang, Y and Chen, Q},
title = {Monomeric C-Reactive Protein Potentiates Microglia-Mediated Neuroinflammation in Alzheimer's Disease via the PLC-PKC-MAPK-NF-κB Pathway.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113527},
doi = {10.1016/j.jbc.2026.113527},
pmid = {42710667},
issn = {1083-351X},
abstract = {Neuroinflammation is a major contributor to the pathogenesis of Alzheimer's disease (AD). Although elevated serum C-reactive protein (CRP) is associated with increased AD risk, the specific conformational forms of CRP operative in the brain and their underlying mechanisms remain unclear. Here, we combined human brain transcriptomic analysis, APP/PS1 mice studies, and functional assays in BV2 cells and primary microglia to elucidate the roles of CRP and its monomeric form (mCRP) in AD-related neuroinflammation. CRP was significantly upregulated in the brains of AD patients and in the hippocampus of APP/PS1 mice, where it extensively co-localized with activated microglia. mCRP directly induced M1 pro-inflammatory microglial polarization and synergistically enhanced neuroinflammation with amyloid-β42-derived diffusible ligands (ADDLs). Additionally, mCRP dissipated mitochondrial membrane potential and promoted intracellular and mitochondrial reactive oxygen species accumulation. Mechanistically, mCRP activated the phospholipase C (PLC)-protein kinase C (PKC)-mitogen-activated protein kinase (MAPK)-nuclear factor-κB (NF-κB) signaling cascade, whereas the PLC inhibitor U-73122 attenuated pathway activation and reduced the production of pro-inflammatory cytokines. Collectively, these findings identify mCRP as a critical mediator linking systemic inflammation to microglia-driven neuroinflammation in AD, offering new mechanistic insights into AD pathogenesis.},
}

@article {pmid42711082,
year = {2026},
author = {Summanwar, D and Lee, L and Willis, DR and Ben Miled, Z and Baucco, C and Webber, ECC and Perkins, AJ and Powell, AY and Fowler, NR},
title = {Passive Digital Marker-enabled identification and engagement for Alzheimer's disease and related dementias care in primary care: the INCLUDE study protocol.},
journal = {BMJ open},
volume = {16},
number = {9},
pages = {e116755},
doi = {10.1136/bmjopen-2026-116755},
pmid = {42711082},
issn = {2044-6055},
mesh = {Humans ; Primary Health Care ; *Alzheimer Disease/diagnosis/therapy ; *Electronic Health Records ; Aged ; Pilot Projects ; Feasibility Studies ; Digital Health ; *Dementia/diagnosis ; *Patient Participation ; Machine Learning ; Research Design ; Risk Assessment ; },
abstract = {INTRODUCTION: More than half of older adults living with Alzheimer's disease and related dementias (ADRD) never receive a formal diagnosis, and when a diagnosis occurs, it is often years after symptom onset. Primary care clinicians are ideally positioned to detect ADRD early; however, current workflows lack scalable tools that support systematic identification and follow-up. The Passive Digital Marker (PDM), a machine learning model that uses structured electronic health record (EHR) data, can identify patients at elevated risk for ADRD without adding burden to clinicians. This protocol outlines a feasibility study to develop and evaluate a patient-informed secure messaging intervention paired with PDM-based risk stratification to enhance patient engagement in cognitive assessment in primary care settings.

METHODS AND ANALYSIS: This will be a non-randomised pilot study conducted across 12 single health system primary care clinics. The PDM will be applied to EHR data to identify patients aged ≥65 years who are at high risk for ADRD. High-risk patients will receive a co-designed secure message prior to and after upcoming primary care visits encouraging follow-up evaluation with a trained nurse, the Brain Health Navigator (BHN). The primary objectives are to: (1) determine the feasibility of applying the PDM to EHR data across 12 primary care clinics; (2) assess the feasibility of engaging patients identified as positive on the PDM through secure text messaging prior to a primary care encounter and (3) evaluate engagement with the BHN following secure text messaging. Study outcomes will assess the feasibility of implementing the PDM and secure messaging workflow, including identification of high-risk patients using the PDM, message delivery and patient engagement measured through message open rates, completion of cognitive concern questions and appointments scheduled with the BHN. Quantitative data will be analysed using descriptive statistics.

ETHICS AND DISSEMINATION: This study was deemed exempt as part of enhanced patient care. The findings will be disseminated through peer-reviewed publications, professional conferences, health system reports and public-facing communications.

TRIAL REGISTRATION NUMBER: NCT07016178.},
}

Humans
Primary Health Care
*Alzheimer Disease/diagnosis/therapy
*Electronic Health Records
Aged
Pilot Projects
Feasibility Studies
Digital Health
*Dementia/diagnosis
*Patient Participation
Machine Learning
Research Design
Risk Assessment

@article {pmid42711162,
year = {2026},
author = {Liu, Y and Peng, L and Li, M and Yan, W and Xiang, Q},
title = {Corrigendum to "Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease" [Exp. Neurol. 406 (2026) 115957; https://doi.org/10.1016/j.expneurol.2026.115957].},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116016},
doi = {10.1016/j.expneurol.2026.116016},
pmid = {42711162},
issn = {1090-2430},
}

@article {pmid42711180,
year = {2026},
author = {Liu, L and Zeng, Q and Luo, X and Hong, H and Xie, L and Zhang, Y and Lin, M and Wang, S and Li, K and Liu, X and Zhang, R and Liu, P and Yang, Y and Huang, P and , },
title = {Basal Ganglia Perivascular Space Enlargement Is Associated with Sustained Amyloid-β Accumulation in the Alzheimer's Disease Continuum: A Longitudinal Study.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.08.054},
pmid = {42711180},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: The perivascular spaces (PVS) serve as primary conduits for brain waste clearance. PVS enlargement (EPVS) is commonly observed in aging and neurodegenerative conditions. However, it remains unclear whether EPVS influences the β-amyloid (Aβ) deposition in Alzheimer's disease (AD).

MATERIALS AND METHODS: We included 524 participants from the ADNI database, all of whom had at least one follow-up [18]F-florbetapir (FBP) PET scan. Using a deep-learning segmentation method, we calculated the PVS volume fraction (PVSVF) in the basal ganglia (BG) and white matter (WM) regions for each participant. Participants were then categorized into high- and low-EPVS-burden groups based on the median PVSVF. Linear mixed-effects models were employed to investigate the relationship between PVSVF and the annual rate of change in FBP PET standardized uptake value ratio (SUVR), incorporating both the linear and quadratic terms of baseline FBP SUVR. Analyses were performed for the entire cohort and within AD subgroups. For WM EPVS, additional analyses were conducted after excluding participants with severe white matter hyperintensity.

RESULTS: We confirmed that the annual rate of change in FBP SUVR follows an inverted U-shaped relationship with baseline FBP SUVR. Regarding BG EPVS, a significant interaction was identified between PVSVF and the squared baseline FBP SUVR in predicting the annual rate of change in FBP SUVR (FBP SUVR² × BG PVSVF: β = 8.350, P = 0.001). The high BG EPVS burden group showed sustained Aβ accumulation at the late disease period. In contrast, WM PVSVF showed no association with the annual rate of change in FBP SUVR. Similar results were observed within the AD continuum groups.

CONCLUSION: Higher baseline BG-EPVS burden was associated with a more sustained rate of amyloid-β accumulation among participants with high baseline amyloid burden.},
}

@article {pmid42711409,
year = {2026},
author = {Veréb, D and Zufiria-Gerbolés, B and Passaretti, M and Mijalkov, M and Veronese, M and Pereira, JB and , },
title = {Mapping the dual functional organization of the substantia nigra.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42711409},
issn = {1476-5578},
abstract = {The human substantia nigra (SN) is a central hub for dopaminergic signalling and a key site of pathology in Parkinson's disease (PD). However, its internal functional organization in human individuals is not well understood. To fill this knowledge gap, here we applied connectopic mapping to the SN in more than 1000 participants from four independent datasets. We identified two main gradients or axes of functional organization within the SN-a mediolateral and a posteroanterior-each showing distinct transcriptomic, behavioural, and pathological associations. Specifically, the mediolateral gradient was related to motor and executive functions, aging and α-synuclein pathology in both PD and Alzheimer's disease (AD). In contrast, the posteroanterior gradient was linked to memory, anxiety, depression and other neuropsychiatric symptoms in all cohorts. We found gradient-specific associations with gene expression profiles, neurotransmitter maps and cerebrospinal fluid biomarkers that further supported their neurobiological differences. Together, these results reveal a dual-gradient architecture that reflects the functional heterogeneity of the SN and offers new markers, grounded in behaviour and pathology, for stratifying neurodegenerative disease risk in aging, PD and AD.},
}

@article {pmid42711429,
year = {2026},
author = {Abellanas, MA and Basurco, L and Purnapatre, M and Burgaletto, C and Castellani, G and Colaiuta, SP and Peralta-Ramos, JM and Ibraheem, A and Murad, S and Antonello, P and Kovacs, M and Androsova, Y and Nathansohn, B and Partney, H and Cahalon, L and Valdes-Mas, R and Josephides, JM and Salame, TM and Espelosin, M and Cuadrado-Tejedor, M and Garcia-Osta, A and Deczkowska, A and Schwartz, M},
title = {Bone marrow myelopoiesis dysfunction in Alzheimer's disease limits monocyte homing to the brain and drives disease progression.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42711429},
issn = {1546-1726},
support = {991/16//Israel Science Foundation (ISF)/ ; },
abstract = {Bone marrow-derived macrophages were shown to play an important role in coping with Alzheimer's disease (AD). Boosting their spontaneous recruitment reduces inflammation and disease pathology and slows cognitive decline in mouse models of amyloidosis. However, the factors limiting their spontaneous homing to the diseased brain remain unclear. In this study, we discovered that monocyte development is impaired in mouse models and in patients. In the 5×FAD mouse model, monocyte differentiation was disrupted due to a maladaptive type I interferon (IFN-I)-mediated bone marrow response. A similar phenotype was found in circulating monocytes from patients with AD. Blocking IFN-I signaling with neutralizing antibodies or reconstituting 5×FAD mice with IFN-I receptor-deficient bone marrow restored myelopoiesis, normalized monocyte phenotypes and ameliorated disease pathology. This was accompanied by increased homing of monocyte-derived macrophages to the brain. Our results reveal a dysfunction in bone marrow myelopoiesis in AD and reinforce the concept that AD progression is driven by maladaptive systemic processes.},
}

@article {pmid42711431,
year = {2026},
author = {},
title = {The hidden role of the bone marrow in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42711431},
issn = {1546-1726},
}

@article {pmid42711466,
year = {2026},
author = {Mimica, N and Dumitrescu, L and Gregorič Kramberger, M and Hort, J and Kovács, T and Popadić, K and Popescu, BO and Rakuša, M and Rejdak, K and Turčáni, P},
title = {Expert opinion on Alzheimer's disease diagnostics and management in Central Eastern European countries representing 88 million population.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42711466},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Europe, Eastern/epidemiology ; *Disease Management ; },
abstract = {The expert panel from Croatia, Czech Republic, Hungary, Poland, Romania, Slovakia and Slovenia discussed the current situation of various topics related to the diagnostics, general management and treatment of Alzheimer's disease (AD) in these Central Eastern European (CEE) countries, representing around 88 million population. The aim was to estimate AD prevalence, confirm the presence of AD patients/caregivers' associations and AD registries, and establish the availability and reimbursement of costs for AD diagnostic biomarkers and treatment. The panel acknowledged similarities and differences among CEE countries and issued recommendations for cross specialty collaboration between experts in neurology, psychiatry and general practitioners for the early AD diagnosis. They also agreed that CEE countries should provide comprehensive education and training and encourage collaboration between health experts. The panel suggested that CEE countries should involve various stakeholders, policymakers, implement routine screening, combine advanced diagnostic tools and use telemedicine and remote monitoring technologies, invest in research to develop AI-based analyses, new AD diagnostic and monitoring methods, digital tools and wearables. The focus is to address the stigma, reimburse costs of diagnostic tests and therapy, and reduce the modifiable risk factors for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology
Europe, Eastern/epidemiology
*Disease Management

@article {pmid42711542,
year = {2026},
author = {Ekman, U and Gyllenhammar, M and Almkvist, O and Ocklind, A and Hallerstam, L and Ferreira, D and Eriksdotter, M and Wahlund, LO and Rennie, A and Westman, E},
title = {The associations between ATN biomarkers and episodic memory diminish as age increases.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {42711542},
issn = {1878-7649},
support = {2015-00174//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; FoUI-962991//Center for Innovative Medicine, Sweden/ ; 20200505//Center for Innovative Medicine, Sweden/ ; FoUI-988826//Center for Innovative Medicine, Sweden/ ; 2022-00916//Vetenskapsrådet/ ; 2024-03599//Vetenskapsrådet/ ; 2016-01840//Vetenskapsrådet/ ; 2016-02282//Vetenskapsrådet/ ; 2021-01861//Vetenskapsrådet/ ; FoUI-962240//The regional agreement on medical training and clinical research between the Stockholm County council and the Karolinska Institutet/ ; FoUI-987534//The regional agreement on medical training and clinical research between the Stockholm County council and the Karolinska Institutet/ ; FO2023-0261//Hjärnfonden/ ; FO2022-0175//Hjärnfonden/ ; FO2021-0131//Hjärnfonden/ ; FO2024-0339//Hjärnfonden/ ; FO2022-0084//Hjärnfonden/ ; FO2024-0239//Hjärnfonden/ ; AF-968032//Alzheimerfonden/ ; AF-980580//Alzheimerfonden/ ; AF-994058//Alzheimerfonden/ ; AF-1010553//Alzheimerfonden/ ; AF-967495//Alzheimerfonden/ ; AF-980387//Alzheimerfonden/ ; FoUI-954459//The Center for Innovative Medicine, Sweden/ ; FoUI-975174//The Center for Innovative Medicine, Sweden/ ; FoUI-975174//Center for Innovative Technology/ ; 2021-02680//VINNOVA/ ; FoUI-952838//The regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet/ ; FoUI-954893//The regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet/ ; 1557/24//Parkinsonfonden/ ; 1521/23//Parkinsonfonden/ ; 186-0660//Olle Engkvists Stiftelse/ ; 224-0069//Olle Engkvists Stiftelse/ ; },
abstract = {PURPOSE: The relationship between age, biomarkers, and cognitive function at advanced ages remains underexplored. By utilizing a naturalistic memory clinic cohort, we aimed to clarify how the A/T/N biomarkers are associated with verbal episodic memory performance and the moderating effect of age.

METHODS: This cross-sectional study included 676 patients from memory clinics in the Stockholm metropolitan region, comprised of 141 with Alzheimer's disease dementia, 403 with mild cognitive impairment, and 132 with subjective cognitive impairment. We used weighted least-squares regressions to evaluate the association between episodic memory and the biomarkers and the moderating effect of age.

RESULTS: There was a significant interaction between age and A (Aβ42), where the negative impact of Aβ42 abnormality on Rey Auditory Verbal Learning (RAVLT) delayed recall was reduced with higher age (β = 0.22, p < 0.001). In addition, a corresponding interaction effect was observed between age and N (MTA) on RAVLT delayed recall (β = 0.13, p < 0.01). Additional exploration analyses showed that at age 80 or older, the ATN biomarkers showed weaker associations with episodic memory performance.

CONCLUSIONS: Although interpretations should be conducted with caution, these findings raise questions about the justification for assessing CSF in patients older than 80 years, given its weak associations with core clinical measures, such as learning and free recall of episodic memory. Further clinical studies are needed to validate these results and also evaluate other core cognitive measures. The naturalistic nature of the memory clinic population, with its clinically driven diagnoses, may help clarify these findings.},
}

@article {pmid42711543,
year = {2026},
author = {Alruwaili, M and Alanazi, MF and Almohaimeed, HM and Alharbi, SS and Alruwais, N and Elkordy, EA and Alshuhri, MS},
title = {Plasma neuroimmune pathway signatures are associated with clinical impairment and lower MRI-derived hippocampal volume across the Alzheimer's disease continuum.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {42711543},
issn = {1878-7649},
abstract = {METHODS: This retrospective observational study included 506 Alzheimer's Disease Neuroimaging Initiative participants: 53 cognitively normal individuals, 352 with mild cognitive impairment, and 101 with dementia. Plasma proteins from the quality-controlled Rules-Based Medicine multiplex dataset were standardized and grouped into five circulating protein scores: complement-acute-phase, endothelial-associated, extracellular matrix remodeling, myeloid, and interleukin. Outcomes included Mini-Mental State Examination, Clinical Dementia Rating Sum of Boxes, Functional Activities Questionnaire, normalized hippocampal volume, and normalized brain volume. Multivariable models were adjusted for age, sex, education, and APOE ε4 carrier status.

RESULTS: In the primary cross-sectional pathway-level analyses, complement-acute-phase scores were higher in participants with dementia than in cognitively normal participants after FDR correction (β = 0.314, 95% CI 0.118 to 0.511; FDR q = 0.018). Higher complement-acute-phase scores were associated with lower MMSE (β = -0.859; FDR q < 0.001), higher CDR-SB (β = 0.622; FDR q < 0.001), and higher FAQ scores (β = 2.473; FDR q < 0.001). Higher endothelial-associated plasma protein scores were associated with lower normalized hippocampal volume (β = -1.47 × 10⁻[4]; FDR q = 0.028).

CONCLUSIONS: Plasma neuroimmune signatures showed pathway-specific associations with Alzheimer's disease-related phenotypes, with complement-acute-phase score linked most consistently to clinical impairment and endothelial-associated circulating protein profile linked to hippocampal volume.},
}

@article {pmid42711626,
year = {2026},
author = {Mahrat, R and Chen, Y and Bruno, JG and Nasaev, S and Ufaev, D and Kudryashova, N},
title = {Preliminary Development of a Hybrid Aptamer and Antibody Fluorescent Lateral Flow Assay for Ultrasensitive Detection of Tau441 Protein in Serum: Toward Point-of-Care Diagnostics for Alzheimer's Disease.},
journal = {Journal of fluorescence},
volume = {},
number = {},
pages = {},
pmid = {42711626},
issn = {1573-4994},
abstract = {A hybrid DNA aptamer and antibody-Europium nanoparticle (Eu NP) fluorescent sandwich lateral flow (LF) assay for Tau441 is described which works well in human serum with an apparent visible detection limit for Tau 441 of ~ 10 pg/ml or 1 pg of Tau protein. The same LF assay appears to detect phosphorylated threonine 217 Tau 441 (phospho Thr-217 Tau) consistently to an even lower level of 1 pg/ml or 100 fg of total phosphorylated Tau protein in human serum. The aptamer was designed in silico on the Xelari computational platform to target an epitope centered around alanine 390 distal from the threonine 217 phosphorylation site, thus the monoclonal antibody must account for the possibly greater affinity for the phosphorylated protein on the other side of the target molecule. Regardless, the hybrid receptor pair exhibits a relatively linear dynamic range of 10 ng/ml to 10 or 1 pg/ml in serum as assessed by visual detection with a high degree of specificity as demonstrated by low cross-reactivity versus other germane human protein targets in buffer, laying the groundwork for a potential rapid and convenient point-of-care (POC) diagnostic for Alzheimer's disease.},
}

@article {pmid42711740,
year = {2026},
author = {Papait, A and Natale, F and Silini, AR and Nifo Sarrapochiello, I and Orecchini, E and Sollazzo, R and Rinaudo, M and Farigu, S and Garofalo, N and Mantini, G and Giuffrè, GM and Romele, P and Ragozzino, E and Dellaria, A and Giacò, L and Marra, C and Ripoli, C and Grassi, C and Parolini, O and Fusco, S},
title = {Human amniotic mesenchymal stromal cell-derived extracellular vesicles reprogram microglia and prevent neurodegeneration in experimental models of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42711740},
issn = {2047-9158},
mesh = {*Alzheimer Disease/pathology/metabolism ; *Extracellular Vesicles/transplantation/metabolism ; Animals ; Humans ; *Microglia/metabolism/pathology ; Female ; Mice ; *Mesenchymal Stem Cells/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Amnion/cytology ; Hippocampus/metabolism ; Administration, Intranasal ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD.

METHODS: hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3 × Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9 months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal Aβ levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients.

RESULTS: The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3 × Tg-AD mice and reduced hippocampal Aβ levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3 × Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability.

CONCLUSIONS: hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.},
}

*Alzheimer Disease/pathology/metabolism
*Extracellular Vesicles/transplantation/metabolism
Animals
Humans
*Microglia/metabolism/pathology
Female
Mice
*Mesenchymal Stem Cells/metabolism
Disease Models, Animal
Mice, Transgenic
*Amnion/cytology
Hippocampus/metabolism
Administration, Intranasal

@article {pmid42711949,
year = {2026},
author = {Deng, S and Gao, S and Zhou, C and Lan, Z and Li, H and Chen, J and Xu, Y and Li, J and Liu, P and Zhang, S and Bao, X and Wang, T and Xu, Y and Zhu, X},
title = {Oligodendrocyte-Targeted SGK1.1 Inhibition Alleviates White Matter Injury and Cognitive Impairment in Alzheimer's Disease via Modulation of HDAC2 Phosphorylation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71150},
doi = {10.1002/cns.71150},
pmid = {42711949},
issn = {1755-5949},
support = {823B2027//National Natural Science Foundation of China/ ; 2022ZD0211800//STI2030-Major Projects/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; },
mesh = {Animals ; *Immediate-Early Proteins/antagonists & inhibitors/metabolism/genetics ; Phosphorylation/physiology ; *Histone Deacetylase 2/metabolism ; *Alzheimer Disease/metabolism/pathology ; Serum-Glucocorticoid Regulated Kinases ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism/genetics ; *Oligodendroglia/metabolism ; Mice ; *White Matter/metabolism/pathology/injuries ; *Cognitive Dysfunction/metabolism/pathology ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {BACKGROUND: White matter (WM) abnormalities contribute to cognitive decline in Alzheimer's disease (AD). However, the mechanisms underlying AD-associated WM vulnerability remain incompletely understood, and effective therapeutic strategies to improve WM pathology are still limited.

METHODS: Sgk1.1-specific RNAscope combined with Olig2 immunostaining was used to assess the cellular distribution of Sgk1.1 transcripts. Oligodendrocyte-targeted adeno-associated virus (AAV)-mediated Sgk1.1 knockdown was performed in 5 × FAD mice. Sgk1.1 overexpression was conducted in primary oligodendrocyte precursor cells (OPCs) in vitro. Phosphoproteomic profiling, co-immunoprecipitation, Phos-tag Western blot, and phospho-site mutagenesis were used to identify downstream mechanisms. A bilateral common carotid artery stenosis (BCAS) model was employed to assess broader relevance.

RESULTS: Sgk1.1 mRNA was predominantly elevated in oligodendrocyte-lineage cells of 5 × FAD mice prior to overt myelin loss. Targeted knockdown of oligodendroglial Sgk1.1 ameliorated cognitive deficits, preserved myelin ultrastructure, and promoted oligodendrocyte maturation. Conversely, Sgk1.1 overexpression arrested OPC differentiation and suppressed myelin gene expression in vitro. Mechanistically, SGK1.1 promoted HDAC2 phosphorylation at S422/S424, and blocking this phosphorylation partially reversed SGK1.1-induced maturation deficits. Furthermore, oligodendrocyte-targeted Sgk1.1 overexpression exacerbated WM injury and cognitive impairment in the BCAS model.

CONCLUSION: Our findings identify oligodendrocyte-targeted SGK1.1 inhibition as a tractable therapeutic strategy to preserve WM integrity and cognitive function, and define HDAC2 S422/S424 phosphorylation as a mechanistic node linking SGK1.1 signaling to impaired myelination in AD and related demyelinating disorders.},
}

Animals
*Immediate-Early Proteins/antagonists & inhibitors/metabolism/genetics
Phosphorylation/physiology
*Histone Deacetylase 2/metabolism
*Alzheimer Disease/metabolism/pathology
Serum-Glucocorticoid Regulated Kinases
*Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism/genetics
*Oligodendroglia/metabolism
Mice
*White Matter/metabolism/pathology/injuries
*Cognitive Dysfunction/metabolism/pathology
Mice, Transgenic
Male
Mice, Inbred C57BL
Cells, Cultured

@article {pmid42711950,
year = {2026},
author = {Hwang, J and Pietras, A and Naasan, G and Elahi, FM and Gandy, S},
title = {Rapid plaque clearance with anti-amyloid therapy for Alzheimer's disease: in consideration of donanemab treatment duration from real-world cases.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/13554794.2026.2730462},
pmid = {42711950},
issn = {1465-3656},
abstract = {To assess the possibility that individualized duration of donanemab treatment might enable early pausing of therapy, and to explore the possible utility of plasma P-tau[217] as a biomarker for treatment response monitoring in real-time, two unrelated patients with early-stage Alzheimer's disease were treated with donanemab at the Icahn School of Medicine at Mount Sinai. Clinical progress was monitored via medical chart review, including serial brain MRI, amyloid PET scans, and blood-based biomarker assays (Quanterix Simoa® and Fujirebio Lumipulse®). Both patients achieved complete amyloid clearance as judged by amyloid PET prior to their 6th and 9th infusions, which were significantly earlier than the 12-month mark typically recommended for follow-up amyloid assessment. In agreement with the amyloid PET, concurrently measured plasma P-tau[217] levels fell within a low range. Treatment was discontinued for both patients. These patients highlight the possibility of individualized treatment durations for anti-amyloid therapy with donanemab, guided by biomarker response. Early cessation following rapid plaque clearance could reduce healthcare costs and minimize exposure to the risk of amyloid-related imaging abnormalities and the generation of neutralizing antibodies. Plasma P-tau[217] warrants further investigation as a reliable, cost-effective surrogate for PET scans to monitor real-time treatment response and guide the timing of discontinuation.},
}

@article {pmid42712082,
year = {2026},
author = {Ottman, R and Wetmore, JB and Leu, CS and Uhlmann, WR and Goldman, J and Rodriguez, S and Diaz Caro, D and Cabán, M and McCain, S and Blasco, D and Lantigua, RA and Abraido-Lanza, A and Chung, WK and Roberts, JS and Siegel, K},
title = {Psychological impacts of APOE genotype disclosure among Latinos in New York City: a randomized controlled trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71796},
doi = {10.1002/alz.71796},
pmid = {42712082},
issn = {1552-5279},
support = {R01AG062528/AG/NIA NIH HHS/United States ; UL1TR001873/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; New York City ; *Hispanic or Latino/psychology/genetics ; Female ; *Alzheimer Disease/genetics/psychology ; Genotype ; Male ; *Apolipoproteins E/genetics ; Middle Aged ; Aged ; Genetic Testing ; Aged, 80 and over ; Return of Individual Research Results ; *Disclosure ; },
abstract = {INTRODUCTION: Latinos face increased Alzheimer's disease (AD) risk but are underrepresented in studies of APOE genotype disclosure. We evaluated the psychological impacts of APOE disclosure in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a randomized controlled trial among Latinos in New York City.

METHODS: Latino northern Manhattan residents without self-reported AD (mean age 52, 69% women, 49% college graduates) were randomized in the period August 2021 to July 2024 to receive AD risk estimates to age 85 incorporating APOE genotype, family history, and ethnicity (disclosure) or the same factors excluding APOE (non-disclosure). Bilingual genetic counselors delivered risk estimates to both groups, unmasked to randomization. Follow-up surveys were completed 6 weeks, 9 months, and 15 months after risk delivery. Primary outcomes were impact of genetic testing in AD (IGT-AD) and Impact of Event Scale-Revised (IES-R). Secondary outcomes were changes from baseline in depression, anxiety, and perceived AD threat. Analyses used intention-to-treat with multiple imputation.

RESULTS: Disclosure (N = 194) and non-disclosure (N = 180) groups did not differ on IGT-AD (mean disclosure-non-disclosure difference [MD] at 6 weeks: -1.5, p = 0.14; 9 months: -1.2, p = 0.35; 15 months: -2.0, p = 0.07), IES-R (MD at 6 weeks: 0.00, p = 0.98; 9 months: 0.01, p = 0.84; 15 months: 0.03, p = 0.64), or change in secondary outcomes. Occurrence of disclosure-related adverse events was similar in the disclosure (N = 2) and non-disclosure (N = 3) groups.

DISCUSSION: In this Latino cohort, APOE disclosure did not have clinically significant adverse psychological effects, addressing an important evidence gap.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04471779.},
}

Humans
New York City
*Hispanic or Latino/psychology/genetics
Female
*Alzheimer Disease/genetics/psychology
Genotype
Male
*Apolipoproteins E/genetics
Middle Aged
Aged
Genetic Testing
Aged, 80 and over
Return of Individual Research Results
*Disclosure

@article {pmid42712102,
year = {2026},
author = {Pellegrini, C and Ravaioli, F and De Fanti, S and Siliquini, A and Sala, C and Rochat, M and Pollarini, V and Polischi, B and Pasti, A and Grasso, M and Rambaldi, M and Cardoni, F and Grotteschi, N and Caraci, F and Cortelli, P and Provini, F and Lodi, R and Morandi, L and Parchi, P and Pirazzoli, GL and Sambati, L and Tonon, C and Bacalini, MG},
title = {Alterations of gut microbiota in Down syndrome and their association with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71815},
doi = {10.1002/alz.71815},
pmid = {42712102},
issn = {1552-5279},
support = {PNC0000002//Italian Complementary National Plan PNC-1.1 "Research initiatives for innovative technologies and pathways in the health and welfare sector" D.D. 931 of 06/06/2022, "DARE-DigitAl lifelong pRvEntion" initiative/ ; B53C22006330001//Italian Complementary National Plan PNC-1.1 "Research initiatives for innovative technologies and pathways in the health and welfare sector" D.D. 931 of 06/06/2022, "DARE-DigitAl lifelong pRvEntion" initiative/ ; GR-2019-12369983-Theory-enhancing//Italian Ministry of Health/ ; //Italian Ministry of Health - "Ricerca Corrente" funding/ ; },
mesh = {Humans ; *Down Syndrome/microbiology/blood/complications ; *Alzheimer Disease/blood/microbiology ; Female ; Male ; *Gastrointestinal Microbiome/physiology ; Middle Aged ; Aged ; Adult ; Biomarkers/blood ; Aged, 80 and over ; tau Proteins/blood ; Feces/microbiology ; Young Adult ; RNA, Ribosomal, 16S/genetics ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; },
abstract = {INTRODUCTION: Adults with Down syndrome (DS) have a higher risk of Alzheimer's disease (AD). As gut microbiota (GM) alterations have been reported in AD, we investigated their association with cognitive decline and plasma AD biomarkers in DS.

METHODS: Fecal and plasma samples were collected from 58 adults with DS (21-75 years) and 30 euploid controls (CTRL; 25-83 years). GM was profiled using 16S rRNA sequencing, filtering low prevalent taxa. Major neurocognitive disorder (NcD) was diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Plasma levels of phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Simoa.

RESULTS: DS showed no changes in overall microbial diversity compared to CTRL, but genera including UBA1819 and Intestinibacter were altered. Specific genera showed changes in DS with NcD, like Alistipes (increased) and Roseburia (decreased), with the latter negatively associated with plasma AD biomarkers.

DISCUSSION: Adults with DS display AD-associated changes in GM partially resembling those reported previously in euploid AD patients.},
}

Humans
*Down Syndrome/microbiology/blood/complications
*Alzheimer Disease/blood/microbiology
Female
Male
*Gastrointestinal Microbiome/physiology
Middle Aged
Aged
Adult
Biomarkers/blood
Aged, 80 and over
tau Proteins/blood
Feces/microbiology
Young Adult
RNA, Ribosomal, 16S/genetics
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood

@article {pmid42712106,
year = {2026},
author = {Gel, A and Phillips, E and Hausle, I and Thropp, P and Tosun, D and , },
title = {MCH-Guard: Multimodal machine learning framework for risk stratification of cerebral microhemorrhage risk in the Alzheimer's Disease Neuroimaging Initiative.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71818},
doi = {10.1002/alz.71818},
pmid = {42712106},
issn = {1552-5279},
support = {//the Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/complications ; *Machine Learning ; Female ; Male ; *Neuroimaging/methods ; Risk Assessment/methods ; *Cerebral Hemorrhage/diagnostic imaging ; Aged ; Aged, 80 and over ; Predictive Learning Models ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Efficient cerebral microhemorrhage (MCH) monitoring is critical for anti-amyloid therapy safety due to amyloid-related imaging abnormalities with hemosiderin deposition (ARIA-H) risk. We developed MCH-Guard, a multimodal machine-learning framework, to stratify MCH risk for Alzheimer's Disease Neuroimaging Initiaitive (ADNI) participants (N = 813).

METHODS: Nested models integrated clinical history, fluid biomarkers, and imaging to predict MCH presence, incidence, and stability.

RESULTS: The comprehensive model detected baseline MCH with high accuracy (area under the curve [AUC] = 0.86). Notably, the minimal model (M1), utilizing only demographics and clinical history, achieved robust performance (AUC = 0.72). Longitudinal models predicted time-to-incidence (R[2] = 0.67) and stratified four-year risk. Furthermore, we identified a transient vascular instability phenotype-where MCH status fluctuates-which was strongly predicted by hepatic factors.

DISCUSSION: MCH-Guard offers a flexible clinical decision-support tool for optimizing spontaneous MCH and ARIA-H surveillance. The strong performance of the clinical-only model supports equitable risk assessment in resource-limited settings, while the characterization of vascular instability addresses a critical confounder in safety monitoring.},
}

Humans
*Alzheimer Disease/diagnostic imaging/complications
*Machine Learning
Female
Male
*Neuroimaging/methods
Risk Assessment/methods
*Cerebral Hemorrhage/diagnostic imaging
Aged
Aged, 80 and over
Predictive Learning Models
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging

@article {pmid42712109,
year = {2026},
author = {Rastegar-Pouyani, S and Lew, C and Pereira, FL and Satpati, A and Arnas, AM and Paes, V and Leite, REP and Suemoto, CK and Spina, S and Son, G and Heinsen, H and Seeley, WW and Walsh, CM and Neylan, TC and Grinberg, LT},
title = {Tau-associated neuronal loss in the intermediate nucleus of the human hypothalamus, a putative VLPO analog, in progressive supranuclear palsy and Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71808},
doi = {10.1002/alz.71808},
pmid = {42712109},
issn = {1552-5279},
support = {//Rainwater Charitable Foundation/ ; R01AG075802/NH/NIH HHS/United States ; R01 AG060477/NH/NIH HHS/United States ; R01AG064314/NH/NIH HHS/United States ; P01AG019724/NH/NIH HHS/United States ; NIA K24 AG053435/NH/NIH HHS/United States ; P30 ADRC AG062422/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Supranuclear Palsy, Progressive/pathology/metabolism ; *tau Proteins/metabolism ; *Neurons/pathology/metabolism ; Female ; Male ; Aged ; Aged, 80 and over ; *Hypothalamus/pathology/metabolism ; Galanin/metabolism ; Phosphorylation ; },
abstract = {BACKGROUND: Sleep phenotypes differ in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). The human intermediate nucleus (IntN), a putative ventrolateral preoptic analog, promotes non-rapid eye movement (NREM) sleep, but its disease-specific vulnerability is unclear.

METHODS: Post mortem hypothalami (n = 30; baseline [Braak stage I-II] n = 6; PSP n = 9; Braak III-IV n = 4; Braak V-VI n = 11) underwent marker-guided IntN delineation, galanin/phospho-tau (T231) immunohistochemistry, and stereology.

RESULTS: Advanced PSP showed profound IntN degeneration (84% neuron reduction vs baseline). In AD neuropathologic change, IntN neuronal loss and phospho-tau burden were greater in higher Braak stages and preferentially affected galanin-positive neurons (≈77% reduction in late AD); phospho-tau burden was higher in galanin-positive neurons.

CONCLUSIONS: The IntN is a disease-sensitive node, with near-ablation in PSP and progressive, preferential loss of detectable galaninergic neurons in AD. Although longitudinal observations and premortem sleep/wake measurements were not available for this sample, these findings are consistent with disease-level differences in NREM/ slow-wave sleep disturbance reported in PSP and AD.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Supranuclear Palsy, Progressive/pathology/metabolism
*tau Proteins/metabolism
*Neurons/pathology/metabolism
Female
Male
Aged
Aged, 80 and over
*Hypothalamus/pathology/metabolism
Galanin/metabolism
Phosphorylation

@article {pmid42712166,
year = {2026},
author = {Reuben, DB},
title = {The Dementia Orchestra.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70706},
pmid = {42712166},
issn = {1532-5415},
}

@article {pmid42712219,
year = {2026},
author = {Wang, H and Li, L and He, X and Shen, S and Chao, L and You, P and Ji, K and Liu, Y and Hong, Z},
title = {UHPLC-Q/TOF-MS Characterization of Danshen-Chuanxiong and Mechanistic Insights Into Its Protective Effects Against Aβ1-42-Induced Brain Endothelial Injury Through Metabolomics.},
journal = {Journal of separation science},
volume = {49},
number = {9},
pages = {e70527},
doi = {10.1002/jssc.70527},
pmid = {42712219},
issn = {1615-9314},
support = {82173777//National Natural Science Foundation of China/ ; 82504742//National Natural Science Foundation of China/ ; 82473885//National Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; *Metabolomics ; Chromatography, High Pressure Liquid ; *Endothelial Cells/drug effects/metabolism ; *Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis ; *Peptide Fragments/antagonists & inhibitors ; Salvia miltiorrhiza/chemistry ; *Brain/drug effects/metabolism ; Cell Survival/drug effects ; Mass Spectrometry ; },
abstract = {Danshen-Chuanxiong is a traditional herb pair used for cardiovascular and cerebrovascular disorders, but its chemical basis and potential effects in Alzheimer's disease (AD)-related endothelial injury remain incompletely defined. Here, an integrated analytical workflow combining reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) with quadrupole time-of-flight mass spectrometry (Q-TOF-MS), cellular assays, metabolomics, and network pharmacology was applied in an amyloid-β1-42 (Aβ1-42) oligomer-induced human brain microvascular endothelial cell (hBMEC) injury model. The complementary RPLC/HILIC and positive/negative electrospray-ionization strategy expanded coverage across a broad polarity range. UHPLC-Q/TOF-MS detected 90 compounds, mainly phenolic acids, phthalides, tanshinones, diterpenoids, and other aromatic or terpenoid constituents. The reductions in cell viability and zonula occludens-1 expression following Aβ1-42 exposure confirmed the successful establishment of the cellular injury model, whereas pretreatment with Danshen, Chuanxiong, or their combination increased cell viability and alleviated Aβ1-42-induced cellular injury. Untargeted metabolomics annotated 38 differential metabolites, of which 30 showed a recovery-associated shift toward the control state after Danshen-Chuanxiong treatment; the associated pathways included amino-acid, purine, glutathione, and glycerophospholipid metabolism. Integrative analysis prioritized seven candidate targets of Danshen-Chuanxiong, namely ACHE, VEGFA, NOS2, NOS3, AKR1B1, MDM2, and XDH. These findings provide a separation-MS-based chemical characterization and mechanistic framework for further validation of Danshen-Chuanxiong in AD-related endothelial injury models.},
}

*Amyloid beta-Peptides/antagonists & inhibitors/metabolism
Humans
*Metabolomics
Chromatography, High Pressure Liquid
*Endothelial Cells/drug effects/metabolism
*Drugs, Chinese Herbal/pharmacology/chemistry/metabolism/analysis
*Peptide Fragments/antagonists & inhibitors
Salvia miltiorrhiza/chemistry
*Brain/drug effects/metabolism
Cell Survival/drug effects
Mass Spectrometry

@article {pmid42712358,
year = {2026},
author = {Simcik, M and Andel, R and Pavlik, J and Marusic, P and Amlerova, J and Hort, J},
title = {Demographic and clinical influences on emotion prosody recognition.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1900291},
pmid = {42712358},
issn = {1664-1078},
abstract = {INTRODUCTION: Emotion recognition from speech prosody is a complex cognitive ability that depends on the functional integrity of a distributed neuronal network and may be shaped by demographic, clinical and lifestyle factors. The Terrapino mobile application was developed as a tool to promote cognitive health, but its digital infrastructure and methodologically rigorous design also render it suitable for research purposes including a comprehensive battery to assess Alzheimer's disease risk factors, as well as measures of perceived stress, metamemory, and prosody recognition.

METHODS: We analyzed data from 2,858 adult Terrapino users aged 18-103 years (median = 60 years) to identify correlates of emotional prosody recognition across a demographically, clinically and lifestyle-diverse population. Participants completed an emotion prosody recognition test comprising 25 audio recordings in which professional actors conveyed one of five basic emotions (fear, sadness, anger, disgust and happiness) solely through vocal intonation.

RESULTS: Consistent with previous research, age, sex, education, hearing problems, subjective cognitive complaints and the number of comorbidities were associated with performance, with several predictors significant in at least one age group. However, other hypothesized factors, such as alcohol consumption, depression, perceived stress, average hours of sleep, or living alone, did not show significant associations with performance in prosody recognition.

DISCUSSION: Together, these findings identify the main demographic and health factors associated with emotional prosody recognition across the adult lifespan and indicate that, in this large appbased cohort, performance is associated with age and health-related factors rather than with the lifestyle variables examined.},
}

@article {pmid42712554,
year = {2026},
author = {Lala Bouali, M and Kezai, AM and Bazin, M and Badiane, PY and Eskandari, N and Lévesque, V and Robillard, J and Côté, SD and Soulet, D and Tremblay, C and Calon, F and Morin, F and Vallières, L and Hébert, SS},
title = {Natural microbial enrichment modulates microglial states and transcriptional programs relevant to Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1843174},
pmid = {42712554},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/immunology/microbiology/genetics/metabolism ; *Microglia/immunology/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Brain/immunology/metabolism ; *Microbiota/immunology ; Transcription, Genetic ; },
abstract = {INTRODUCTION: The diversity of environmental microbial exposure is a key driver of immune maturation and host defense; however, its impact on brain immunity and neurodegenerative diseases remains poorly documented.

METHODS: Here, we show that controlled indoor rewilding, by introducing a natural farm-like environment into laboratory housing, reshapes peripheral and central nervous system (CNS) immune networks in wild-type (WT) and 5xFAD mice, a model of Alzheimer's disease (AD).

RESULTS: Compared with traditional specific pathogen-free (SPF) housing, rewilded mice exhibited systemic shifts toward mature immune phenotypes, including increases in effector and memory B and T cells, expansion of antibody-secreting cell subsets, and changes in immunoglobulin isotypes. In the brain, indoor rewilding recalibrated microglial activation of 5xFAD mice, attenuating pro-inflammatory transcriptional programs while enhancing homeostatic, complement, and phagocytic signatures. A strong transcriptional convergence was observed between rewilded and wild mice, with rewilded 5xFAD mice exhibiting greater similarity to human AD transcriptional profiles. Morphological and histochemical analyses confirmed that rewilded microglia adopt metabolically adaptable, homeostatic states that influence amyloid-β plaque binding and clearance.

DISCUSSION: Collectively, these findings suggest that microbial diversity through "dirty" mouse modeling could enhance the translational relevance of neuroimmunology and neurodegenerative disease research.},
}

Animals
*Alzheimer Disease/immunology/microbiology/genetics/metabolism
*Microglia/immunology/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
Humans
Brain/immunology/metabolism
*Microbiota/immunology
Transcription, Genetic

@article {pmid42712578,
year = {2026},
author = {Bhogal, I and Frydrych, I and Modi, A and Pankaj, V and Kumar, A and Khairnar, A and Das, V and Roy, S},
title = {Naringenin as a dual-target modulator of RAGE-NF-κB signaling and Aβ fibrillization in Alzheimer's disease: integrated computational and experimental analyses.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1901236},
pmid = {42712578},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation and aggregation of β-amyloid (Aβ) and chronic neuroinflammation mediated by the receptor for advanced glycation end products (RAGE). Current therapeutic candidates targeting RAGE signaling or Aβ aggregation continue to face challenges, including off-target toxicity, poor blood-brain barrier (BBB) penetration, and limited multi-target efficacy.

METHODS: Naringenin (NAR), a naturally occurring flavanone polyphenol prioritized through structure-based virtual screening and preliminary biological evaluation, was selected for further mechanistic investigation as a potential dual-target modulator of RAGE-associated inflammatory signaling and Aβ42 fibrillization.

RESULTS: Molecular docking analyses showed that NAR interacts with the RAGE interface (PDB: 6XQ3) via π-cation interactions with ARG_98 and LYS_110 (docking score: -5.072 kcal/mol). At the Aβ fibril (PDB: 2MXU), NAR showed a superior docking score than ALZ-801 (valiltramiprosate), involving hydrogen bonding and π-π stacking with HIS_A14 (docking score: -8.098 kcal/mol). 100 ns molecular dynamics simulations supported the stability of these binding modes, with RMSD and RMSF values within acceptable ranges. MM-GBSA rescoring indicated competitive predicted binding free energies (ΔGBind: -30.260 kcal/mol at RAGE; -220.162 kcal/mol at the fibril, compared to ALZ- 801's -214.482 kcal/mol), influenced by electrostatic and hydrophobic interactions. Per-residue energy decomposition indicated PHE_20 (-9.10 kcal/ mol) as the dominant hotspot residue, alongside ARG_98 (-4.71 kcal/mol) and LYS_52 (-3.96 kcal/mol) as key RAGE anchors. In silico ADMET profiling suggested favorable predicted BBB accessibility (score: 0.001), Caco-2 permeability, Lipinski compliance, and a more favorable predicted cardiac safety profile (hERG: 0.145) relative to V6Y. Experimentally, NAR reduced Aβ42-induced NF-κB activation in RAGE-positive C6 cells, protected SH-SY5Y neurons from Aβ42 toxicity, and inhibited Aβ42 fibrillization in vitro, producing non-seeding aggregates consistent with impaired fibril formation, and attenuated rotenone-induced α-synuclein-associated cellular stress.

DISCUSSION: Collectively, these findings support further investigation of NAR as a mechanistically plausible multi-target candidate for protein aggregation and RAGE-associated inflammatory signaling in neurodegenerative disease models.},
}

@article {pmid42712639,
year = {2026},
author = {Song, J and Yan, S and Liu, S and Sridhar, A and Sung, K and Pillai, J and Wu, C},
title = {Correlations of PSEN1, PSEN2, and APP missense variants on the production of Aβ peptides against variant effect prediction.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70320},
pmid = {42712639},
issn = {2352-8737},
abstract = {INTRODUCTION: Early-onset Alzheimer's disease (EOAD) is mostly caused by mutations in presenilin-1/2 (PSEN1, PSEN2) and amyloid precursor protein (APP) genes. Both genetic and experimental evidence have supported the PSEN-APP amyloid hypothesis as the leading pathogenesis of Alzheimer's disease (AD). Thus far, 276 missense variants from PSEN1, 2, and APP have been identified. Herein, we report the abilities of variant effect predictors (VEPs) for identifying the degree of pathogenicity among alleles linked with EOAD.

METHODS: We performed pairwise correlations between 276 in vitro functional assays of missense variants from PSEN1, PSEN2, and APP and clinical data among EOAD patients against 37 VEPs. Furthermore, we used the predicted biophysical data of all three proteins to refine our understanding of the molecular basis of missense variants in dominant negative (DN) or loss-of-function (LoF) effects.

RESULTS: We found that VEPs were consistently correlated with age at onset (AAO) among EOAD patients and the amyloid-β (Aβ) 42/Aβ40 ratio biomarker. Regarding the ratio, we observed discrepancies in the predictor variables influencing the Aβ42/Aβ40 ratio, with conflicting evidence as to whether the elevated ratio stems from diminished Aβ40 levels or augmented Aβ42 production. We also identified that with increased predicted pathogenicity, there were decreased Aβ38 levels. Conversely, this study found no direct correlations with Aβ37 and Aβ43. Lastly, structural studies show characteristics of both DN and LoF mechanisms, as there are variants positioned in buried hydrophobic domains and charged surfaces.

DISCUSSION: Currently, a major clinical challenge in the field is the lack of reliable approaches for predicting the pathogenicity of variants in EOAD. Our study also illuminates the need for experimental studies to identify the predictor variable causing the increased Aβ42/Aβ40 biomarker.

HIGHLIGHTS: We performed correlations of 37 VEPs against in vitro data of EOAD variants.VEPs demonstrate potential as diagnostic tools for early onset Alzheimer's disease.Pathogenic missense variants show characteristics of DN and LoF effects.},
}

@article {pmid42712645,
year = {2026},
author = {Reed, J and Bain, SC and Kanamarlapudi, V},
title = {Evaluation of distinct and similar pathological features between diabetes and Alzheimer's disease.},
journal = {EXCLI journal},
volume = {25},
number = {},
pages = {1124-1170},
pmid = {42712645},
issn = {1611-2156},
abstract = {Type 1 diabetes (T1D), type 2 diabetes (T2D) and Alzheimer's disease (AD), which are heterogeneous multifactorial diseases, have become major global healthcare burdens and significant concerns for the future. Historically, the pathogeneses of these diseases were regarded as being largely distinct, but recent research suggests that this view is now outdated, with a lack of insulin and/or insulin resistance playing an important role in both forms of diabetes and AD. The current state of knowledge on the epidemiology, aetiology, and pathogenesis of T1D, T2D, and AD is summarised in this review. The evidence demonstrating overlapping pathological features between these diseases is also discussed here. Studies have demonstrated that islet autoimmunity, dysfunctional glucagon secretion, insulin resistance and islet amyloidosis manifest in both T1D and T2D. AD has been suggested to be type 3 diabetes (T3D), due to the associated abnormal brain insulin resistance, which is speculated to drive the progressive pathogenesis. Additionally, T1D and T2D are risk factors for AD and vice versa, and most AD patients also have diabetes or glucose intolerance, indicating bidirectional relationships. Thus, the association between AD and diabetes is already well established. Further understanding the connection between these diseases using recent scientific evidence may allow for the development of more efficient therapeutic strategies, which is highly desirable, given the prevalence of post-diagnosis complications. Evidence suggests that GLP-1R agonists can alleviate the phenotypes of all of these diseases, and these agonists could be used in the future to simultaneously treat them in subjects or prevent/delay their manifestation in at-risk individuals. See also the graphical abstract(Fig. 1).},
}

@article {pmid42712668,
year = {2026},
author = {Li, X and Huang, J and Zhou, L and Liu, B and Zhou, K and Lin, S and Qin, H and Sun, R and Wei, Y and Liu, Y and Huang, J and Deng, D and Liang, L},
title = {Acute taVNS modulates lateralized hypoactivity in the right cerebral hemisphere in individuals with subjective cognitive decline.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1884933},
pmid = {42712668},
issn = {1662-4548},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is considered a preclinical stage of Alzheimer's disease and represents a critical window for early intervention. Transcutaneous auricular vagus nerve stimulation (taVNS) can modulate cognition-related brain networks. However, its effects in SCD remain unclear.

PURPOSE: This study aimed to investigate the immediate neural responses of the brain to taVNS at different frequencies in individuals with SCD.

METHODOLOGY: Fifty-one individuals with SCD and forty healthy controls (HCs) were enrolled. Individuals with SCD underwent acute taVNS at 1 Hz and 20 Hz, as well as sham stimulation. The amplitude of low-frequency fluctuation (ALFF) was used to assess regional brain activity and the immediate effects of different taVNS frequencies in SCD.

RESULTS: Forty-nine SCD and 39 HC were included. Compared with HCs, SCD exhibited reduced ALFF values in the right inferior frontal gyrus (opercular part), right inferior temporal gyrus, right middle temporal gyrus, and right superior frontal gyrus, and these reductions were associated with subjective cognitive complaints and some standard neuropsychological measures. In SCD, 1 Hz taVNS increased ALFF values in the right fusiform, lingual, inferior occipital, middle temporal, and inferior temporal gyri, and decreased ALFF in the left superior and middle frontal gyri. Similar patterns were observed with 20 Hz taVNS, with additional modulation of the left insula.

CONCLUSION: SCD showed right-frontotemporal hypoactivity that may reflect an underlying pathophysiological mechanism. Both 1 Hz and 20 Hz taVNS can modulate the intrinsic neural activity within multiple cognitive-related brain networks SCD. Long-term intervention and comprehensive cognitive testing are required to verify persistent clinical benefits.},
}

@article {pmid42712681,
year = {2026},
author = {Oatman, SR and Quicksall, ZS and Wang, X and Bergman, J and Reddy, JS and Vanelderen, F and Nguyen, T and Malphrus, K and Lincoln, SJ and Martens, YA and Zhao, N and Yamazaki, Y and DeTure, M and Murray, ME and Liu, CC and Bu, G and Kanekiyo, T and Dickson, DW and Allen, M and Ertekin-Taner, N},
title = {Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag326},
pmid = {42712681},
issn = {2632-1297},
abstract = {Identification of gene expression changes in postmortem brain tissue of Alzheimer's disease donors compared to controls has implicated numerous biological pathways for Alzheimer's disease pathophysiology. Nonetheless, there is still limited understanding of how gene expression dysregulation underpins specific proteinopathies core to Alzheimer's disease. Here, we investigate brain transcriptomic changes in a well-characterized cohort of Alzheimer's disease donors to identify genes and networks that associate with Alzheimer's disease endophenotypes, including neuropathology measures (Braak stage, Thal phase and cerebral amyloid angiopathy score) and Alzheimer's disease-related brain protein levels (Apolipoprotein E, Amyloid-β 40, Amyloid-β 42, tau and phospho-Tau). Bulk transcriptome measures were collected from the temporal cortex tissue of 477 Alzheimer's disease donors. Following quality control, transcriptome-wide association studies were performed for each endophenotype. We used weighted gene co-expression network analysis to build co-expression networks and integrated transcriptome with epigenetic and genetic data from the same donors. We detected a total of 5740 Bonferroni-significant temporal cortex gene associations with Alzheimer's disease endophenotypes, most of which were with brain tau levels. We discovered tau-associated co-expression modules enriched in known and novel Alzheimer's disease pathways. We found that a beneficial (or neutral) brain biochemical state of higher total tau and lower phospho-Tau is associated with increased levels of synaptic, DNA damage/repair, nucleic acid metabolism and myelin processes. In contrast, in a detrimental state with lower total and higher phospho-Tau, there is upregulation of vascular and immune, and downregulation of mitochondrial and myelin pathways. There are brain gene expression perturbations that are associated with Alzheimer's disease endophenotypes. While some of these associations are common across multiple endophenotypes, many are distinct for different Alzheimer's disease-related proteins. Based on these findings, we propose a hypothetical model of dynamic brain gene expression changes that track with progressive Alzheimer's disease proteostasis. These expression changes hold potential to serve as dynamic, precision biomarkers of brain Alzheimer's disease progression. This study demonstrates the potential of integrative multi-omics and deep Alzheimer's disease endophenotypes in well-characterized brain tissues to precisely uncover the complex biology of Alzheimer's disease.},
}

@article {pmid42712815,
year = {2026},
author = {Dienel, GA},
title = {Anesthesia, perimortem conditions, and brain harvest method govern the measured metabolome: analysis of substandard samples generates flawed metabolite levels.},
journal = {Oxford open neuroscience},
volume = {5},
number = {},
pages = {kvag011},
pmid = {42712815},
issn = {2753-149X},
abstract = {Metabolism and energetics are closely integrated with brain function, and understanding how metabolic dysfunction contributes to neurological disease may help improve therapeutic approaches. Characterization of in situ metabolite levels, spatial distributions, and metabolomes requires special attention to anesthesia use, perimortem conditions, and tissue harvest. Anesthesia, CO2 asphyxiation, vascular perfusion, and decapitation alter metabolism, thereby substantially changing the metabolome, lipidome, and neurotransmitter profile. Analysis of flawed samples produces artifactual data, raising concerns about conclusions regarding the cellular basis of metabolism, metabolite shuttling, pathway activities, labeled metabolite profiling and imaging, and relationships between metabolism, function, and neurological disorders. Appropriate procedures for in vivo metabolic assays and tissue harvest are widely-unrecognized but essential components of metabolic and metabolomic studies.},
}

@article {pmid42712833,
year = {2026},
author = {Braun, M and Simon, MJ and Jang, J and Sanderson, K and Swierz, J and Sevao, M and Pincus, AB and Schaser, AJ and Elliott, JE and Lim, MM and Unni, VK and Schindler, AG and Keene, CD and Latimer, CS and Iliff, JJ},
title = {Aquaporin-4 mis-localization decreases glymphatic clearance of α-synuclein in an alpha-syntrophin knock out mouse model and promotes α-synuclein pathology and aggregate propagation.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag327},
pmid = {42712833},
issn = {2632-1297},
abstract = {The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of α-synuclein aggregates, which may not only enhance cell death but also contribute to disease progression by seeding the formation of additional aggregates in neighbouring cells. The mechanisms driving intercellular transmission of aggregates remain unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular aquaporin-4 localization, inhibits α-synuclein clearance and facilitates α-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical α-synuclein pathology was associated with aquaporin-4 mis-localization throughout the grey matter. Using a transgenic mouse model lacking the adapter protein α-syntrophin, we observed that loss of perivascular aquaporin-4 localization impairs the glymphatic clearance of α-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of α-synuclein propagation using pre-formed fibril injection, we observed that loss of perivascular aquaporin-4 localization increased α-synuclein aggregates. Our results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that aquaporin-4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy body dementia and Parkinson's disease.},
}

@article {pmid42712875,
year = {2026},
author = {Byeon, G and Lee, JW and Kim, S and Um, YH and Wang, SM and Ha, S and Park, SY and Shin, I and Jang, J and Lee, CU and Lim, HK and Kang, DW},
title = {Baseline plasma C1q and C3 as potential biomarkers for lecanemab efficacy and ARIA risk in early Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70313},
pmid = {42712875},
issn = {2352-8737},
abstract = {INTRODUCTION: The classical complement cascade has been implicated in amyloid beta (Aβ) clearance and in the pathogenesis of amyloid-related imaging abnormalities (ARIA) during anti-amyloid monoclonal antibody therapy. Clinically accessible peripheral biomarkers of this cascade remain uncharacterized in real-world cohorts.

METHODS: We conducted a retrospective, hypothesis-generating cohort study of 62 patients with early Alzheimer's disease initiating lecanemab. ARIA risk was evaluated in the safety cohort (N = 62), and absolute amyloid reduction at week 26 was evaluated in the efficacy cohort with paired baseline and 26-week amyloid positron emission tomography (N = 34). Associations of baseline plasma C1q, C3, and apolipoprotein E ε4 (APOE ε4) carrier status with these outcomes were examined using Firth's penalized logistic regression and bootstrap linear regression (2000 iterations), with prespecified sensitivity analyses. Within-subject changes in C3 (N = 30) and C1q (N = 19) were assessed by paired Wilcoxon test.

RESULTS: Lower baseline C3 was nominally associated with higher ARIA risk (odds ratio [OR] per 1 SD = 0.44, 95% CI: 0.15 to 0.97, p = 0.040, uncorrected), and this association persisted in international normalized ratio (INR)-adjusted and simplified models. C3 ≤ 25th percentile (≤99 mg/dL) showed a trend (OR: 4.78, 95% CI: 0.98 to 26.34, p = 0.052). In the efficacy cohort, higher baseline C1q was associated with smaller amyloid reduction (β = -6.86, 95% CI: -12.19 to -3.06, p = 0.002); carriers of at least one APOE ε4 allele, a status that in this cohort jointly reflects genotype and dose-titration, showed less amyloid reduction (β = -19.50, 95% CI -31.57 to -8.40, p < 0.001). Within-subject changes in C1q and C3 were not significant (p = 0.248 and 0.114, respectively).

DISCUSSION: Lower baseline C3 was consistently associated with ARIA risk across sensitivity analyses and higher baseline C1q with smaller amyloid reduction at week 26. Findings are exploratory given the limited single-center sample.},
}

@article {pmid42712882,
year = {2026},
author = {Zhu, W and Zhang, Y and Li, P and Zhong, Y and Lin, Y and Liu, X},
title = {Multi-Omics Analysis Reveals That Aβ42- Me3 Co-Aggregation Induces Mitophagy Blockade in Early Stages of Alzheimer's Disease.},
journal = {MedComm},
volume = {7},
number = {9},
pages = {e70984},
pmid = {42712882},
issn = {2688-2663},
abstract = {Mitochondrial dysfunction is one of the earliest pathological features of Alzheimer's disease (AD), preceding overt neurodegeneration and cognitive decline. Amyloid-β (Aβ) accumulation has long been considered a central pathogenic event in AD, yet how Aβ toxicity is mechanistically linked to mitochondrial impairment during early disease stages remains incompletely understood. To address this, we combined multi-omics with in vivo and in vitro genetic interventions. Here, we show that malic enzyme 3 (Me3) links Aβ aggregation to mitochondrial dysfunction in APP/PS1 mice and neuronal cells. At ultra-early and early AD stages (3 and 6 months), Me3 was upregulated and accumulated within mitochondria, where it colocalized with Aβ42 and physically interacted with it, an association linked to oxidative stress and impaired mitophagy. Knockdown of Me3 reduced mitochondrial reactive oxygen species, improved mitochondrial morphology, and alleviated mitophagy defects in both cellular and mouse models, with statistical significance across these functional measurements (p < 0.05). These results suggest that Me3 functions not only as a metabolic responder to Aβ-associated stress but also as a contributor to early mitochondrial pathology. By identifying the Aβ-Me3 axis, this study provides mechanistic insight into early mitochondrial dysfunction in AD, while further validation in human AD samples remains necessary.},
}

@article {pmid42712987,
year = {2026},
author = {Gupta, A and Dembitskaya, Y and Pushkarev, A and Popov, A},
title = {Mapping and modulating brain dynamics in aging and neurodegeneration with electroencephalography and integrated neurotechnologies in primates.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1689222},
pmid = {42712987},
issn = {1662-4548},
abstract = {Non-human primates (NHPs) provide an essential translational platform for investigating neural mechanisms underlying brain aging and neurodegenerative diseases. Their neuroanatomical organization, cortical complexity, and cognitive capacities share close parallels with those of humans, enabling a degree of experimental precision that rodent models cannot achieve. Electroencephalography (EEG) offers a non-invasive method for monitoring neuronal population activity with high temporal resolution, capturing oscillatory patterns and connectivity changes that emerge over the course of aging and in pathological states. In humans, such measures have revealed alterations in dominant frequency bands, network synchrony, and event-related potentials that serve as candidate biomarkers for cognitive decline. Extending EEG to NHP models permits the direct examination of mechanistic hypotheses and assessment of therapeutic interventions in a brain closely resembling that of humans. We emphasize study-level examples and quantitative anchors, including frequency-band ranges and the direction of EEG changes across aging and neurodegenerative disease models. Recent work has expanded EEG applications in NHPs to longitudinal studies, invasive/non-invasive signal comparisons, and integration with other modalities, including magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), and invasive electrophysiology. Furthermore, pairing EEG with neuromodulation techniques such as transcranial magnetic stimulation (TMS), transcranial direct and alternating current stimulation (tDCS, tACS), temporal interference (TI) stimulation, and transcranial focused ultrasound (tFUS) offers a framework for causally probing and modifying network function. This review synthesizes EEG methodologies in NHPs, examines their applications to models of normative aging, Alzheimer's disease, and Parkinson's disease, and discusses multimodal integration, neuromodulation strategies, ethical considerations, and translational relevance for human neuroscience. Sections are organized around five linked goals: establishing EEG measurement validity in primates, summarizing aging and disease-associated EEG signatures, integrating EEG with imaging and invasive recordings, using stimulation to test causality, and translating biomarkers and interventions to human studies.},
}

@article {pmid42712997,
year = {2026},
author = {Malfer, L and Mullan, AF and Lynott, E and Troxel, C and Ali, F and Benarroch, EE and Boeve, BF and Bower, JH and Savica, R},
title = {Cumulative incidence and risk factors of dementia in Parkinson's disease and parkinsonism: a population-based study.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag330},
pmid = {42712997},
issn = {2632-1297},
abstract = {Cognitive impairment is among the most common non-motor symptoms in parkinsonism and Parkinson's disease, ranging from subjective complaints to dementia. Although several predictive factors have been described, their prognostic relevance remains uncertain. This study aimed to examine the predictive association between clinical features and the risk of dementia and determine the incidence of dementia in a population-based cohort of incident Parkinsonism cases. Patients with parkinsonism onset between 1991 and 2020 were identified using the Rochester Epidemiology Project records-linkage system. Subjects with cognitive impairment preceding motor symptoms onset or concomitant Alzheimer's disease were excluded. Diagnoses of dementia and mild cognitive impairment were established using neuropsychological testing or brief cognitive screening. Development of dementia was assessed using a Cox proportional hazards regression model. Associations between dementia and each risk factor were individually estimated in adjusted Cox models. All risk factors were also included in a least absolute shrinkage and selection operator penalized multivariable Cox model. A total of 1104 patients were included: 153 (13.9%) developed mild cognitive impairment, and 543 (49.2%) developed dementia during follow-up. The cumulative incidence of dementia was 30.3% at 5 years, 48.6% at 10 years, 61.4% at 15 years and 69.3% at 20 years, indicating that a considerable portion of patients remained free of dementia after a prolonged follow-up. The majority of patients with dementia were males (61.5%), and older age at disease onset was associated with risk of dementia (hazard ratio [HR] = 1.32, P < 0.001 per 5-year increment). In the penalized model, dementia risk was significantly higher among individuals presenting with impaired postural reflexes (HR = 1.26, P = 0.014), consistent with a poorer prognosis in akinetic-rigid-predominant parkinsonism. Eye movement abnormalities, including reduced ocular range of motion (HR = 1.86, P < 0.001) and smooth pursuit alterations (HR = 1.34, P = 0.024), were also associated with dementia. Non-motor symptoms, including rapid eye movement sleep behaviour disorder (HR = 1.51, P < 0.001), orthostatic hypotension (HR = 1.30, P = 0.009) and constipation (HR = 1.24, P = 0.022), were linked to dementia risk, supporting a potential involvement of non-dopaminergic and central autonomic pathways in cognitive decline. These findings were largely confirmed in the Parkinson's disease/Parkinson's disease with dementia group, in which 77 (13.5%) developed mild cognitive impairment and 249 (43.5%) developed dementia. Among these patients, smooth pursuit alterations, reduced ocular range of motion, orthostatic hypotension and constipation were associated with dementia.},
}

@article {pmid42713005,
year = {2026},
author = {Belaidi, AA and Furtado, DL and Alves, F and Nisbet, RM and Ayton, S and Bush, AI},
title = {Engineering mRNA-LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases.},
journal = {Exploration (Beijing, China)},
volume = {},
number = {},
pages = {70223},
pmid = {42713005},
issn = {2766-2098},
abstract = {Messenger RNA (mRNA) therapeutics delivered by lipid nanoparticles (LNPs) have advanced from concept to clinic at unprecedented speed, yet their promise for neurodegenerative diseases remains largely untapped. Currently intractable age-related proteinopathies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis demand new therapies that combine molecular precision with scalable manufacturing. This review surveys recent advances in engineering LNPs that traverse the blood-brain barrier (BBB), evade innate immune surveillance, and achieve cell-selective expression in the ageing brain. We highlight emerging chemistries, including BBB-shuttling ionizable lipids, peptide-functionalized shells, and liver-detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS-directed mRNA-LNP has yet reached clinical trials, first-in-human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID-19 mRNA vaccines and ongoing liver-targeted programmes, we outline a translational roadmap for brain applications. Major hurdles that are critically assessed include efficient endosomal escape in aged neurons, heterogeneity of the senescent BBB, chronic-dose immunogenicity, and large-scale synthesis of next-generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age-related BBB alterations. Together, these insights chart a path for engineering mRNA-LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.},
}

@article {pmid42713223,
year = {2026},
author = {Suri, K and Yadav, A and Tripathi, A and Murugan, NA},
title = {Cross-docking and redocking reveal distinct determinants of success in physics-based and AI-driven binding pose prediction in protein-ligand complexes.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42713223},
issn = {2046-2069},
abstract = {Protein-ligand pose prediction is central to structure-based drug discovery, yet the relative performance of physics-based and AI-driven methods under realistic cross-docking conditions remains insufficiently characterized. Here, we compare physics-based docking methods (AutoDock4, AutoDock Vina, and DOCK 6) with data-driven approaches, including the deep-learning model GNINA 1.3 and the diffusion-based frameworks AlphaFold 3, Boltz-2, and DiffDock. Performance was evaluated using standardised redocking and cross-docking protocols across three Alzheimer's disease targets representing distinct binding-site architectures: acetylcholinesterase (AChE; deep gorge), β-secretase 1 (BACE1; flexible flap-controlled site), and glycogen synthase kinase-3β (GSK-3β; open, solvent-exposed pocket). Physics-based methods were competitive during redocking but showed substantial performance reductions under cross-docking, whereas diffusion-based approaches generally maintained higher cross-docking accuracy. GNINA 1.3 rigid achieved an 87.7% minimum heavy-atom RMSD success rate during redocking, which decreased to 13.5% during cross-docking, whereas AlphaFold 3, Boltz-2, and DiffDock achieved cross-docking success rates of 93.1%, 89.6%, and 85.7%, respectively. AlphaFold 3 consistently outperformed Boltz-2 despite its smaller training set, suggesting that predictive performance is influenced not only by training-data volume but also by factors such as model architecture and confidence calibration. Training-overlap analysis further showed that AI-based methods retained substantial failure rates even for complexes represented in their training data, indicating that training-data overlap alone does not ensure reliable pose prediction. Under the current protocol conditions, rigid docking outperformed flexible protocols, while flexible-docking pocket volumes showed more restricted sampling relative to experimental holo structures. Among the GNINA 1.3 configurations, CNN rescoring with refinement produced the highest pose-recovery success rates, followed by CNN rescoring alone and the default Vina/empirical scoring approach in cross-docking. Receptor conformational preference was target-dependent: holo structures provided higher docking accuracy for AChE and BACE1, whose ligand-bound cavities exhibited greater structural complexity and geometric confinement that favoured pose discrimination, whereas the apo GSK-3β structure contained a larger, more solvent-exposed cavity that improved ligand accessibility and docking performance. Overall, these findings demonstrate the importance of cross-docking and training-overlap-aware evaluation for assessing docking performance under realistic conditions and provide cavity-topology-based considerations for selecting docking strategies in structure-based drug discovery.},
}

@article {pmid42713462,
year = {2026},
author = {Hojjati, SH and Wang, XH and Zhou, L and Keil, S and Tanzi, E and Maloney, T and Feiz, F and Shah, S and Glodzik, L and Li, Y and Chiang, GC and Butler, TA},
title = {In the absence of Alzheimer's Disease pathology, PET-measured hippocampal tau is reduced in association with greater depressive symptoms: Could tau PET be sensitive to physiological tau involved in neurogenesis?.},
journal = {Journal of affective disorders reports},
volume = {25},
number = {},
pages = {101071},
pmid = {42713462},
issn = {2666-9153},
abstract = {BACKGROUND: Tau Positron Emission Tomography (PET) visualizes hyperphosphorylated tau tangles which, together with Aβ plaques, are hallmark pathologies of Alzheimer's disease (AD). Greater tau, measured by PET or neuropathology, is robustly linked to worse cognition in AD, but associations with mood are less studied. We previously reported an unexpected inverse relationship between depressive symptoms and PET-measured medial temporal tau in individuals without AD. Here, we confirm and extend this finding in an independent cohort.

METHODS: We analyzed cross-sectional data from 403 Alzheimer's Disease Neuroimaging Initiative participants who underwent flortaucipir (tau) PET, Aβ PET, MRI, and clinical assessments including the Geriatric Depression Scale (GDS). Participants were categorized as Aβ- or Aβ+. Associations between GDS scores and mean hippocampal flortaucipir uptake were assessed using Spearman correlation and multiple regression.

RESULTS: In Aβ- individuals (n = 252), higher hippocampal tau was significantly associated with lower depression scores, whereas Aβ+ individuals (n = 151) showed a trend-level positive association. This difference was supported by a significant interaction between depression and Aβ status in regression analyses. Results were unchanged after adjustment for age, diagnostic group, and hippocampal volume.

CONCLUSIONS: In the absence of AD pathology, greater severity of depressive symptoms is associated with lower PET-measured hippocampal tau. Because impaired hippocampal neurogenesis is considered a key mechanism in depression, and tau is a normal component of cell division including neurogenesis, this replicated inverse relationship may reflect reduced hippocampal neurogenesis. Whether tau PET can provide a window into this process in humans requires further study.},
}

@article {pmid42713682,
year = {2026},
author = {Cacho-Gutiérrez, J and García García-Patino, R and García-García, R and Cuevas-Pérez, Y and Vicente-Villardón, JL and Perea-Bartolomé, MV and Benito-León, J},
title = {Distinguishing early cognitive impairment in older adults with CogniScan: a nine-item composite derived from the Mini-Mental State Examination and Clock Drawing Test.},
journal = {Epidemiology and psychiatric sciences},
volume = {35},
number = {},
pages = {e50},
doi = {10.1017/S2045796026100912},
pmid = {42713682},
issn = {2045-7979},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; Female ; Cross-Sectional Studies ; Male ; *Alzheimer Disease/diagnosis/psychology ; *Neuropsychological Tests ; *Mental Status and Dementia Tests ; Spain ; Aged, 80 and over ; ROC Curve ; Sensitivity and Specificity ; },
abstract = {AIMS: Identifying cognitive impairment in routine care is essential, yet many brief screening instruments exhibit ceiling or floor effects. To our knowledge, no widely used brief cognitive screening instrument has incorporated the qualitative Clock Drawing Test (CDT) command-copy discrepancy, in which the copied clock is better organized than the clock drawn to command, into a composite score.

METHODS: In this cross-sectional study, patients with amnestic multidomain mild cognitive impairment (aMD-MCI) or early Alzheimer's disease (AD) were consecutively recruited from a tertiary memory clinic at Salamanca University Hospital, Spain, and compared with cognitively unimpaired community-dwelling controls. All participants underwent the Mini-Mental State Examination and the CDT. CogniScan was derived post hoc from nine elements retained through binary partial least squares regression: five temporal-orientation items, three delayed-recall words and one CDT command-copy discrepancy indicator. Factor maps from the fitted model were used to visualize group separation, and receiver operating characteristic analyses were used to estimate apparent discriminative performance and candidate cutoffs.

RESULTS: The final sample included 183 older adults (median age, 75 years): 35 with aMD-MCI, 75 with early AD and 73 cognitively unimpaired controls. All nine CogniScan elements were strongly associated with cognitive status, with large effect sizes. In the primary binary analysis, discrimination was excellent (area under the curve [AUC] 0.99, 95% confidence interval 0.98-1.00). The Youden-optimized cutoff was ≥2 errors (sensitivity 96%, specificity 99%). In secondary exploratory analyses restricted to cognitively impaired participants, discrimination between aMD-MCI and early AD was lower (AUC 0.89, 95% confidence interval 0.82-0.97), consistent with partial overlap on the latent maps. In exploratory models, categorical educational level was not significantly associated with CogniScan score among controls and was not an independent predictor of cognitive status in the adjusted model.

CONCLUSIONS: CogniScan showed excellent apparent discriminative performance, but external validation across broader cognitive phenotypes and wider age and educational ranges is needed. It appears best suited as a binary detector of impairment rather than as a definitive stage classifier.},
}

Humans
*Cognitive Dysfunction/diagnosis/psychology
Aged
Female
Cross-Sectional Studies
Male
*Alzheimer Disease/diagnosis/psychology
*Neuropsychological Tests
*Mental Status and Dementia Tests
Spain
Aged, 80 and over
ROC Curve
Sensitivity and Specificity

@article {pmid42713737,
year = {2026},
author = {Guthknecht, A and Steinacker, P and Abu-Rumeileh, S and Otto, M},
title = {A comparative evaluation of p-tau217 stability in serum and plasma using two validated assays.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42713737},
issn = {1437-4331},
}

@article {pmid42713877,
year = {2026},
author = {Langford, O and Raman, R and Aisen, P and Sperling, R and Johnson, K and Molina-Henry, D and Sachdev, P and Li, D and Jimenez-Maggiora, GA and Johnson, SC and Braunstein, JB and Birkenbihl, C and Cuppels, M and Buckley, RF and Rissman, RA and Donohue, MC},
title = {More efficient screening for preclinical Alzheimer's clinical trials using mixture of experts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71681},
doi = {10.1002/alz.71681},
pmid = {42713877},
issn = {1552-5279},
support = {U24AG057437/AG/NIA NIH HHS/United States ; R01AG054029/AG/NIA NIH HHS/United States ; R01AG061848/AG/NIA NIH HHS/United States ; R01AG079142/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/drug therapy/diagnosis/diagnostic imaging ; *Amyloid beta-Peptides/blood ; Positron-Emission Tomography ; Biomarkers/blood ; tau Proteins/blood ; Female ; Male ; Algorithms ; Peptide Fragments/blood ; Aged ; *Patient Selection ; Clinical Trials as Topic ; Prediction Algorithms ; Antibodies, Monoclonal, Humanized ; },
abstract = {INTRODUCTION: Blood plasma biomarkers identifying Alzheimer's disease (AD) neuropathology offer accessible and scalable alternatives to lumbar puncture and positron emission tomography (PET) scans, with potential efficiency gains in clinical trial recruitment.

METHODS: We evaluated the impact of a blood-based screening algorithm on recruitment for the AHEAD 3-45 trial testing lecanemab in preclinical AD. The algorithm was developed during initial screening without blood plasma and subsequently deployed using a Mixture of Experts prediction model to estimate amyloid PET positivity; analyses reflect prospective enrichment and model characterization.

RESULTS: The algorithm incorporating amyloid beta A β 42 / A β 40 and subsequently adding percent phosphorylated tau 217 (%p-tau217), reduced ineligibility on amyloid PET from 71% to 31%. Latent class analysis identified low, intermediate, and high amyloid groups. Model-based analyses indicated %p-tau217 predicts High amyloid group, whereas A β 42 / A β 40 was more specific for the low group.

DISCUSSION: Blood plasma screening reduced participant and site burden, while preserving enrichment for amyloid positivity for a preclinical AD trial.},
}

Humans
*Alzheimer Disease/blood/drug therapy/diagnosis/diagnostic imaging
*Amyloid beta-Peptides/blood
Positron-Emission Tomography
Biomarkers/blood
tau Proteins/blood
Female
Male
Algorithms
Peptide Fragments/blood
Aged
*Patient Selection
Clinical Trials as Topic
Prediction Algorithms
Antibodies, Monoclonal, Humanized

@article {pmid42714032,
year = {2026},
author = {Li, Y and Ye, T and Lu, H and Wang, S and Yu, T and Li, H and Cheng, X},
title = {Effects of Qi-fu-yin on Improving Cognitive Impairment and Reducing Cellular Senescence in the Brains of 5xFAD Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/72118},
pmid = {42714032},
issn = {1940-087X},
mesh = {Animals ; Mice ; *Brain/drug effects/metabolism/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cellular Senescence/drug effects ; *Drugs, Chinese Herbal/pharmacology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Male ; },
abstract = {Although the mechanism of Qi-fu-yin (QFY), a traditional Chinese medicine prescription, remains incompletely understood, it has shown therapeutic potential in Alzheimer's disease (AD). This study aimed to investigate the association between QFY treatment and cognitive impairment in 5xFAD mice. We used grip strength, gait, colony nesting, shuttle box, Morris water maze test, and ELISA to evaluate the levels of Amyloid-β protein 1-42 (Aβ1-42), Aβ1-40, Growth-associated protein 43 (GAP-43), Synaptophysin (SYN), and Postsynaptic density protein 95 (PSD-95) in the brains of 5xFAD mice. Luminex cytokine analysis was used to quantify Senescence-associated secretory phenotype (SASP) levels in the cortex. The amount of Senescence-associated β-galactosidase (SA-β-Gal), Aβ deposition, and dendritic spines in the animals' brains was measured by SA-β-Gal staining, immunohistochemistry, and Golgi-Cox staining, respectively. QFY treatment dramatically reduced cortical Aβ plaque burden and decreased p21 expression in 5xFAD mice, according to immunofluorescence tests. In 5xFAD mice, QFY therapy markedly enhanced learning and memory performance, alleviated aging, and increased the amounts of GAP-43, PSD-95, and SYN proteins in the mice's cortex. Following QFY treatment, there was a significant decrease in Aβ plaque and SA-β-Gal activity in the brain, as well as Aβ1-42 and Aβ1-42/Aβ1-40 levels in the hippocampus. The levels of IL-1α, IL-1β, IL-6, IL-17A, and IFN-γ were considerably reduced in the cortex of the 5xFAD mice. PCA and Pearson correlation analyses demonstrated a strong negative association between SASP cytokines and synaptic protein levels. These findings suggest an association between QFY treatment and improvements in age‑related cognitive decline and cellular senescence phenotypes in 5xFAD mice, alongside mitigated synaptic structural damage. These findings support further investigation of QFY as a potential therapeutic candidate for Alzheimer's disease.},
}

Animals
Mice
*Brain/drug effects/metabolism/pathology
*Alzheimer Disease/drug therapy/metabolism/pathology
*Cellular Senescence/drug effects
*Drugs, Chinese Herbal/pharmacology
Mice, Transgenic
Amyloid beta-Peptides/metabolism
*Cognitive Dysfunction/drug therapy/metabolism/pathology
Male

@article {pmid42714593,
year = {2026},
author = {Kang, S and Jeon, S and Lee, D and Lee, H and Jeon, SH and Choi, M and Lee, YG and Shin, NY and Yun, M and Ye, BS},
title = {APOE4-dependent cholinergic/dopaminergic contributions to clinical symptoms across Alzheimer's disease spectrum: A retrospective observational study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42714593},
issn = {1619-7089},
support = {RS-2025-25467534//Korea Health Industry Development Institute/ ; HI14C1324//Korea Health Industry Development Institute/ ; RS-2022-NR072434//Ministry of Science and ICT, South Korea/ ; },
abstract = {PURPOSE: Clinical heterogeneity in Alzheimer's disease (AD) may reflect differential involvement of neurotransmitter systems, but whether the associations of cholinergic and dopaminergic imaging biomarkers with cognitive and neuropsychiatric symptoms differ according to apolipoprotein E ε4 (APOE4) status remains unclear.

METHODS: We studied 387 patients across the amyloid-confirmed AD spectrum. Patients were stratified by APOE4 status into 205 carriers and 182 non-carriers. Basal forebrain volume (BFV), striatal dopamine transporter uptake (DAT), and regional brain perfusion were examined in relation to cognitive performance and neuropsychiatric inventory scores.

RESULTS: APOE4 carriers showed lower BFV than non-carriers, whereas APOE4 non-carriers showed lower DAT. In APOE4 carriers, lower BFV was associated with memory dysfunction and AD-typical temporoparietal hypoperfusion; the BFV-memory association was attenuated after inclusion of posterior cingulate perfusion. Lower BFV was also associated with several neuropsychiatric symptoms, including hallucinations, delusions, anxiety, apathy, aberrant motor behavior, and appetite changes, with direct associations remaining for hallucinations, delusions, and apathy after accounting for regional perfusion. In APOE4 non-carriers, lower DAT was associated with poorer performance across widespread cognitive domains and with hallucinations, delusions, and anxiety. These DAT associations largely persisted even after adjustment for regional perfusion.

CONCLUSION: APOE4 status was associated with differences in the clinical and brain perfusion correlates of cholinergic and dopaminergic degeneration in AD. APOE4 carriers showed a BFV-dominant pattern linked to AD-typical perfusion changes and memory dysfunction, whereas non-carriers showed a DAT-dominant pattern with largely perfusion-independent associations with cognitive and neuropsychiatric manifestations.},
}

@article {pmid42714614,
year = {2026},
author = {Schnieder, M},
title = {[Antibody therapy in Alzheimer's disease].},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {},
number = {},
pages = {},
pmid = {42714614},
issn = {1435-1269},
abstract = {Alzheimer's disease, the leading cause of dementia, is defined by extracellular amyloid‑β (Aβ) plaques, intracellular tau aggregates and neurodegeneration. Lecanemab and donanemab, are the first disease-modifying antibodies available for early Alzheimer's disease. Both reduce Aβ plaques and slow cognitive decline. Lecanemab targets soluble protofibrils and donanemab targets fibrillar Aβ. The primary side effect is amyloid-related imaging abnormalities (ARIA), which can occur as edema (ARIA-E) or hemorrhages (ARIA-H). The risk is higher in APOE4 homozygotes, anticoagulation or cerebrovascular diseases. Therefore, during treatment a regular monitoring with magnetic resonance imaging (MRI) is mandatory.},
}

@article {pmid42714664,
year = {2026},
author = {Aiello, EN and Canu, E and Castelnovo, V and Frisco, F and Curti, B and Moreschi, A and De Luca, G and Sibilla, E and Freri, F and Tripodi, C and Bianchi, A and Lamorgese, B and Gilioli, A and Spinelli, EG and Cecchetti, G and Ratti, A and Maranzano, A and Patisso, V and Caroppo, P and Prioni, S and Villa, C and Tremolizzo, L and Appollonio, I and Verde, F and Silani, V and Ticozzi, N and Filippi, M and Agosta, F and Poletti, B},
title = {Discriminating behavioral variant frontotemporal dementia from Alzheimer's disease via the Frontal Assessment Battery.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42714664},
issn = {1432-1459},
support = {StG-2016_714388_NeuroTRACK/ERC_/European Research Council/International ; DM 1557 11.10.2022//Next Generation EU/ ; },
mesh = {Humans ; *Frontotemporal Dementia/diagnosis ; *Alzheimer Disease/diagnosis ; Female ; Male ; Retrospective Studies ; *Neuropsychological Tests ; Aged ; Diagnosis, Differential ; Middle Aged ; Severity of Illness Index ; Mental Status and Dementia Tests ; ROC Curve ; },
abstract = {BACKGROUND: This study aimed to assess the ability of the frontal assessment battery (FAB) to differentiate Alzheimer's disease (AD) from behavioral variant frontotemporal dementia (bvFTD), as well as to test whether its discriminatory accuracy varies as a function of disease stage.

METHODS: The present retrospective cohort included N = 595 participants-153 with biomarker-supported AD, 96 with probable bvFTD, and 346 healthy controls (HCs). All HCs scored within the normal range on the Montreal Cognitive Assessment. In patients, disease severity was staged according to Clinical Dementia Rating scores, retrospectively derived from the Mini-Mental State Examination. Receiver operating characteristic (ROC) analyses were performed to assess the ability of demographically adjusted FAB scores to differentiate both patient groups from HCs and AD from bvFTD patients, including severity-stratified analyses. Binary logistic regression models adjusted for age and sex examined the contribution of individual FAB subtests to diagnostic classification.

RESULTS: The FAB showed excellent accuracy in distinguishing patients from HCs. In contrast, its ability to differentiate AD from bvFTD was modest overall and depended on disease severity, with adequate discrimination emerging solely at moderate-to-severe stages. At the subtest level, Lexical fluency was the only subtests that significantly differentiated bvFTD from AD, particularly in patients at the MCI/questionable dementia and moderate-to-severe dementia stage. No significant differences emerged for the remaining subtests.

DISCUSSION: The FAB is an excellent screening test for executive dysfunction in both bvFTD and AD, but its contribution to the differential diagnosis between these two conditions emerges only at moderate-to-severe stages.},
}

Humans
*Frontotemporal Dementia/diagnosis
*Alzheimer Disease/diagnosis
Female
Male
Retrospective Studies
*Neuropsychological Tests
Aged
Diagnosis, Differential
Middle Aged
Severity of Illness Index
Mental Status and Dementia Tests
ROC Curve

@article {pmid42714762,
year = {2026},
author = {Göttsche Esperança Clara, C and Michael, S and Roeser, SP and Schilling, K and Baader, SL},
title = {TNIP1 As A Potential Factor In Neuronal Survival, Growth and Differentiation in the Cerebellar Cortex.},
journal = {Cerebellum (London, England)},
volume = {25},
number = {5},
pages = {},
pmid = {42714762},
issn = {1473-4230},
mesh = {Animals ; *Neurons/metabolism/physiology/cytology ; Humans ; *Cerebellar Cortex/growth & development/metabolism/cytology ; *DNA-Binding Proteins/metabolism/genetics ; Cell Survival/physiology ; RNA, Messenger/metabolism ; *Cell Differentiation/physiology ; Cell Proliferation/physiology ; HEK293 Cells ; Mice ; Caspase 3/metabolism ; Mice, Inbred C57BL ; },
abstract = {Tumor Necrosis Factor-Induced Protein 1 (TNIP1) is a well-known ubiquitin-binding signaling molecule involved in innate and adaptive inflammatory processes. It has been implicated in diverse immunological diseases, but also associated with various neuro-psychiatric conditions, including Alzheimer's disease, glioma formation, and demyelination. However, a systematic analysis of TNIP1 expression and function in the central nervous system is missing. Here, we combine immunohistochemical staining, Western blotting, quantitative PCR and the re-analysis of publicly available single cell- and in situ hybridization-mRNA datasets to document the expression of TNIP1 in the developing and adult murine cerebellum. We document that TNIP1 is broadly expressed in cerebellar neurons and macroglial cells, where it is localized to discrete puncta within cell nuclei and somata, including Purkinje cell dendrites. Both TNIP1 and its mRNA are developmentally regulated in the early postnatal cerebellum, and levels of the latter vary systematically across the cell cycle. Consistently, overexpression of TNIP1 in human embryonic kidney cells inhibits proliferation and activates cleaved caspase-3 expression. These observations support a role for TNIP1 in neur(on)al development and function and establish a paradigm to study the mechanistic basis of its function in the normal and diseased nervous system.},
}

Animals
*Neurons/metabolism/physiology/cytology
Humans
*Cerebellar Cortex/growth & development/metabolism/cytology
*DNA-Binding Proteins/metabolism/genetics
Cell Survival/physiology
RNA, Messenger/metabolism
*Cell Differentiation/physiology
Cell Proliferation/physiology
HEK293 Cells
Mice
Caspase 3/metabolism
Mice, Inbred C57BL

@article {pmid42714771,
year = {2026},
author = {Rehman, U and Datta, K and Liu, SC and Park, JM and Sriram, R and Hong, D and Chen, Q and Mori, H and Trinh, V and Berman, R and Hurd, R and Spielman, D and Jue, T},
title = {Hyperpolarized NMR study of the impact of alzheimer's disease on diabetes using a novel rat model.},
journal = {Journal of physiology and biochemistry},
volume = {82},
number = {1},
pages = {},
pmid = {42714771},
issn = {1877-8755},
support = {18-10923//California Department of Public Health/ ; 18-10923//California Department of Public Health/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/complications/genetics/pathology ; *Diabetes Mellitus, Type 2/metabolism/complications/pathology/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; Disease Models, Animal ; *Brain/metabolism/pathology ; Magnetic Resonance Spectroscopy/methods ; Humans ; Rats ; Presenilin-1/genetics/metabolism ; Rats, Transgenic ; Rats, Inbred F344 ; Pyruvate Dehydrogenase Complex/metabolism ; Male ; },
abstract = {Most researchers have long focused on linkage between type 2 diabetes (T2D) and the increased risk of Alzheimer's disease (AD) but have often overlooked whether AD modulates T2D. Investigating the reciprocal interaction between two complex diseases provides perspectives on the mechanistic linkage. The endeavor, however, confronts challenges without a robust rodent model that develops T2D and AD as the animal ages. Cross breeding a T2D rat with a hemizygous TgF344AD +/- rat that contains the mutant human amyloid precursor protein (APPsw) and the presenilin 1 (PS1ΔE9) genes has produced a new T2D-AD +/- rat model. The T2D-AD +/- rat expresses both the T2D and AD phenotypes as the animal ages. As AD progresses, the time to T2D onset decreases, and the diabetes severity increases. Hyperpolarized NMR experiments using dynamic nuclear polarization (DNP) show that T2D and T2D-AD rats share a common metabolic impairment in the brain pyruvate dehydrogenase (PDH) activity as reflected in the NMR determined decline in the bicarbonate/lactate (bic/lac) ratio. The bic/lac ratio decreases in both T2D and T2D-AD brain. AD exacerbates the decline of the bic/lac ratio.},
}

Animals
*Alzheimer Disease/metabolism/complications/genetics/pathology
*Diabetes Mellitus, Type 2/metabolism/complications/pathology/genetics
Amyloid beta-Protein Precursor/genetics/metabolism
Disease Models, Animal
*Brain/metabolism/pathology
Magnetic Resonance Spectroscopy/methods
Humans
Rats
Presenilin-1/genetics/metabolism
Rats, Transgenic
Rats, Inbred F344
Pyruvate Dehydrogenase Complex/metabolism
Male

@article {pmid42714783,
year = {2026},
author = {Verma, E and Mishra, S and Chellammal, HSJ and Khandige, PS and Gasmi, A},
title = {Gut microbiota as a modulator of HDAC: insights into Alzheimer's disease treatment.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {42714783},
issn = {2299-5684},
abstract = {The human gut microbiota (GMB) has a significant impact on physiological function, including gastrointestinal health, immune regulation, and redox homeostasis. It consists of diverse microorganisms that support digestion, nutrient absorption, and intestinal barrier function. Emerging evidence suggests that gut microbiota-derived metabolites may influence the gut-brain axis and regulate epigenetic mechanisms through modulation of histone deacetylases (HDAC). HDAC are key enzymes involved in gene expression, neuronal survival, neuroinflammation, and the pathogenesis of Alzheimer's disease (AD). Gut microbiota-derived metabolites have been reported to modulate HDAC activity and may contribute to neuroprotective and anti-inflammatory effects. Through these mechanisms, the GMB may influence cognitive function and the progression of AD. However, the precise molecular mechanisms involved in these interactions are not yet fully understood and continue to be extensively investigated. Therefore, this review focuses on the correlation between HDAC and the restoration of a healthy GMB as a therapeutic approach for the treatment and prevention of AD. It emphasizes the role of gut-derived metabolites, peptides, and dietary bioactive compounds in regulating HDAC-mediated epigenetic pathways. These interactions may influence gene expression, neurotransmitter biosynthesis, neuroinflammation, and neuroprotective signalling associated with cognitive function. Furthermore, the review delineates the bidirectional interplay among neurotransmitter signalling, GMB composition, and HDAC-mediated epigenetic regulation, along with their potential roles in the pathophysiology of neurodegenerative disorders.},
}

@article {pmid42607706,
year = {2026},
author = {Lyu, Z and Song, Z and Fu, S and Yu, H and Guo, X},
title = {An explicit functional-map framework for structure-function correspondence in brain connectivity.},
journal = {Journal of neural engineering},
volume = {23},
number = {5},
pages = {},
doi = {10.1088/1741-2552/ae9acb},
pmid = {42607706},
issn = {1741-2552},
mesh = {Humans ; *Brain/physiology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Nerve Net/physiology/diagnostic imaging ; *Brain Mapping/methods ; Female ; Male ; *Connectome/methods ; },
abstract = {Objective. Characterizing the relationship between structural connectivity (SC) and functional connectivity (FC) is a central problem in multimodal neuroimaging. SC-to-FC prediction accuracy is often used to summarize this relationship, but a high score may largely reflect population-level regularities shared across subjects and does not reveal whether regional, network-level, or subject-specific correspondence is preserved. We therefore developed a framework that makes these different levels of SC-FC correspondence explicit and directly testable.Approach.For each subject, we constructed separate spectral representations of SC and FC and estimated an explicit linear map between them. Signal transfer was evaluated against matched controls that disrupted node identity, within-network organization, or subject pairing, allowing aggregate transfer to be distinguished from more specific forms of correspondence. A training-derived reference map was further used to define the functional component expected under a reference SC-FC relationship and the deviation from that expectation for downstream aging and disease-related analyses.Main results.Across four independent datasets, all primary matched-control gaps were positive after false-discovery-rate correction, although their magnitudes varied across cohorts. Strong aggregate transfer did not necessarily imply strong subject-level correspondence. Compared with external baselines, the proposed framework more consistently preserved regional identity, within-network organization, and correct subject pairing. In aging analyses, reduced alignment with a young-reference SC-FC relationship was robust in CamCAN but not significant in NKI, whereas empirical FC magnitude showed no comparable decline. In Alzheimer's Disease Neuroimaging Initiative, reference-conditioned markers showed exploratory disease-related signals, but the associated uncertainty did not support definitive diagnostic or incremental-value claims.Significance.The proposed framework separates the ability to transfer SC-derived signals into FC space from the specificity of the correspondence being preserved. It provides an interpretable basis for testing population-level, network-level, and subject-sensitive SC-FC relationships and for constructing reference-conditioned individual deviation measures without treating prediction accuracy as direct evidence of biological constraint.},
}

Humans
*Brain/physiology/diagnostic imaging
*Magnetic Resonance Imaging/methods
*Nerve Net/physiology/diagnostic imaging
*Brain Mapping/methods
Female
Male
*Connectome/methods

@article {pmid42702638,
year = {2026},
author = {Sfikas, E and Constantinides, V and Koros, C and Smaragdaki, E and Angelopoulou, G and Toulas, P and Stefanis, L and Papageorgiou, S},
title = {Intersecting pathologies in atypical Alzheimer's disease: a case of logopenic PPA with cerebral amyloid angiopathy.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42702638},
issn = {1590-3478},
}

@article {pmid42702643,
year = {2026},
author = {Bergner, A and Musaeus, CS and Simonsen, AH and Munch, TN and Carlsen, JF and Hasselbalch, SG},
title = {Association between p-tau181 in cerebrospinal fluid and shunt response in patients with normal-pressure hydrocephalus.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42702643},
issn = {1590-3478},
mesh = {Humans ; *Hydrocephalus, Normal Pressure/cerebrospinal fluid/surgery ; *tau Proteins/cerebrospinal fluid ; Female ; Male ; Retrospective Studies ; Biomarkers/cerebrospinal fluid ; Aged ; *Cerebrospinal Fluid Shunts ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Phosphorylation ; Peptide Fragments/cerebrospinal fluid ; Treatment Outcome ; },
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a treatable condition, but predicting shunt response remains challenging. Cerebrospinal fluid (CSF) biomarkers, including phosphorylated tau (p-tau181), have been suggested as potential predictors, although existing evidence is inconsistent.

METHODS: In this retrospective single-center study, we included 230 patients with probable or possible iNPH who underwent shunt surgery and had available CSF biomarker data for Amyloid beta42, total tau and phosphorylated tau 181. Patients were divided into two cohorts based on assay method (Innotest[®] and Elecsys[®]). The primary outcome was improvement in gait score. Secondary outcomes included cognition, continence, and overall clinical response. Predictive performance of CSF p-tau181 was evaluated using logistic regression and receiver operating characteristic (ROC) analyses.

RESULTS: Mean CSF p-tau181 levels did not differ significantly between responders and non-responders in either cohort. In multivariable logistic regression analyses adjusted for age and sex, CSF p-tau181 was not associated with shunt response (Innotest[®]: OR 0.997 (0.972-1.024), p = 0.815; Elecsys[®]: OR 1.091 (0.910-1.419), p = 0.429). Findings were consistent across two CSF p-tau181 assay platforms, although the Elecsys[®] cohort was underpowered for calculating AUC with only 14 non-responders. Similar results were observed across secondary outcomes and after exclusion of patients with high CSF p-tau181 levels to reduce potential confounding by concomitant Alzheimer's disease pathology.

CONCLUSION: CSF p-tau181 does not demonstrate clinically meaningful predictive value for shunt response in patients with iNPH and cannot alone guide patient selection for shunt surgery. Future research should focus on multimodal approaches integrating clinical, radiological, and biochemical markers.},
}

Humans
*Hydrocephalus, Normal Pressure/cerebrospinal fluid/surgery
*tau Proteins/cerebrospinal fluid
Female
Male
Retrospective Studies
Biomarkers/cerebrospinal fluid
Aged
*Cerebrospinal Fluid Shunts
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Phosphorylation
Peptide Fragments/cerebrospinal fluid
Treatment Outcome

@article {pmid42702666,
year = {2026},
author = {Elgenidi, A and Shir, D and Piura, YD and Sokol, LL and Duara, R and Lachner, C and Day, GS},
title = {Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42702666},
issn = {1432-1459},
support = {K23AG064029/AG/NIA NIH HHS/United States ; R01AG089380/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; Diagnosis, Differential ; *Prion Diseases/diagnosis/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; },
abstract = {BACKGROUND: Prion disease and Alzheimer disease (AD) are common causes of rapidly progressive dementia (RPD). Although most patients with prion disease are distinguished by MRI and CSF findings, selected cases mimic rapidly progressive AD. We characterized AD-prion disease mimics within a prospective cohort and the extant literature to identify the clinical features and tests that support accurate diagnoses in these patients.

METHODS: Patients with prion disease initially diagnosed as rapidly progressive AD were identified from a prospective cohort study at Mayo Clinic (February 2020-June 2026) and through systematic review of MEDLINE and Embase.

RESULTS: Of 204 patients with RPD, five (2.5%) were initially diagnosed with clinically probable AD but ultimately determined to have prion disease. Systematic review identified 10 additional cases (n=15, median age-at-onset, 59 years; 67% male). Presentations reproduced amnestic (53%), dysexecutive (27%), primary progressive aphasia (13%), and posterior cortical atrophy (7%) AD phenotypes; median time from AD diagnosis to consideration of prion disease was 2 months. Diffusion-weighted MRI abnormalities were absent in Mayo Clinic cases and absent/equivocal (n=2) or overlooked (n=8) in published cases. CSF biomarkers were consistent with AD in 6/9 tested patients, with elevated total tau levels in 11/13 patients and total-tau/p hosphorylated-tau181 ratios in 5/9 patients. Real-time quaking-induced conversion assays for prions were positive in the CSF of 9/12 patients. Prion disease was confirmed by neuropathology (n=7), genetics (n=2), or real-time quaking-induced conversion (n=6) assays.

CONCLUSIONS: Prion disease may rarely mimic rapidly progressive AD. Disproportionate elevations in CSF total-tau levels or total-tau/p hosphorylated-tau181 ratios should prompt consideration of prion disease.},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid
Diagnosis, Differential
*Prion Diseases/diagnosis/cerebrospinal fluid
Female
Male
Middle Aged
Aged
Disease Progression
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid

@article {pmid42702948,
year = {2026},
author = {Zang, W and Vithoulkas, J and Zuo, Z},
title = {Surgery Is Not Associated With Early Presentation of Alzheimer's Disease and Mild Cognitive Impairment or Increased Risk for Both.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71149},
pmid = {42702948},
issn = {1755-5949},
support = {Robert M. Epstein Professorship Endowment//School of Medicine, University of Virginia/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis/surgery ; *Cognitive Dysfunction/epidemiology/diagnosis/surgery ; Female ; Aged ; Male ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; Cohort Studies ; Risk Factors ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in elderly patients. Mild cognitive impairment (MCI) may be a prodromal status of AD. Previous studies show inconsistent findings on whether surgery increases MCI and AD incidence. Moreover, it remains unknown whether surgery expedites the development of MCI or AD.

METHODS: This was a retrospective propensity score-matched cohort study using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database between September 2005 (ADNI initiation time) and May 2025 (time of data downloaded). Two outcomes were assessed: age at first diagnosis of MCI or AD, and incidence of MCI or AD. Nearest-neighbor matching was used to balance demographic and comorbidity covariates.

RESULTS: The study was composed of 1114 subjects with MCI, 760 subjects with AD, and 397 subjects with normal cognition. Surgery was not associated with a decrease in the age of patients when MCI was diagnosed but was associated with a delayed presentation of AD by 1.7 years. Surgery performed on patients younger than 60 years was associated with a decrease in age when the first diagnosis of MCI or AD was made. Surgery at an age older than 60 years was associated with an increase in the age at MCI or AD diagnosis (mean difference: 5.1 and 5.6 years, respectively). Surgery was not associated with a change in the incidence of MCI or AD.

CONCLUSION: Surgery may be associated with delayed presentation of AD or MCI, except for the surgery performed in patients younger than 60 years. Surgery may not affect the incidence of MCI or AD. These findings do not support deferring clinically indicated surgery for the concern of development of MCI or AD.},
}

Humans
*Alzheimer Disease/epidemiology/diagnosis/surgery
*Cognitive Dysfunction/epidemiology/diagnosis/surgery
Female
Aged
Male
Retrospective Studies
Middle Aged
Aged, 80 and over
Cohort Studies
Risk Factors

@article {pmid42702949,
year = {2026},
author = {Moro, V and Vianello, G and Gambina, G and Gobbetto, V and Gasparini, M and Beccherle, M},
title = {The clinical implications of anosognosia in Alzheimer's disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2726416},
pmid = {42702949},
issn = {1744-8360},
abstract = {INTRODUCTION: Assessing awareness of patients with Alzheimer's disease (AD) is essential for diagnosis and treatment. Anosognosia, defined as impaired awareness of cognitive and functional deficits, is associated with poorer prognosis, reduced decision-making capacity, increased risk of accidents, and earlier institutionalization.

AREAS COVERED: This narrative review examines 53 studies. After outlining the main theoretical models of awareness in dementia, the multidimensional nature of anosognosia and its impact on patients' autonomy and decision-making abilities are discussed. This review also describes the main instruments available for assessing awareness deficits and highlights their relevance in clinical practice. Particular attention is given to the implications of anosognosia for treatment adherence, patient care, and decision making.

EXPERT OPINION: Taking care of unaware AD patients represents a challenge, and anosognosia is often underestimated in clinical practice. Evidence suggests that awareness deficits may emerge even in the earliest stages of AD, affecting patients' autonomy and capacity to make informed decisions. A two-step assessment process is recommended, consisting of an initial screening followed by a comprehensive evaluation carried out by specialized neuropsychologists. Targeted caregiver training is also essential to address the challenges associated with impaired awareness.},
}

@article {pmid42702988,
year = {2026},
author = {Singh, S and Naithani, D and Raj, G and Narang, J},
title = {High-Performance Screen-Printed OECT-Inspired with Encased Cassette Based on PEDOT:GO for Sensitive and Specific Electrochemical Aptasensing of Aβ-42 in Management of Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {9},
number = {17},
pages = {7945-7960},
doi = {10.1021/acsabm.6c00105},
pmid = {42702988},
issn = {2576-6422},
mesh = {*Amyloid beta-Peptides/analysis ; *Alzheimer Disease/diagnosis ; Humans ; *Biosensing Techniques/methods ; *Electrochemical Techniques ; *Polymers/chemistry ; *Peptide Fragments/analysis ; *Bridged Bicyclo Compounds, Heterocyclic/chemistry ; *Graphite/chemistry ; *Biocompatible Materials/chemistry/chemical synthesis ; Materials Testing ; Particle Size ; *Aptamers, Nucleotide/chemistry ; },
abstract = {Recently, substantial interest has emerged in developing point-of-care diagnostic devices for Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aβ1-42) peptides that act as critical biomarkers for early detection. In response to the growing demand for noninvasive and accessible diagnostic tools, this study presents a highly sensitive organic electrochemical transistor-inspired biosensor for the detection of Aβ-42 in saliva. The device is based on a paper substrate modified with a PEDOT:GO composite and a Ag-Au nanocomposite, which together enhance electrical conductivity and improve the electrochemical response. A highly selective Aβ1-42-binding aptamer is immobilized on the sensor surface. This platform enables real-time signal amplification, allowing the detection of Aβ-42 over a dynamic range of 1 pg/mL to 10 μg/mL. This biosensor demonstrates excellent sensitivity, selectivity, and reproducibility, making it a potential tool for noninvasive, point-of-care detection. The use of artificial saliva as a diagnostic medium further enhances its applicability for early screening, especially in decentralized or resource-limited healthcare environments.},
}

*Amyloid beta-Peptides/analysis
*Alzheimer Disease/diagnosis
Humans
*Biosensing Techniques/methods
*Electrochemical Techniques
*Polymers/chemistry
*Peptide Fragments/analysis
*Bridged Bicyclo Compounds, Heterocyclic/chemistry
*Graphite/chemistry
*Biocompatible Materials/chemistry/chemical synthesis
Materials Testing
Particle Size
*Aptamers, Nucleotide/chemistry

@article {pmid42703295,
year = {2026},
author = {Zhao, J and Li, X and Wu, M and Zhang, Z},
title = {Physical inactivity in preclinical Alzheimer's disease: Risk factor, early symptom, or both?.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70316},
pmid = {42703295},
issn = {2352-8737},
abstract = {Physical inactivity is a key modifiable risk factor for Alzheimer's disease (AD). However, emerging evidence suggests a bidirectional relationship where inactivity also serves as an early manifestation of AD pathology. This perspective synthesizes recent findings from long-term epidemiological cohorts, brainstem neuropathology, and digital phenotyping to reconceptualize the role of inactivity in preclinical AD. Early tau accumulation in catecholaminergic nuclei (locus coeruleus and ventral tegmental area) disrupts circuits essential for reward valuation and effort calculation. We hypothesize that this neurobiological failure may manifest as prodromal apathy and declining physical activity years before cognitive impairment. Standard metrics like step counts fail to capture these nuances. We propose a multidimensional digital phenotype - incorporating temporal complexity, circadian rhythms, and life-space mobility - to distinguish "behavioral" from "biologically constrained" inactivity. This framework has critical implications for trial enrichment and the design of personalized lifestyle interventions.},
}

@article {pmid42703487,
year = {2026},
author = {Boşgelmez, Iİ and Mertaş, B and Deliser, H},
title = {Exposome influences: a multi-omics perspective on the combined toxic effects of pharmaceuticals and personal care products in Alzheimer's disease.},
journal = {Frontiers in toxicology},
volume = {8},
number = {},
pages = {1871830},
pmid = {42703487},
issn = {2673-3080},
abstract = {According to WHO data, approximately 57 million people worldwide were affected by dementia in 2021, with prevalence projected to rise. Alzheimer's disease (AD), responsible for 60%-80% of dementia cases, continues to be a leading cause of mortality, with current treatments offering limited efficacy and disease-modifying therapies lacking widespread adoption or conclusive safety evidence, shifting the focus toward prevention and risk modification. Risk factors for AD include both non-modifiable elements, such as age, genetics, and gender, and modifiable factors, like environmental pollution, health status, and diet. While age remains the primary non-modifiable risk factor, early-onset dementia represents only up to 9% of cases. Addressing modifiable factors is essential, as it could prevent or delay almost half of dementia cases, with interventions-such as increased physical activity, smoking cessation, alcohol limitation, and overall health management-being significantly associated with a reduced risk. In this context, the exposome approach offers a comprehensive, integrative framework in which both modifiable and non-modifiable risk factors interact to influence individual susceptibility. Within the neural exposome, chronic low-dose exposure to xenobiotics-such as industrial chemicals, pesticides, metals, pharmaceuticals and personal care products (PPCPs), and air pollutants-may induce neurodegeneration via mechanisms including oxidative stress, neuroinflammation, proteinopathies, and epigenetic modifications, although establishing causality remains challenging. Integration of genomics, transcriptomics, proteomics, metabolomics, and lipidomics, combined with artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL), provides promising avenues for biomarker discovery, enhanced preventive strategies, early non-invasive diagnosis, and therapeutic target identification by integrating multi-layered biological data with exposure profiles. This review highlights emerging AD risk factors-including PPCPs-underscoring complex, multifactorial nature of AD and exposome, and the requirement for an interdisciplinary research approach, while also addressing several critical research gaps and methodological limitations.},
}

@article {pmid42704084,
year = {2026},
author = {Sassi, KLM and Thomson, A and Young, VM and Rocha, NP and Teixeira, AL},
title = {Mild behavioral impairment and risk of incident dementia: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480315},
doi = {10.1177/13872877261480315},
pmid = {42704084},
issn = {1875-8908},
abstract = {BackgroundLate-life emergence of persistent behavioral changes has been recognized as a clinically meaningful sign of neurodegeneration. These neuropsychiatric symptoms, operationalized as mild behavioral impairment (MBI), represent a unique pathway through which early dementia symptoms may become observable. By capturing this neurobehavioral dimension of risk, MBI expands the traditional focus on cognitive decline and may provide a complementary framework for understanding the early manifestations of neurodegeneration.ObjectiveThis systematic review evaluated longitudinal evidence on the association between MBI and incident dementia, including conversion rates, dementia subtypes, domain-specific risk patterns, and biomarker correlates.MethodsWe systematically searched five databases up to November 2025. Eligible studies were longitudinal prospective or retrospective cohorts including adults ≥ 50 years without dementia at baseline, assessing MBI using ISTAART-aligned instruments and reporting incident dementia outcomes. Two reviewers independently screened studies and extracted data. Hazard ratios were synthesized using random-effects meta-analysis, with heterogeneity and publication bias formally assessed.ResultsDespite significant study heterogeneity, MBI was associated with increased risk of incident dementia. Alzheimer's disease was the most frequently reported outcome. Among different neurobehavioral domains, apathy and affective dysregulation emerged as particularly strong predictors of dementia risk. A few biomarker studies linked MBI to greater amyloid burden, elevated plasma phosphorylated tau, and structural brain changes, supporting a biological connection between MBI and early neurodegeneration.ConclusionsMBI seems to represent a clinically meaningful syndrome that identifies individuals at elevated risk for dementia. Future studies must confirm the clinical and epidemiological value of MBI and/or its subdomains, exploring their biological substrates.},
}

@article {pmid42704086,
year = {2026},
author = {Jung, HE and Heo, SJ and Lee, YJ and Han, TH and Kwon, YJ and Lee, JW},
title = {Association between oxidative balance score and cardiovascular risk factors, aging, and incidence of dementia risk score: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485588},
doi = {10.1177/13872877261485588},
pmid = {42704086},
issn = {1875-8908},
abstract = {BackgroundOxidative stress is a key contributor to the pathogenesis of Alzheimer's disease and other dementias. The oxidative balance score (OBS), which reflects combined dietary and lifestyle exposure to pro-oxidant and antioxidant factors, serves as an integrated measure of oxidative stress burden.ObjectiveTo investigate the association between OBS and predicted late-life dementia risk using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score.MethodsWe analyzed data from 5088 participants aged 40-69 years without dementia at baseline from the Korean Genome and Epidemiology Study. Participants were categorized by OBS tertiles. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for developing a high risk of late-life dementia, defined by a CAIDE score ≥8. Longitudinal changes in CAIDE scores were assessed using linear mixed-effects models.ResultsDuring a mean follow-up of 12.8 years, 1468 participants (28.9%) progressed to CAIDE-predicted high risk for late-life dementia. Compared with the lowest OBS tertile (T1), participants in the highest tertile (T3) had a significantly lower risk for developing high-risk late-life dementia (HR 0.74, 95% CI 0.65-0.84) and exhibited the lowest CAIDE scores (p < 0.001). Each one-point increase in the OBS was associated with a 3% reduction in CAIDE-predicted dementia risk.ConclusionsA higher OBS was significantly associated with a lower predicted risk of late-life dementia. These findings suggest that maintaining an antioxidant-rich diet and a healthy lifestyle during midlife may be effective strategies for dementia prevention.},
}

@article {pmid42704090,
year = {2026},
author = {Fu, X and Cui, M and Yue, A and He, Q and Nan, H and Ye, H and Rosa-Neto, P and Wu, L and Nie, B and Chu, M},
title = {Disease-specific hypometabolic epicenters in dementia: Neural networks and clinical correlations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481091},
doi = {10.1177/13872877261481091},
pmid = {42704090},
issn = {1875-8908},
abstract = {BackgroundIn dementia, it remains unclear how the hypometabolism pattern relates to the intrinsic network, where the disease-specific hypometabolism epicenters are located, and what the epicenter's clinical effects are.ObjectiveIn this cross-sectional study, we aim to identify disease-specific hypometabolism epicenters in Alzheimer's disease (AD), posterior cortical atrophy (PCA), and frontotemporal dementia (FTD) using a data-driven network-based approach; to determine whether intrinsic structural and functional brain networks shape the spatial distribution of hypometabolism; and to examine the clinical relevance of epicenter hypometabolism by assessing its association with network disruption and disease-related clinical features.MethodsDisease-specific epicenters were identified using data-driven analysis in AD (n = 98), PCA (n = 40), and FTD (n = 71). Hypometabolism was measured by [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET). Brain regions with reduced network connectivity to the epicenter were identified, and the correlation between changes in the epicenter and clinical features was examined.ResultsRegional hypometabolism was significantly correlated with that of the network-connected neighbors. The disease-specific hypometabolism epicenters were the bilateral angular gyrus in AD, the angular and middle occipital gyri in PCA, and the rectus and anterior cingulate gyri in FTD. The hypometabolism of the epicenters contributed to the disruption of the network and was correlated with clinical features.ConclusionsThe hypometabolism epicenters are disease-specific and correlated with clinical features in dementia, providing insight into neuromodulation targets.},
}

@article {pmid42704398,
year = {2026},
author = {Zhu, Z and Jiang, X and Huang, R and Guo, X and Wang, Y and Liu, T and Wang, J and Huang, J and Huang, W and Zhang, D and Li, Q and Chen, S and Yang, Z and Liu, Q and Wei, Z},
title = {Deferiprone Modulates Ferroptosis to Protect Macrophages and Liver during Neospora caninum Infection.},
journal = {Acta parasitologica},
volume = {71},
number = {5},
pages = {},
pmid = {42704398},
issn = {1896-1851},
support = {32002309//the National Natural Science Foundation of China/ ; 2022A1515010960//Guangdong Basic and Applied Basic Research Foundation/ ; NJTG20240253//Guangdong Provincial Department of Agriculture and Rural Affairs - Guangdong Agricultural Technical Service "Light Cavalry" Project 2024/ ; SWU-KQ24021//Central University Basic Scientific Research Program of Southwest University/ ; },
mesh = {Animals ; *Ferroptosis/drug effects ; *Neospora/drug effects/physiology ; *Deferiprone/pharmacology/administration & dosage ; *Coccidiosis/drug therapy/parasitology ; *Liver/parasitology/drug effects ; Mice ; *Macrophages/drug effects/parasitology ; Mice, Inbred C57BL ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Female ; },
abstract = {BACKGROUND: Neospora caninum (N. caninum), an obligate intracellular apicomplexan parasite, infects nucleated cells across diverse mammalian hosts, resulting in severe clinical outcomes, including reproductive failure (abortion, stillbirth) and neurological impairment. Ferroptosis, an iron-dependent, non-apoptotic cell death pathway characterized by excessive lipid peroxidation, is closely associated with disrupted iron metabolism and oxidative stress. Deferiprone (DFP), a clinically approved iron chelator, is widely used in the treatment of iron overload disorders such as β-thalassemia, Alzheimer's disease, and superficial hemosiderosis. While ferroptosis has been implicated in various disease states, its role in N. caninum infection remains unknown.

METHODS: This study established in vitro and in vivo infection models to investigate the role of ferroptosis in N. caninum pathogenesis and the protective mechanism of DFP. In vitro, RAW 264.7 were infected with N. caninum and treated with DFP, followed by comprehensive assessment of reactive oxygen species (ROS), glutathione (GSH) levels, intracellular iron content, GPX4 expression, and parasite proliferation via qPCR. In vivo, C57BL/6 mice were intraperitoneally inoculated with 1 × 10[^7] tachyzoites and orally administered DFP for seven days. Body weight, food intake, hepatic pathology, oxidative stress markers (GSH and MDA), iron levels, and ferroptosis-related gene expression (GPX4, FTH1, and TRF) were monitored.

RESULTS: Our in vitro findings demonstrated that N. caninum infection significantly elevated ROS production and intracellular iron accumulation while depleting GSH and suppressing GPX4 transcription-hallmarks of ferroptosis. Remarkably, DFP treatment reversed these effects, restoring redox balance and protecting host tissue, not host control of infection. In vivo, DFP alleviated N. caninum-induced hepatic ferroptosis, as evidenced by normalized iron homeostasis, upregulated GPX4 and ferritin expression, and reduced histopathological damage. However, DFP exacerbated weight loss, suggesting a potential trade-off between ferroptosis inhibition and metabolic adaptation.

CONCLUSIONS: In summary, these results establish ferroptosis as a critical pathogenic mechanism in N. caninum infection and highlight DFP's dual role in mitigating oxidative injury while possibly impairing host metabolic responses. Our findings provide novel insights into iron-targeted therapeutic strategies for combating intracellular parasitic infections, paving the way for future investigations into optimizing host-directed antiparasitic interventions.},
}

Animals
*Ferroptosis/drug effects
*Neospora/drug effects/physiology
*Deferiprone/pharmacology/administration & dosage
*Coccidiosis/drug therapy/parasitology
*Liver/parasitology/drug effects
Mice
*Macrophages/drug effects/parasitology
Mice, Inbred C57BL
Iron/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Female

@article {pmid42704497,
year = {2026},
author = {Tudella, GCN and Klostermann, AU and Menegucci, G and Fernandes, JVA and Pacheco, JPG},
title = {Efficacy and safety of cannabinoid-based interventions for behavioral and cognitive symptoms in dementia: systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42704497},
issn = {1590-3478},
mesh = {Humans ; *Cannabinoids/therapeutic use/adverse effects ; *Dementia/drug therapy/complications ; *Psychomotor Agitation/drug therapy ; },
abstract = {BACKGROUND: Behavioral and cognitive symptoms are frequent in Alzheimer's disease and dementia, and available pharmacological options offer limited benefit. Cannabinoid-based therapies have been proposed as alternatives, but evidence remains inconclusive.

METHODS: We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library through November 2025 for randomized controlled trials evaluating cannabinoids in Alzheimer's disease or dementia. Primary outcomes were agitation measured by the Cohen-Mansfield Agitation Inventory (CMAI) and neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory-Nursing Home version (NPI-NH). Secondary outcomes included cognition using the Mini-Mental State Examination (MMSE) and adverse events. Standardized Mean Differences (SMDs) and Risk Ratios (RRs) were synthesized using random-effects (REML) and Bayesian random-effects models. Risk of bias was evaluated with RoB 2, and certainty of evidence with GRADE.

RESULTS: Nine trials (334 participants) met inclusion criteria. Cannabinoids did not improve CMAI (SMD -0.58, 95% CI -1.71 to 0.55; I2 = 84%), NPI-NH total (SMD -0.02, 95% CI -1.00 to 0.96; I2 = 67%), NPI-NH agitation (SMD -0.44, 95% CI -1.45 to 0.57; I2 = 48%), or MMSE (SMD 0.86, 95% CI -16.33 to 18.06; I2 = 96%). Bayesian posterior estimates were close to zero, supporting the absence of effect. Leave-one-out analyses reduced heterogeneity only after excluding influential trials but did not alter results. Certainty of evidence was moderate for behavioral outcomes and low for cognition. Overall adverse events were similar to placebo, while somnolence was more frequent with cannabinoids (RR 2.03, 95% CI 1.29-3.20).

CONCLUSIONS: Cannabinoid-based therapies do not improve agitation, neuropsychiatric symptoms, or cognition in Alzheimer's disease and increase somnolence.},
}

Humans
*Cannabinoids/therapeutic use/adverse effects
*Dementia/drug therapy/complications
*Psychomotor Agitation/drug therapy

@article {pmid42704522,
year = {2026},
author = {Joshi, A and Salunkhe, J and Ugale, V},
title = {UPS-mediated P-glycoprotein regulation in Alzheimer's disease: pharmacological implications for the amyloid pathology.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42704522},
issn = {1573-4978},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Blood-Brain Barrier/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Animals ; Oxidative Stress ; Ubiquitination ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid β (Aβ), tau pathology, neuroinflammation, oxidative stress, and neurovascular dysfunction. Growing evidence suggests that impaired clearance of Aβ across the blood-brain barrier (BBB), rather than overproduction alone, is a key factor driving progression of AD. P-glycoprotein (P-gp) plays a crucial role in Aβ removal and is consistently reduced in AD. This review focuses on the mechanisms underlying P-gp dysfunction, particularly its regulation by the ubiquitin-proteasome system. Herein, we have discussed multiple factors associated with the AD, such as Aβ, oxidative stress, and inflammatory signaling, contributing to the phosphorylation, ubiquitination, internalization, and degradation of P-gp. These processes result in impaired transporter function and a compromised integrity of the BBB. The review further examines experimental and clinical evidence linking altered P-gp turnover with defective Aβ clearance in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Amyloid beta-Peptides/metabolism
*ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
Blood-Brain Barrier/metabolism
*Proteasome Endopeptidase Complex/metabolism
Ubiquitin/metabolism
Animals
Oxidative Stress
Ubiquitination

@article {pmid42704561,
year = {2026},
author = {Huang, T and Hao, Z and Shen, J and Lai, T and Wu, Y and Zhu, X and Wu, H and Bao, C},
title = {Microbiota-Gut-Brain Axis Mechanisms in Cognitive Impairment Associated with Central Obesity.},
journal = {Current obesity reports},
volume = {15},
number = {1},
pages = {},
pmid = {42704561},
issn = {2162-4968},
support = {No. 202310268066//Shanghai College Students Innovation and Entrepreneurship Training Program Project/ ; No. SHUTCM2023010//the 16th Batch of Science and Technology Innovation Projects of Shanghai University of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Obesity, Abdominal/complications/microbiology/psychology/physiopathology ; *Gastrointestinal Microbiome/physiology ; *Cognitive Dysfunction/etiology/microbiology/physiopathology ; *Brain/physiopathology ; Intra-Abdominal Fat ; Risk Factors ; Dysbiosis ; *Brain-Gut Axis ; Animals ; },
abstract = {PURPOSE OF REVIEW: Central obesity (CO), characterized by excessive visceral adipose tissue (VAT) accumulation, is increasingly recognized as a risk factor for cognitive decline, dementia, and Alzheimer's disease (AD). This review summarizes current evidence linking CO, particularly VAT accumulation, to cognitive impairment and discusses the microbiota-gut-brain axis as a mechanistic framework for interpreting this association.

RECENT FINDINGS: Studies published in recent years suggest that VAT-related indices, such as waist circumference, waist-to-hip ratio, and imaging-derived VAT measures, are more closely associated with cognitive dysfunction than body mass index. Recent neuroimaging studies have linked VAT accumulation with brain atrophy, white matter abnormalities, altered functional connectivity, and increased AD-related pathological burden. Emerging multi-omics evidence further indicates that VAT expansion shows an association with gut microbial dysbiosis, altered microbial metabolites, impaired intestinal barrier function, systemic low-grade inflammation, insulin resistance, and neuroendocrine disturbances. These findings support a model in which VAT-related metabolic and inflammatory alterations may influence brain structure and function through microbiota-mediated, immune, endocrine, and barrier-related pathways. Current evidence is consistent with a VAT-centered model in which CO is associated with cognitive impairment through interconnected inflammatory, metabolic, endocrine, and microbiota-mediated mechanisms. The microbiota-gut-brain axis may provide a useful mechanistic framework linking peripheral metabolic dysfunction with AD vulnerability. Future longitudinal cohort studies and mechanistically informed intervention studies are needed to clarify temporal relationships and to determine whether VAT reduction or microbiota-targeted strategies can improve cognitive or neuroimaging outcomes.},
}

Humans
*Obesity, Abdominal/complications/microbiology/psychology/physiopathology
*Gastrointestinal Microbiome/physiology
*Cognitive Dysfunction/etiology/microbiology/physiopathology
*Brain/physiopathology
Intra-Abdominal Fat
Risk Factors
Dysbiosis
*Brain-Gut Axis
Animals

@article {pmid42704803,
year = {2026},
author = {Yang, L and Cui, X and Li, T and Zhang, X and Chang, R and Lu, J and Li, D and Wang, B},
title = {NDIB-Sim: A Multimodal Bidirectional PINN Model for Simulating Brain Dynamics.},
journal = {IEEE transactions on neural networks and learning systems},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNNLS.2026.3728665},
pmid = {42704803},
issn = {2162-2388},
abstract = {Constructing dynamic virtual brain models is essential for understanding brain functions and pathological mechanisms, crucial in computational neuroscience. Current modeling methods can be grouped into two paradigms: deep learning models for accurate simulation, and neural dynamics models emphasizing physiological interpretability. However, these methods entail a fundamental tradeoff between accuracy and interpretability. To address this challenge, we introduce the neurodynamics-informed brain simulator (NDIB-Sim), a multimodal bidirectional physics-informed neural network (PINN) model. NDIB-Sim is a unified framework integrating a data-driven module constrained by multimodal data and a multiscale neural dynamics mechanism module, jointly optimized under a composite loss function. It contains two data loss and two physical constraint terms. This design ensures that the generated brain signals adhere to fundamental neurophysiological principles while achieving high fidelity to empirical data. We also designed a dynamic weighting strategy to adaptively balance these objectives during optimization. This framework simultaneously addresses the forward problem of predicting long-term brain activity and the inverse problem of estimating individual-specific neurophysiological parameters. Extensive experiments demonstrate that NDIB-Sim can achieve high-fidelity long-term brain activity prediction from short-term observations, with an average functional connectivity similarity above 0.97. The inferred effective connectivity (EC) shows excellent reliability and strong alignment with underlying structural and functional architecture. When applied to Alzheimer's disease (AD) classification, these subject-specific parameters achieve high accuracy in distinguishing cognitively normal (CN) individuals from AD patients. This work presents a powerful computational framework that effectively reconciles mechanistic interpretability with data-driven performance, offering a novel approach for exploring brain dynamics and identifying potential disease biomarkers.},
}

@article {pmid42705087,
year = {2026},
author = {Kong, X and Jiang, H and Hu, B and Shu, Q and Luo, X and Pan, F and Hu, J and Wang, Z},
title = {A signal-locked clamped hybridization chain reaction nanoamplifier for rapid and highly sensitive analysis of Aβ42.},
journal = {Talanta},
volume = {312},
number = {Pt C},
pages = {130596},
doi = {10.1016/j.talanta.2026.130596},
pmid = {42705087},
issn = {1873-3573},
abstract = {Amyloid-beta 42 (Aβ42) is a core biomarker associated with Alzheimer's disease (AD), but accurate quantification of low-abundance plasma Aβ42 remains challenging because of matrix interference, limited assay sensitivity, and time-consuming procedures in conventional methods. Herein, we developed an enzyme-free fluorescence biosensing platform integrating a triple-helix aptamer probe (THAP) with clamped hybridization chain reaction (cHCR), termed T-cHCR, for sensitive Aβ42 analysis. In this system, Aβ42 recognition induces controlled release of a trigger probe from the triplex-locked THAP module, which subsequently initiates a two-hairpin cHCR cascade for low-background signal amplification. Under optimized conditions, the T-cHCR assay exhibited a linear response to Aβ42 from 1 to 1000 pg/mL with a limit of detection of 1.16 pg/mL, showing an 8.1-fold lower LOD than the manufacturer-reported minimum detectable dose of the ELISA kit used in this study. The assay also displayed acceptable specificity, reproducibility, and storage stability. Preliminary analysis of clinical plasma samples showed significantly different Aβ42 levels between AD patients and age-matched healthy controls, supporting the potential of T-cHCR for further validation in plasma AD biomarker analysis. Overall, this integrated THAP-cHCR strategy provides a rapid, enzyme-free, and low-background approach for ultrasensitive plasma Aβ42 detection.},
}

@article {pmid42705121,
year = {2026},
author = {Yang, MT and Temkin-Greener, H and Cai, S},
title = {Pattern of Audio Telehealth Among Medicare Beneficiaries With Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106471},
doi = {10.1016/j.jamda.2026.106471},
pmid = {42705121},
issn = {1538-9375},
abstract = {OBJECTIVES: The Medicare telehealth expansion increased telehealth use, but the utilization patterns of audio-only telehealth remain unclear among those with Alzheimer's disease and related dementias (ADRDs). We aimed to describe 2020 to 2022 trends in audio-only telehealth utilization and provider specialty and to examine variations in utilization patterns by patient characteristics within the ADRD population.

DESIGN: Cohort study.

SETTING AND PARTICIPANTS: We identified 5,021,632 Medicare beneficiaries with a diagnosis of ADRD enrolled in Medicare fee-for-service plans between 2020 and 2022.

METHODS: Using Medicare fee-for-service claims data from 2020 to 2022, we described the modality of evaluation and management (E&M) visits. We calculated the proportion of E&M visits delivered via telehealth and audio-only and described the provider specialty. To further explore the pattern of telehealth use during the later stages of the pandemic, we used 2022 data to classify telehealth users into audio-only, supplementary, and video-only categories. We examined its association with individual race, ethnicity, socioeconomic status, and rurality using a linear probability model and a multinomial logistic regression. Average marginal effects were estimated.

RESULTS: Overall, E&M telehealth visits among beneficiaries with ADRD declined from 21% in 2020 to 8% in 2022, whereas the audio-only share remained stable at around 20%. Over half of audio-only visits were furnished by primary care providers. Among telehealth users, traditionally underserved populations were significantly more likely to rely exclusively on audio-only visits and less likely to use them as supplemental care. For example, higher adjusted probabilities of exclusive audio-only use were observed among Black individuals (+0.4 percentage points; P < .01) and rural beneficiaries (+0.8 percentage points; P < .01).

CONCLUSIONS AND IMPLICATIONS: Audio-only telehealth services were consistently used by Medicare beneficiaries with ADRD during the study period. Continued coverage for audio-only services could be a potential approach to promote digital health equity for older adults with ADRD.},
}

@article {pmid42705154,
year = {2026},
author = {Li, JN and Zhang, SW and Zhang, TH},
title = {Diagnosis-guided multimodal adversarial graph masked autoencoder network for association analysis between brain imaging and gene expression in Alzheimer's disease.},
journal = {Computer methods and programs in biomedicine},
volume = {287},
number = {},
pages = {109620},
doi = {10.1016/j.cmpb.2026.109620},
pmid = {42705154},
issn = {1872-7565},
abstract = {Identifying the associations between brain imaging and gene expression data is crucial for uncovering potential biomarkers of Alzheimer's disease (AD). Although various methods have been developed for association analysis using imaging genetics data, most rely on single nucleotide polymorphisms (SNPs) that reflect genetic variation, while overlooking gene expression data that reflect the impact of environmental factors on the progression of AD. Moreover, existing imaging-genetics association methods rely on unsupervised learning, thus fail to utilize the diagnostic information related to AD. To address these limitations, we propose a novel diagnosis-guided Multimodal Adversarial Graph Masked Autoencoder network (MAGMA), an end-to-end deep learning framework to integrate functional magnetic resonance imaging (fMRI) and gene expression data for association analysis between brain imaging and gene expression in AD. MAGMA comprises two major components: (1) a multimodal graph representation module, which is designed to extract the diagnosis-guided latent embeddings of brain fMRI and gene expression data by employing two Adversarial Graph Masked Autoencoders (AGMAs) with random feature masking, and the diagnosis information is incorporated to guide the learning of disease-relevant representations; and (2) An association analysis module, which models nonlinear relationships between brain imaging and gene expression data by nonlinearly mapping gene representations to imaging representations. To demonstrate the validity of MAGMA, we conducted experiments on Alzheimer's Disease Neuroimaging Initiative dataset and analyzed the results from diverse perspectives. Experimental results demonstrate that MAGMA can identify potential disease-related biomarkers, many of which are biologically interpretable and supported by existing AD-related studies. These findings suggest that MAGMA may offer new insights into the pathological mechanisms of AD and contribute to its early diagnosis.},
}

@article {pmid42705162,
year = {2026},
author = {Guarneri, L and Beh, C and de Campo, L and Whitten, AE and Moir, M and Hung, A and Clulow, AJ and Conn, CE and van 't Hag, L},
title = {Nanoscale localisation of memantine governs structural modulation and loading in bicontinuous cubic phase systems.},
journal = {Journal of colloid and interface science},
volume = {726},
number = {},
pages = {141405},
doi = {10.1016/j.jcis.2026.141405},
pmid = {42705162},
issn = {1095-7103},
abstract = {Memantine is a primary pharmacological treatment for moderate-to-severe Alzheimer's disease but its efficacy and brain delivery remain limited. Lipid bicontinuous cubic phases and their nanoparticle dispersions (cubosomes) offer platforms for enhancing central nervous system drug delivery, yet the rigid adamantane scaffold of memantine can destabilise lipid organisation. This study resolves how an amphiphilic, adamantane-containing drug interacts with non-lamellar lipid bilayers using monoolein-based bulk cubic mesophases and cubosomes formulated with biomimetic lipid compositions and multiple stabilisers. SAXS revealed that lipid composition primarily governed mesophase structure, while memantine induced only modest structural changes in bulk cubic phases. Following memantine incorporation, cubosomes retained cubic symmetry and colloidal stability across stabilisers, although they were more susceptible than bulk phases to additive-induced disorder, with cryo-TEM showing transitions toward less ordered, lower curvature sponge-like structures. Bulk mesophases exhibited 3-5-fold higher apparent drug retention than nanoparticle dispersions. Under excess hydration, however, even bulk phases released memantine rapidly, losing ∼65% of the drug within 24 h. SANS and molecular dynamics simulations revealed a mobile state of memantine with predominantly interfacial localisation rather than stable burial within the hydrophobic tails, providing a mechanistic explanation for its mesophase-dependent structural effects and its limited retention. These findings show that the adamantane scaffold alone is insufficient to ensure efficient incorporation into cubic phases. Localisation, accommodation, and retention are governed by the balance between hydrophobic anchoring and the hydration demands of attached functionalities, establishing a mechanistic framework for predicting the behaviour of amphiphilic adamantane-containing therapeutics in non-lamellar lipid nanocarriers.},
}

@article {pmid42705844,
year = {2026},
author = {Zhou, Q and Yang, MX and Zhang, QQ and Li, YQ and Wang, ZQ},
title = {Efficacy and Durability of Repetitive Transcranial Magnetic Stimulation on Cognitive Function in Patients With Mild-to-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70199},
doi = {10.1111/psyg.70199},
pmid = {42705844},
issn = {1479-8301},
support = {2022ZD0208506//STI 2030-Major Projects/ ; 82201628//National Natural Sciencen Foundation of China/ ; U24A20274//National Natural Sciencen Foundation of China/ ; S23042//SiChuan Province Medical Research Project Program/ ; 513//2024 Annual Specialized Research Project on Traditional Chinese Medicine of SiChuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Treatment Outcome ; Cognitive Enhancement ; Randomized Controlled Trials as Topic ; Aged ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has shown potential for improving cognitive function in Alzheimer's disease (AD), though findings remain inconsistent. This meta-analysis evaluated the efficacy and durability of rTMS in patients with mild to moderate AD and explored potential moderating factors. Randomised controlled trials (RCTs) comparing active rTMS with sham stimulation were identified through systematic searches of major databases. Effect sizes were calculated using Hedges' g, with random-effects models applied. Risk of bias was assessed using the Cochrane RoB 2 tool. Five RCTs (N = 143) were included in the primary analysis. rTMS showed a small-to-moderate improvement in MMSE scores (g = 0.41, 95% CI [0.06, 0.75], p = 0.021, I[2] = 6.5%). Excluding two studies with methodological concerns yielded a similar effect (g = 0.46), though with wider confidence intervals. Sensitivity analysis including studies with change scores confirmed the robustness of results (g = 0.48). Given the limited number of studies (k < 10), formal publication bias tests and trim-and-fill adjustment were not applied, in line with current methodological guidance. Notably, all five studies employed excitatory stimulation protocols (high-frequency rTMS or iTBS), with four of five targeting the left dorsolateral prefrontal cortex (DLPFC), suggesting that excitatory stimulation of key cognitive network hubs represents the most consistent evidence base to date. Meta-regression identified treatment duration as a significant moderator (β = -0.193, p = 0.034), suggesting shorter, more intensive protocols may be more effective. Follow-up analyses indicated a nonsignificant trend towards sustained benefits (g = 0.25), while time-trend analysis demonstrated a stable overall effect (g = 0.38). In conclusion, rTMS provides modest cognitive benefits in mild to moderate AD, with excitatory protocols targeting the left DLPFC showing the most consistent efficacy and treatment duration influencing outcomes. However, evidence remains limited, highlighting the need for larger, standardised, multi-centre trials with long-term follow-up.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Transcranial Magnetic Stimulation/methods
*Cognition/physiology
Treatment Outcome
Cognitive Enhancement
Randomized Controlled Trials as Topic
Aged

@article {pmid42705860,
year = {2026},
author = {Matsui, H and Omori, Y and Furuta, K},
title = {Improvement in Delusional Jealousy and Caregiver Distress After Switching From Oral Galantamine to a Donepezil Transdermal Patch in Alzheimer's Disease: A Case Report.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70217},
doi = {10.1111/psyg.70217},
pmid = {42705860},
issn = {1479-8301},
mesh = {Humans ; Female ; *Donepezil/administration & dosage ; *Galantamine/administration & dosage/therapeutic use ; *Alzheimer Disease/drug therapy/psychology ; *Caregivers/psychology ; Transdermal Patch ; *Cholinesterase Inhibitors/administration & dosage/therapeutic use ; Aged ; *Jealousy ; *Delusions/psychology/drug therapy ; Middle Aged ; Treatment Outcome ; Administration, Oral ; *Indans/administration & dosage ; Nootropic Agents/administration & dosage ; *Piperidines/administration & dosage ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are common and strongly associated with caregiver distress. Switching cholinesterase inhibitors (ChEIs) may be considered when NPS remain clinically problematic. Although switching ChEIs may improve NPS in some patients, published reports describing improvement in delusional jealousy after switching to a donepezil transdermal patch remain limited.

CASE PRESENTATION: We report a woman in her 60s with probable AD who developed caregiver-reported delusional jealousy and near-daily marital conflicts during oral galantamine therapy. NPS were assessed using the caregiver-rated Neuropsychiatric Inventory Questionnaire (NPI-Q) at three time points: prior to initiating galantamine (baseline symptoms were predominantly non-psychotic), immediately prior to switching and 6 months after switching. Total NPI-Q severity increased from 4 to 20 and then decreased to 11; total caregiver distress increased from 3 to 31 and then decreased to 13. After switching from oral galantamine, 16 mg/day, to a donepezil transdermal patch, 27.5 mg/day, improvements in domain-level severity were observed in the delusions domain, driven mainly by reduced caregiver-rated delusional jealousy, as well as in agitation/aggression, disinhibition and irritability/lability. Clinically, the conviction of delusional jealousy gradually diminished with a reduction in conflict frequency; at 6 months, delusional jealousy had almost completely resolved, whereas caregiver-attributed negative self-appraisals (e.g., a persistent belief that she was useless, perceived by the caregiver as delusional) persisted. No psychotropic medications were initiated or dose-adjusted from immediately prior to switching through the 6-month follow-up. Subsequently, the patient became able to attend day care services.

CONCLUSION: This case suggests that switching from oral galantamine to a donepezil transdermal patch may be associated with improvement in delusional jealousy, selected caregiver-rated NPS domains and caregiver distress in some patients, although causal inference is not possible in a single case and responses may vary.},
}

Humans
Female
*Donepezil/administration & dosage
*Galantamine/administration & dosage/therapeutic use
*Alzheimer Disease/drug therapy/psychology
*Caregivers/psychology
Transdermal Patch
*Cholinesterase Inhibitors/administration & dosage/therapeutic use
Aged
*Jealousy
*Delusions/psychology/drug therapy
Middle Aged
Treatment Outcome
Administration, Oral
*Indans/administration & dosage
Nootropic Agents/administration & dosage
*Piperidines/administration & dosage

@article {pmid42706463,
year = {2026},
author = {Hunt, JN and Kortagere, S},
title = {When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42706463},
issn = {1559-1182},
mesh = {*alpha-Synuclein/metabolism ; Humans ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are becoming increasingly prevalent in today's aging population and with significant cost to society. While these diseases were traditionally defined by distinct protein aggregates, namely, tau tangles and amyloid-β (Aβ) plaques in AD and α-synuclein (α-syn) inclusions in PD, substantial evidence reveals frequent mixed pathologies, with tau, α-syn, and Aβ aggregates coexisting in patients. This copathology complicates understanding disease mechanisms, classification, and progression, highlighting the need to examine mixed pathologies in neurodegenerative diseases to develop disease-modifying therapies. The presence of mixed proteinopathies suggests shared or converging pathological mechanisms, including synergistic aggregation, enhanced seeding capabilities, and shared protein-protein interactions. Understanding these molecular mechanisms is essential for identifying disease modifiers and refining experimental models. This review explores the pathogenic mechanisms of α-syn and tau individually, followed by exploration of their molecular interactions and potential mechanisms of coaggregation and exacerbation of pathology. By recognizing the intersection of these pathologies, further research can refine disease classifications for neurodegenerative diseases.},
}

*alpha-Synuclein/metabolism
Humans
*tau Proteins/metabolism
*Neurodegenerative Diseases/pathology/metabolism
Animals
Amyloid beta-Peptides/metabolism

@article {pmid42706500,
year = {2026},
author = {Ding, J and Miao, J and Zhang, L and Liu, Q and Zhang, Y and Li, J and Li, Y},
title = {Cognitive safety of statin use in the elderly: Evidence from a nationally representative sample.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70159},
pmid = {42706500},
issn = {1365-2796},
support = {SCYG2025-1//Sichuan Hospital Management and Development Research Center/ ; YF25-Y15//Sichuan Medical and Health Rule of Law Research Center-Chinese Society of Health Law Joint Project/ ; scsyxh202502//Hospital Pharmaceutical Research Funding Project of 'Yue·Stealth' of Sichuan Province Pharmaceutical Association/ ; 26MSZX599//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; 26MSZX601//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; CSXL-26209//Foundation of the Sichuan Research Center of Applied Psychology/ ; MZSJ202602//Mianyang Key Laboratory of Anesthesia and Neuroregulation/ ; 17PJ332//Sichuan Province Health Commission Project/ ; },
abstract = {OBJECTIVE: To systematically evaluate the association between current statin use and global cognitive impairment in US older adults and examine potential variations across treatment intensity, duration, and specific cognitive domains to guide clinical cardiometabolic management.

METHODS: This survey-weighted cross-sectional study included 3137 National Health and Nutrition Examination Survey 2011-2014 participants aged ≥60 years. Cognitive performance across Consortium to Establish a Registry for Alzheimer's Disease, animal fluency, and digit symbol substitution test (DSST) was composite-summarized to define impairment (Z-score ← 1.5 standard deviation). Survey-weighted multivariable models adjusted for sociodemographic, lifestyle, cardiometabolic, psychotropic medication, polypharmacy, and substance-use proxies, supplemented by inverse probability of treatment weighting (IPTW) and multiple imputation.

RESULTS: In the primary fully adjusted model, current statin use was not associated with global cognitive impairment (odds ratio [OR] = 0.90, 95% confidence interval: 0.48-1.67, p = 0.736). Results remained consistent across psychotropic-adjusted (OR = 0.91), IPTW (OR = 1.03), and multiply imputed models (OR = 0.86). Domain-specific analyses showed statin use was associated with lower odds of DSST impairment (OR = 0.51, p = 0.009), with no clear trend across statin intensity or duration categories.

CONCLUSION: Current statin use was not significantly associated with global cognitive impairment in older adults. Although cross-sectional observational neutrality precludes inferring long-term safety, indicated statin therapy should not be routinely withheld over cognitive concerns, with prescribing remaining firmly guided by established atherosclerotic cardiovascular disease risk guidelines.},
}

@article {pmid42706501,
year = {2026},
author = {Chai, L and Huang, Y and Ni, J and Zuo, S and Huang, J and Lin, B},
title = {A meta-refined human Alzheimer's disease-associated gene subset shows partial mouse-model pathway correspondence and limited cross-cohort machine-learning transportability.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71804},
doi = {10.1002/alz.71804},
pmid = {42706501},
issn = {1552-5279},
support = {2023J01876//Natural Science Foundation of Fujian Province/ ; 2025Y9599//Joint Funds for the Innovation of Science and Technology/ ; },
mesh = {*Alzheimer Disease/genetics ; Animals ; Humans ; Mice ; *Disease Models, Animal ; *Machine Learning ; Brain/metabolism/pathology ; Cohort Studies ; },
abstract = {INTRODUCTION: Common Alzheimer's disease (AD) mouse models are widely used, but their molecular correspondence with human AD remains uncertain.

METHODS: We analyzed 15 post mortem human brain datasets, four human non-brain or in vitro sensitivity datasets, and nine AD-related mouse-model molecular-profiling datasets; GSE222494 was analyzed separately for single-nucleus localization. Refined107, a meta-refined 107-gene human AD-associated gene subset, was evaluated using recurrence-matched control sampling, independent pathway-level comparison, within cohort out-of-fold (OOF) classification, and ordered cross-cohort transportability.

RESULTS: Refined107 comprised 37 Tier 1 and 70 Tier 2 genes and showed greater statistical consistency than recurrence-matched controls. Functional annotation implicated inflammatory, blood-brain barrier, metabolic, neuronal, and developmental programs. Among 636 recurrent human pathways, 226 showed same-direction support in at least one evaluated mouse-model family, indicating partial and model-dependent human-mouse correspondence. Post-selection within-cohort OOF areas under the curve (AUCs) were 0.833 to 0.980, whereas ordered cross-cohort AUCs were 0.288 to 0.720.

DISCUSSION: Refined107 represents a statistically consistent, meta-refined human AD-associated gene subset rather than a comprehensive disease signature. Human-mouse pathway correspondence was partial and model-dependent, and within-cohort classification did not translate into robust cross-cohort transportability.},
}

*Alzheimer Disease/genetics
Animals
Humans
Mice
*Disease Models, Animal
*Machine Learning
Brain/metabolism/pathology
Cohort Studies

@article {pmid42706510,
year = {2026},
author = {Ilardi, A and Ilardi, CR},
title = {Thyroid dysfunction: Another piece in the complex puzzle of Alzheimer's disease?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485579},
doi = {10.1177/13872877261485579},
pmid = {42706510},
issn = {1875-8908},
abstract = {An expanding body of evidence suggests that thyroid dysfunction may be clinically relevant in Alzheimer's disease (AD), although the significance of this association remains unsettled. Rather than reflecting a single biological pathway, thyroid hormone alterations in AD may involve downstream systemic adaptations related to inflammation and frailty, central dysregulation of thyroid hormone bioavailability and signaling, and upstream vulnerability mechanisms. Clarifying how these pathways intersect with cognitive and functional decline may help refine the biological interpretation of clinical heterogeneity in patients with AD.},
}

@article {pmid42706511,
year = {2026},
author = {Islam, AS and Saif, R and Alghalyini, B and Zia Zaidi, AR},
title = {Epidemiology, risk determinants, and research trends of dementia in Saudi Arabia: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485493},
doi = {10.1177/13872877261485493},
pmid = {42706511},
issn = {1875-8908},
abstract = {BackgroundDementia is an emerging public health priority in Saudi Arabia, driven by population aging and a high prevalence of vascular and metabolic disease. Despite increasing research activity, evidence remains fragmented, limiting understanding of the national burden and determinants of dementia.ObjectiveTo synthesize evidence on dementia epidemiology, risk factors, awareness, comorbidities, caregiving challenges, and research trends in Saudi Arabia.MethodsA systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar were searched for studies reporting dementia-related outcomes in Saudi populations. Given heterogeneity in study designs, sampling methods, and diagnostic criteria, findings were narratively synthesized.ResultsFifty-five studies met the inclusion criteria. Alzheimer's disease was the most common dementia subtype. Prevalence estimates among adults aged 60 years and older ranged from 3.8% to 6.3%, reflecting differences in diagnostic approaches and sampling methods. Diabetes and hypertension were the most consistently identified risk factors, while depression and anxiety were also associated with dementia. Public awareness was low, with stigma contributing to delayed recognition and underdiagnosis. Caregiving was family-based and associated with significant burden. Dementia commonly co-occurs with cardiometabolic, neuropsychiatric, and other chronic conditions. Research activity increased after 2020, with over half of the included studies published between 2020 and 2024; however, methodological inconsistencies and limited rural representation remain.ConclusionsDementia research in Saudi Arabia has expanded, yet epidemiological estimates remain inconsistent. Standardized diagnostic practices, enhanced surveillance, and public health strategies addressing risk reduction, awareness, and caregiver support are needed to address the dementia burden.},
}

@article {pmid42706564,
year = {2026},
author = {Zhang, Z and Cao, L and Liu, P and Yang, S and Yan, Y and Kwapong, WR and He, Y and Yang, M and Wang, H and Wang, Y and Feng, Z and Zhou, J and Liu, M and Lei, P and Wu, B and Zhang, S},
title = {Distinct ocular microvascular alterations in Alzheimer's disease and cerebral small vessel disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71809},
doi = {10.1002/alz.71809},
pmid = {42706564},
issn = {1552-5279},
support = {82371210 U24A20690 U25A2073//National Natural Science Foundation of China/ ; ZYGXQNJSKYCXNLZCXM-H14//Scientific Research Innovation Capability Support Project for Young Faculty/ ; 2025B-07-11//Changping Laboratory/ ; 2026NSFSC1623//Sichuan Science and Technology Program/ ; 2023YFC2506603//National Key R&D Program of China/ ; HXQMX0052//Qimingxing Research Fund for Young Talents/ ; 2024HXFH023 ZYYC23016//West China Hospital, Sichuan University/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Cerebral Small Vessel Diseases/diagnostic imaging/pathology ; Female ; Cross-Sectional Studies ; Male ; Tomography, Optical Coherence ; Aged ; *Retinal Vessels/diagnostic imaging/pathology ; *Microvessels/pathology/diagnostic imaging ; Aged, 80 and over ; *Choroid/blood supply ; },
abstract = {INTRODUCTION: While both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) involve vascular dysfunction, the ocular microvascular differences between them remain largely underinvestigated.

METHODS: This cross-sectional study included 650 participants (149 AD, 276 CSVD, and 225 cognitively unimpaired individuals). Optical coherence tomography angiography (OCTA) metrics were analyzed to characterize ocular microvascular alterations.

RESULTS: CSVD patients exhibited a higher burden of retinal ischemic perivascular lesions (RIPLs) than AD patients (all p < 0.05), whereas AD patients showed reduced choriocapillaris (CC) density (p = 0.031). In the CSVD group, RIPLs were associated with total CSVD score (p = 0.049), while reduced CC density was associated with elevated phosphorylated tau 181 in the AD group (p = 0.001). Machine learning models integrating OCTA metrics effectively differentiated AD from CSVD (area under the curve = 0.86).

DISCUSSION: AD and CSVD exhibit distinct ocular microvascular alterations, supporting OCTA-derived measures as potential non-invasive biomarkers.

TRIAL REGISTRATION NUMBER: ChiCTR2000041386.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Cerebral Small Vessel Diseases/diagnostic imaging/pathology
Female
Cross-Sectional Studies
Male
Tomography, Optical Coherence
Aged
*Retinal Vessels/diagnostic imaging/pathology
*Microvessels/pathology/diagnostic imaging
Aged, 80 and over
*Choroid/blood supply

@article {pmid42706570,
year = {2026},
author = {Müller, L and Köhler, C and Lindner, T and Polei, S and Vollmar, B and Weber, MA and Krause, BJ and Kirschstein, T and Porath, K and Engel, N and Teipel, S and Radbruch, A and Deike, K and Kuhla, A},
title = {No evidence of major integrative brain clearance impairment in an Alzheimer´s disease model of transgenic APPswe/PS1dE9 mice.},
journal = {Fluids and barriers of the CNS},
volume = {23},
number = {1},
pages = {},
pmid = {42706570},
issn = {2045-8118},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice, Transgenic ; Disease Models, Animal ; Mice ; *Brain/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Contrast Media/pharmacokinetics ; Mice, Inbred C57BL ; Plaque, Amyloid/pathology/metabolism ; Microglia/metabolism/pathology ; },
abstract = {BACKGROUND: Brain clearance pathways via the interstitial fluid and cerebrospinal fluid are essential for maintaining homeostasis and removing metabolic waste. Disruptions in these processes are linked to neurodegenerative diseases, particularly Alzheimer's Disease (AD), where an imbalance between amyloid β (Aβ) production and clearance leads to cerebral amyloidosis. Although AD research continues to rely heavily on murine models, including APPswe/PS1dE9 mice, it remains unclear to what extent these models replicate the deficits in brain clearance observed in human AD.

METHODS: We examined AD pathology in transgenic APPswe/PS1dE9 (tg) mice and wildtype (wt) littermates at six, nine and twelve months using immunohistochemistry for Aβ plaques (6E10[+]) and activated microglia (Iba1[+]). To assess integrative parameters contributing to brain clearance, we applied two complementary approaches. First, we performed daytime-dependent intrahippocampal injections of a fluorescent tracer in six-month-old tg and wt mice, followed by histological analysis of tracer dispersion 1 h and 3 h after injection. Second, we present a novel, longitudinal and non-invasive approach utilizing washout kinetics of intravenously administered gadolinium-based contrast agents (GBCA) as an integrative proxy to assess brain clearance dynamics. In this novel approach DOTAREM[®] was administered intravenously and imaging was done with anesthetized tg and wt mice at nine and twelve months of age. Integrity of the blood-brain-barrier was further evaluated via western blot analysis of occludin protein expression.

RESULTS: Despite tg mice displayed characteristic AD-like phenotype, with significant, age-dependent Aβ plaque deposition and neuroinflammation no significant differences in the integrative GBCA washout kinetics were detected between wt and tg mice, suggesting that no major deficits in the combined clearance pathways are present. However, contrast-agent uptake showed a general age-dependent increase consistent with aging-related changes known from human studies.

CONCLUSION: Our findings indicate that the APPswe/PS1dE9 mouse model does not exhibit evidence of major integrative brain clearance impairment, despite this being a hallmark of sporadic AD in humans. These results suggest limitations of this model for studying clearance-related mechanisms of late-onset AD, which should be acknowledged when planning future studies using this murine model.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
Mice, Transgenic
Disease Models, Animal
Mice
*Brain/metabolism/pathology
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
Contrast Media/pharmacokinetics
Mice, Inbred C57BL
Plaque, Amyloid/pathology/metabolism
Microglia/metabolism/pathology

@article {pmid42706593,
year = {2026},
author = {Engelmann, GTO and de Alvarenga, JC and Moro, GCP and Bolaños Burgos, IC and Miranda, MF and Miranda, MF and de Souza, AS and Saldanha, MF and Hansen, EO and Dias, NS and da Cunha Cintra, FCM and Dias, BF and da Silva Souza, AL and Carvalho, AT and Martino-Adami, PV and Cintra, MTG and Labanca, L and Lanna, IN and de Ávila, RT and de Paula, JJ and Costa-Silva, L and Freitas Rosa, DV and de Miranda, DM and Romano-Silva, MA and de Marco, LAC and Ramírez, A and de Mattos Viana, B and Camargos Bicalho, MA},
title = {The Cog-Aging: a 15-year cohort study of cognition in Brazilian older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71780},
doi = {10.1002/alz.71780},
pmid = {42706593},
issn = {1552-5279},
support = {436735/2018-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 309953/2018-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 315133/2021-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 406016/2025-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 313895/2026-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 406935/2022-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) through the National Institute of Science and Technology in Responsible Neurotechnology (INCT NeuroTec-R)/ ; 88887.569376/2020-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; APQ-02662-14//Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)/ ; APQ-02465-23//Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)/ ; APQ-04706-10//Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)/ ; },
mesh = {Humans ; Brazil/epidemiology ; Male ; Female ; Aged ; *Cognitive Dysfunction/epidemiology ; Longitudinal Studies ; Disease Progression ; *Dementia/epidemiology ; Incidence ; *Aging ; Cohort Studies ; Aged, 80 and over ; *Cognition/physiology ; *Alzheimer Disease/epidemiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Prevalence of dementia is higher in low- and middle-income countries (LMICs). However, longitudinal studies characterizing cognitive decline and its clinical and epidemiological predictors remain scarce in Brazil.

METHODS: Participants were enrolled from 2011 to 2025 and followed through May 2026. A total of 887 participants were classified as cognitively unimpaired (CU) (n = 274), mild cognitive impairment (MCI) (n = 378), or dementia of the Alzheimer's type (DAT) (n = 235). CU and MCI participants were followed until dementia conversion, which was analyzed under competing risks using cumulative incidence functions and Fine-Gray models.

RESULTS: Overall, annualized dementia conversion rate in the MCI group was 10.72 per 100 person-years (95% confidence interval [CI]: 8.54% to 13.29%). In addition, 40.39% of participants progressed to dementia during a mean follow-up time of 3.75 years (standard deviation: 3.28), with an estimated cumulative incidence of 29.85% at 3 years (95% CI: 22.74% to 36.96%), accounting for death as a competing event.

DISCUSSION: This study adds valuable information for LMICs. However, estimates should be interpreted considering attrition and competing mortality.},
}

Humans
Brazil/epidemiology
Male
Female
Aged
*Cognitive Dysfunction/epidemiology
Longitudinal Studies
Disease Progression
*Dementia/epidemiology
Incidence
*Aging
Cohort Studies
Aged, 80 and over
*Cognition/physiology
*Alzheimer Disease/epidemiology
Neuropsychological Tests

@article {pmid42706797,
year = {2026},
author = {Ye, YF and Deng, C and Ge, XF and Zhang, R and Long, JL and Jia, JX and Ye, HY and Li, CJ and Cai, X and Witter, MP and Lu, L},
title = {Regional and laminar organization of the entorhinal cortex in tree shrews based on cytoarchitecture, chemoarchitecture, and connectivity.},
journal = {Zoological research},
volume = {47},
number = {5},
pages = {1714-1736},
doi = {10.24272/j.issn.2095-8137.2025.618},
pmid = {42706797},
issn = {2095-8137},
mesh = {Animals ; *Entorhinal Cortex/anatomy & histology/physiology/cytology ; *Tupaiidae/anatomy & histology/physiology ; *Tupaia/anatomy & histology ; },
abstract = {The entorhinal cortex (EC) is a pivotal interface that integrates multimodal cortical and subcortical information into the hippocampal formation and distributes hippocampal output to widespread telencephalic targets. It is also one of the earliest and most severely affected regions in Alzheimer's disease (AD). The tree shrew (Tupaia belangeri chinensis) has emerged as a promising model for AD research. However, the uncharted organization of tree shrew EC has limited its application in modeling early stages of AD. In this study, we provide a comprehensive anatomical reference for the tree shrew EC by delineating its boundaries, parcellating its medial and lateral subregions, and mapping its laminar connectivity based on cyto- and chemoarchitecture combined with tracing experiments. We found that the tree shrew EC exhibits an intermediate architecture between rodents and monkeys, mirroring its phylogenetic position and potentially links to the gradual evolution of place codes from rodents to primates. This study provides the first detailed entorhinal atlas of this species, establishing a critical foundation for future neural-tracing and electrophysiological investigations. It enhances the utility of the tree shrew in mechanistic studies of spatial coding and conscious memory, as well as a naturalistic model for incipient AD.},
}

Animals
*Entorhinal Cortex/anatomy & histology/physiology/cytology
*Tupaiidae/anatomy & histology/physiology
*Tupaia/anatomy & histology

@article {pmid42706972,
year = {2026},
author = {Yu, X and Yi, Y and Liu, X and Zhao, C and Li, C and Shang, Y and He, K and Zhai, Y},
title = {Scutellaria Barbata Flavonoids Mitigate Alzheimer's Disease-related Aβ25-35 Toxicity in N2a Cells through CREB Phosphorylation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673438931260822121059},
pmid = {42706972},
issn = {1875-533X},
abstract = {BACKGROUND: Mouse neuroblastoma cells (N2a) are spontaneously derived from mice and possess the characteristics of neural stem cells. The proliferation, differentiation, and protrusion growth of N2a cells in vitro are consistent with those in vivo. Flavonoids isolated from the aerial parts of Scutellaria barbata (SBFs) can improve learning and memory deficits and protect against neuronal injury in many in vivo AD-- like models. N2a cells exposed to Aβ25-35 for Alzheimer's disease-related toxicity were subsequently used to observe the ameliorative effects of SBFs, and the effective mechanism through which SBFs promote the phosphorylation of CREB was further studied by using BI-D1870, an indirect inhibitor, and Rolipram, an activator of CREB phosphorylation.

METHODS: Immunofluorescence (IF) was used to detect the protein expression of the neuron-specific proteins NeuN, NeuroD1, and DCX. N2a cells were exposed to 100 μM Aβ25-35 and treated with SBFs at doses of 17.5, 35 and 75 mg·L-1 or 363 μM Rolipram. Cell morphology was observed under an inverted microscope, the cell survival rate was detected by the Cell Counting Kit-8 (CCK-8) method, and the release of lactate dehydrogenase (LDH) into the cell culture medium was determined by the pyruvate reduction method. The mRNA expression levels of ERK, RSK, CREB, and EGR-1 in cells were detected by real-time quantitative polymerase chain reaction (qPCR). IF and/or western blotting (WB) were used to measure the protein expression levels of BDNF, NGF, TrkB, Ras, ERK/p-ERK, Rsk/p90RSK, CREB/p-CREB-Ser133, and EGR-1 in N2a cells.

RESULTS: NeuN, NeuroD1, and DCX expression in N2a cells was positive, as indicated by green fluorescence. Both Aβ25-35 and BI-D1870 resulted in abnormal morphological changes in N2a cells, reduced the cell survival rate (P<0.01), increased the release of LDH (P<0.01) into the culture medium, and decreased the mRNA expression levels of ERK, RSK, and CREB and the protein expression levels of p-ERK, TrkB, p90RSK, pCreb-SER133, BDNF, NGF and EGR-1 (P<0.01) in cells. However, SBFs, to varying degrees, reversed the aforementioned abnormal changes in N2a cells caused by Aβ25-35 or BI-D1870, and the effects of SBFs were consistent with those of Rolipram.

CONCLUSION: SBFs protected against N2a cell damage induced by toxic Aβ25-35, and the effective mechanism by which SBFs promote the phosphorylation of CREB at the Ser133 site was confirmed through the application of the indirect CREB phosphorylation inhibitor BI-D1870 and the activator Rolipram. These findings suggest that SBFs may be helpful in the treatment of AD by intervening in CREB phosphorylation.},
}

@article {pmid42706977,
year = {2026},
author = {Saxena, B and Sisodiya, N and Khabiya, R and Pandit, A and Rajput, MS and Gupta, R},
title = {AI-Driven Precision Medicine in Alzheimer's Disease: Drug Repurposing, Digital Therapeutics and Clinical Decision Support.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128478269260818075055},
pmid = {42706977},
issn = {1873-4286},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disease that causes significant clinical, social, and economic burden worldwide. Despite improvements in understanding its multifaceted pathogenesis, current treatments are mostly symptomatic and ineffective across varied patient populations. To overcome these constraints, AI-driven precision medicine allows tailored risk assessment, treatment selection, and disease monitoring. This review covers AI's role in AD precision medicine, focusing on drug repurposing, digital therapies and clinical decision support systems. Machine and deep learning models are used to predict medication response, integrate heterogeneous data sources such as genomics, transcriptomics, neuroimaging and electronic health records, and uncover pharmacogenomic treatment success factors. The paper covers AIenabled precision pharmacology, including tailored dosing algorithms, adaptive therapeutic monitoring, and adverse drug reaction prediction. Bioinformatics-based target identification, network pharmacology, graphbased AI models, virtual screening, and real-world and clinical data validation are emphasized in AI-driven medication repurposing. AI-powered digital treatments like personalized cognitive training platforms, wearable- derived digital biomarkers, virtual and mixed reality interventions, adherence monitoring, and digital twins for therapy optimization have been discussed. AI-based clinical decision support systems are also thoroughly assessed for clinical value, accuracy, and explainability in disease subtyping, trajectory prediction, and risk stratification in preclinical and prodromal AD. Despite these promises, data heterogeneity, algorithmic bias, legal barriers, and privacy concerns exist. Federated learning enables safe multi-center collaboration and hybrid AI-human approaches, and it represents the future. AI's ability to alter AD care opens the door to precision medicine paradigms that use repurposed medications, digital tools and intelligent decision-making to improve patient outcomes.},
}

@article {pmid42706981,
year = {2026},
author = {Gou, KJ and Chen, Y and Sheng, Z and Yu, W and Wang, L and Lü, Y},
title = {Psychotropic Polypharmacy in Alzheimer's Disease: A Potentially Inappropriate Medication Perspective in Older Adults.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050502495260812063626},
pmid = {42706981},
issn = {1875-5828},
abstract = {Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). Consequently, potentially inappropriate medication (PIM) use is particularly common among older adults with AD. Psychotropic polypharmacy may increase the risk of various adverse outcomes beyond cognitive decline. Although geriatric prescribing criteria and dementia-care guidelines offer important safety recommendations, a clinically integrated framework for potentially inappropriate psychotropic medication use in older adults with AD remains insufficiently developed. This article is a narrative review rather than a systematic review or meta-analysis. The authors searched the literature in PubMed, Embase, and the Cochrane Library, focusing on studies, guidelines, consensus statements, regulatory safety warnings, and medication-safety criteria published between January 2015 and June 2026. This review specifically examines anticholinergic drugs, antipsychotics, benzodiazepines and Z-drugs, tricyclic antidepressants, and select newer antidepressants-including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, trazodone, and paroxetine-guided by the 2023 American Geriatrics Society (AGS) Beers Criteria®. Current evidence indicates that these medications may contribute to cognitive decline through anticholinergic burden, sedation, and pharmacodynamic interactions with cholinesterase inhibitors, such as donepezil and memantine. However, the strength of evidence varies considerably across drug classes and study designs, ranging from randomized controlled trials to observational studies and expert consensus. This study also summarizes current nonpharmacological strategies and proposes a structured clinical medication review framework. Overall, this review highlights the importance of minimizing inappropriate psychotropic use in AD, prioritizing non-pharmacological interventions, and conducting individualized risk-benefit assessments in clinical practice.},
}

@article {pmid42706996,
year = {2026},
author = {O'Shea, DM and Wang, L and Lukacsovich, D and Zhang, W and Galvin, JE},
title = {A blood DNA methylation marker of cognitive ability is associated with six-year cognitive performance independent of blood Alzheimer's disease biomarkers.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag222},
pmid = {42706996},
issn = {1758-535X},
abstract = {MethylCog is a 29-CpG blood DNA methylation (DNAm) score developed to index general cognitive ability (g). Whether it captures cognition-related information associated with later cognitive performance that is not fully represented by blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) remains unclear. Using the held-out Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) test set from the original MethylCog study (N = 605), we examined associations with baseline g after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), and amyloid-β 42/40 ratio (Aβ42/40). Prospective associations with six-year follow-up g were examined after adjustment for baseline g, age, sex, education, and APOE ε4 carrier status, with additional adjustment for the ADRD biomarker panel. MethylCog remained associated with baseline g in the fully adjusted cross-sectional model (standardized β=.178, 95% CI: .111-.244, p<.001; ΔAdjR[2]=.025). MethylCog was also associated with six-year follow-up g after adjustment for baseline g and all covariates and biomarkers (standardized β=.101, 95% CI: .033-.170, p=.004; N = 331; ΔAdjR[2]=.007). Findings were similar among participants without baseline cognitive impairment. These findings provide preliminary evidence that a cognition-trained DNAm signature captures variation in later cognitive performance not fully represented by baseline cognition or available ADRD blood biomarkers.},
}