@article {pmid42468248,
year = {2026},
author = {Zhao, B and Shang, S and Zhang, M and Guo, X and Zhou, R and Qu, Q and Cao, H},
title = {Comparison of sleep characteristics between Alzheimer's disease dementia and Parkinson's disease dementia.},
journal = {Sleep medicine},
volume = {147},
number = {},
pages = {109140},
doi = {10.1016/j.sleep.2026.109140},
pmid = {42468248},
issn = {1878-5506},
abstract = {BACKGROUND: Alzheimer's disease (AD) dementia and Parkinson's disease dementia (PDD) both frequently involve sleep disturbances, but the characteristics of sleep disruption differ between the two patient groups, and the extent of these differences remains unclear.

METHODS: We consecutively enrolled 105 patients with AD and 104 with PDD from a memory clinic. All participants underwent assessments of global cognition (MMSE, MoCA), daily living (ADL), anxiety and depression (HAMA, HAMD), and sleep characteristics (PSQI, RBD, daytime nap questionnaire, Epworth Sleepiness Scale). Multivariable regression analyses were conducted to examine whether sleep characteristics differed independently between the two groups. ROC curves evaluated discriminative performance.

RESULTS: Global PSQI scores did not differ between the two groups. In univariate analyses, PDD patients reported worse subjective sleep quality (the first PSQI component), more sleep disturbances, greater use of hypnotics, higher daytime nap frequency and duration, and a much higher prevalence of RBD. After full adjustment, PDD remained independently associated with poorer sleep quality (B = 0.355, 95% CI: 0.092-0.619, p = 0.008), higher daytime nap frequency (B = 2.124, 95% CI: 1.327-2.920, p < 0.001), and RBD (OR = 18.482, 95% CI: 3.297-103.603, p = 0.001). A combination of sleep items (sleep quality, nap frequency, RBD) distinguished PDD from AD with an AUC of 0.763.

CONCLUSIONS: Despite a comparable total PSQI score, PDD patients showed significantly poorer sleep quality (the first PSQI component), more frequent daytime napping, and a much higher prevalence of RBD compared with AD patients. Subjective sleep profiling may help to understand the differential sleep burden in these common dementias.},
}

@article {pmid42468306,
year = {2026},
author = {Khalafi, M and Hojjati, SH and Wang, XH and Tanzi, EB and Liao, V and Kumar, S and Parikh, NS and Chiang, GC},
title = {Liver steatosis and cognitive performance in aging: A pilot cross-sectional study.},
journal = {Clinical imaging},
volume = {138},
number = {},
pages = {110903},
doi = {10.1016/j.clinimag.2026.110903},
pmid = {42468306},
issn = {1873-4499},
abstract = {PURPOSE: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to dementia. We investigated whether liver steatosis or fibrosis is associated with early cognitive changes, while exploring related mechanisms like body mass index (BMI) and cerebral β-amyloid deposition.

METHODS: In this cross-sectional study, we enrolled 26 cognitively unimpaired individuals, who underwent amyloid PET and comprehensive clinical, neurological, and neuropsychological evaluations, including the Telephone Interview for Cognitive Status (TICS). Liver steatosis and fibrosis were quantified noninvasively using vibration-controlled transient elastography (FibroScan®; Echosens, Paris, France) with an M-probe, with the controlled attenuation parameter (CAP) used to quantify liver steatosis. Multivariate regression models were used to assess relationships between liver and cognitive measures, adjusting for age.

RESULTS: In our cohort (mean age 72.2 ± 8.4 years), greater liver steatosis was associated with lower TICS scores, using both the CAP score (β = -0.03, p = 0.021) and steatosis grade (β = -1.39, p = 0.023). Higher liver stiffness was also negatively associated with TICS scores (β = -1.39, p = 0.042). BMI was significantly associated with greater cerebral amyloid burden (β = 9.03, p = 0.01), higher steatosis grade (β = 0.30, p = 0.03), and higher CAP scores (β = 9.47, p = 0.003).

CONCLUSION: Liver steatosis associates with lower cognitive scores in older adults. BMI associates with both steatosis and amyloid burden, which may reflect co-occurring metabolic pathways. These findings provide evidence for targeting metabolic health to preserve cognition and mitigate Alzheimer's pathology.},
}

@article {pmid42468396,
year = {2026},
author = {Du, H and Zhao, P and Yang, Z and Li, B and Bao, Y and Shi, X},
title = {Development and validation of a parsimonious and noninvasive clinical decision machine learning model for predicting the risk of long-term mild cognitive impairment in older adults: A multinational cohort study.},
journal = {International journal of medical informatics},
volume = {220},
number = {},
pages = {106612},
doi = {10.1016/j.ijmedinf.2026.106612},
pmid = {42468396},
issn = {1872-8243},
abstract = {BACKGROUND: Early identification of mild cognitive impairment (MCI) is crucial for delaying the progression of dementia. However, existing prediction models often require expensive testing or invasive biomarkers, limiting their scalability in primary care settings.

METHODS: Data were drawn from three prospective cohorts: the Chinese Longitudinal Healthy Longevity Survey (CLHLS), the English Longitudinal Study of Ageing (ELSA), and the Health and Retirement Study (HRS). We included 11,069 participants aged ≥60 years who were free of cognitive impairment at baseline. Incident MCI was defined via cohort-specific assessments. The CLHLS was used for internal training and testing, and the ELSA and HRS were used for independent external validation. After feature selection via Shapley additive explanations (SHAP) and recursive feature elimination, 9 machine learning models were developed. Model performance was evaluated on the basis of discrimination, calibration, and clinical utility. SHAP was used for model interpretation.

RESULTS: Over the 6-year follow-up period, 2486 participants developed MCI (CLHLS: n = 1008; ELSA: n = 488; HRS: n = 990). Five easily accessible baseline predictors were selected: age, sex, education, instrumental activities of daily living, and baseline cognitive score. The gradient boosting classifier demonstrated favorable overall performance, achieving an internal area under the curve (AUC) of 0.869 (95% CI 0.84-0.90). It maintained robust generalizability during external validation in the ELSA (AUC 0.786, 95% CI 0.76-0.81) and HRS (AUC 0.745, 95% CI 0.73-0.76) cohorts. Furthermore, an interactive web tool incorporating Shapley additive explanations was deployed to conduct a transparent risk assessment.

CONCLUSIONS: This study developed and externally validated a parsimonious, cross-national machine learning model utilizing five noninvasive features to predict long-term MCI risk. Integrated with a transparent SHAP framework and deployed as an interactive web application, it provides a cost-effective clinical decision support tool for early MCI screening in primary care (https://mcipredictor.streamlit.app/).},
}

@article {pmid42468562,
year = {2026},
author = {Lim, L and Little, D and Redman, S and Cookson, AN},
title = {Machine learning for predicting full-count FDG PET brain images from low-count acquisitions in suspected dementia: a clinical and quantitative evaluation.},
journal = {Physics in medicine and biology},
volume = {},
number = {},
pages = {},
doi = {10.1088/1361-6560/ae8c9f},
pmid = {42468562},
issn = {1361-6560},
abstract = {Objective.Artificial intelligence methods for denoising low-count FDG PET brain images are usually evaluated using image quality metrics alone, with limited direct clinical assessment, particularly in suspected dementia. This study evaluated a machine-learning image quality transfer (IQT) method for predicting full-count FDG PET brain images from low-count acquisitions using both quantitative metrics and blinded clinical assessment. Approach.Forty-one FDG PET/CT patients with suspected dementia were retrospectively included, with low-count images simulated using 5% of list-mode data. An IQT random forest model employing patch-wise regression was evaluated using image quality metrics, regional Z-scores, and blinded radiologist assessment against standard-count references. Main results.AI-predicted images showed an average peak signal to noise ratio (PSNR) improvement of approximately 4 dB and reduced root mean square error (RMSE) compared with low-count images. Clinically, uninterpretable scans were reduced to 0% for each reader, down from 20% and 50% respectively, with a shift from tentative to confident agreement with the reference standard reports. By contrast, the structural similarity index measure (SSIM) and regional Z-score agreement showed no improvement. Significance.In patients with suspected dementia, where motion and limited tolerance of long acquisitions are common, this study demonstrates for the first time the potential of an image quality transfer (IQT) method to improve the clinical usability of low-count FDG PET scans. The findings also indicate the importance of task-based clinical evaluation, since quantitative metrics alone were insufficient to capture the clinically relevant improvements observed in image interpretability and reader confidence.},
}

@article {pmid42468638,
year = {2026},
author = {Fu, T and Wei, C and Shen, D and Zhong, J and Liu, B and Xu, F},
title = {Ceanothane-type triterpenoids: Phytochemistry, biosynthesis, pharmacological activities, and therapeutic potential.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107390},
doi = {10.1016/j.fitote.2026.107390},
pmid = {42468638},
issn = {1873-6971},
abstract = {Ceanothane-type triterpenoids (CTTs) are a class of natural triterpenoids characterized by a distinctive 5/6/6/6/5 pentacyclic skeleton featuring a five-membered A-ring. They are mainly distributed in plants of the Rhamnaceae family, such as Ziziphus, Hovenia, Paliurus. To date, 64 natural CTTs and 28 synthetic derivatives have been reported. This review systematically summarizes their structural classification, pharmacological activities, putative biosynthetic pathways, and pharmacokinetic profiles. CTTs exhibit a broad spectrum of bioactivities, including antitumor, antimicrobial, antiinflammatory, hepatoprotective, anti-Alzheimer's disease (AD), antimalarial, and immunomodulatory effects, with mechanisms involving multi-target regulation. Furthermore, we discuss current challenges and future perspectives in structural modification, structure-activity relationship (SAR) studies, and mechanistic exploration, aiming to provide a comprehensive reference for the further development of CTTs as therapeutic agents.},
}

@article {pmid42468644,
year = {2026},
author = {Li, M and Zhao, Y and Xu, B and Wang, L and Luo, W and Tan, R and Zhang, X and Jiang, H},
title = {Polygonatum sibiricum polysaccharides and Alzheimer's disease: A review of preparation, structure, mechanisms, and application.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107393},
doi = {10.1016/j.fitote.2026.107393},
pmid = {42468644},
issn = {1873-6971},
abstract = {Polygonatum sibiricum is a well-established botanical resource with dual medicinal and edible applications. Polygonatum sibiricum polysaccharides (PSP), the principal bioactive constituent of P. sibiricum, have long attracted research interest due to their structural diversity and broad spectrum of biological activities. Beyond its well-documented antioxidant, antibacterial, anti-inflammatory, antitumor, and anti-aging properties, PSP has recently demonstrated promising therapeutic potential in alleviating Alzheimer's disease (AD). However, current research findings on PSP remain fragmented, and a comprehensive framework elucidating the specific mechanisms by which it ameliorates AD is lacking. Based on this, this review begins with the extraction, isolation, purification, and structural characterization of PSP, systematically summarizes the multiple mechanisms by which PSP ameliorates AD, and provides an overview of its structural modification, toxicological studies, and multi-domain applications, aiming to offer theoretical support for the further development and translational application of PSP in the prevention and treatment of AD.},
}

@article {pmid42468665,
year = {2026},
author = {Girish Oswal, D and Rane, M},
title = {Is Urolithin A(UA) a Pharmacologically Credible Neuro-Nutraceutical? A Critical Review of Mechanisms, Brain Exposure, and Evidence Gaps in Alzheimer's and Parkinson's Disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106224},
doi = {10.1016/j.neuint.2026.106224},
pmid = {42468665},
issn = {1872-9754},
abstract = {Urolithin A(UA) is a gut microbiota-derived metabolite of dietary ellagitannins and ellagic acid, generated by specific gut bacterial species and absent from food in free form. Preclinical evidence indicates that UA restores PINK1/Parkin-mediated mitophagy, attenuates NF-κB, NLRP3 inflammasome and cGAS-STING-driven neuroinflammation, and preserves synaptic and cognitive function across rodent and cell-culture models of Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. However, circulating UA in humans exists predominantly as phase II glucuronide and sulfate conjugates rather than free aglycone, and human clinical evidence to date establishes UA's safety, favorable pharmacokinetics, mitochondrial target engagement, and benefits to muscle strength and physical function in middle-aged and older adults, with no completed trial yet evaluating cognitive or neurodegenerative disease-modifying outcomes. This review critically examines whether UA's neuroprotective mechanisms are pathway-specific and supported by convergent preclinical and human data, while explicitly separating mechanistic plausibility from demonstrated clinical efficacy.UA therefore represents a promising but still investigational neuro-nutraceutical candidate, with a mechanistic foundation strong enough to justify dedicated, CNS-endpoint-focused clinical trials as the next logical step toward establishing its neuroprotective potential in humans.},
}

@article {pmid42468794,
year = {2026},
author = {Li, J and Wang, Y and Ma, X and Bi, X and Wu, T and Zhang, N and Wang, F and Liu, T and Geng, F},
title = {Microneedle-mediated drug delivery systems for brain diseases.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {102996},
doi = {10.1016/j.nano.2026.102996},
pmid = {42468794},
issn = {1549-9642},
abstract = {Brain diseases pose a major global health challenge, with the blood-brain barrier (BBB) as the core obstacle for intracranial drug delivery. Microneedles, a minimally invasive technology, can bypass the BBB via intracranial implantation, nose-to-brain, trigeminal nerve, and transdermal systemic routes. This review covers the structural classification, biomaterials, and bypass BBB delivery mechanisms of brain-targeted microneedles. Using glioblastoma, Alzheimer's disease, and Parkinson's disease as models, we overview preclinical microneedle formulations and key signaling pathways, and establish a matching framework linking therapeutic targets, drugs, and microneedle types. We further analyze clinical translation bottlenecks including limited drug loading, unclear long-term biosafety, manufacturing challenges, and regulatory gaps, and propose future directions in technical innovation, standardized evaluation, and regulatory improvement. This work may guide the rational design and clinical translation of microneedle-mediated brain-targeted drug delivery systems.},
}

@article {pmid42468803,
year = {2026},
author = {Zhang, X and Huang, Q and Huang, J and Zhang, P and Feng, X and Li, Z and Raper, DMS and Mao, C},
title = {Frailty-related plasma proteomic signatures and key biomarkers for new-onset dementia and its subtypes: A prospective cohort study.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.07.040},
pmid = {42468803},
issn = {2090-1224},
abstract = {BACKGROUND: Frailty is a well-established clinical risk factor for dementia, but its underlying mechanisms remain poorly defined. We aimed to investigate whether proteomic signatures and individual proteins linked to frailty could predict and characterize the association between frailty and dementia.

METHODS: We analyzed over 52,000 UK Biobank participants free of dementia at baseline, with plasma profiles of 2,915 proteins. Physical frailty (PF) and a 49-item frailty index (FI) were assessed. Proteomic signatures were derived using multivariable linear regression and 100 repeated LASSO selections. Incident dementia was ascertained via linkage to hospital and mortality records. Associations with incident dementia were assessed using multivariable Cox proportional hazards models, dose-response, and mediation analyses.

RESULTS: During 13.6 years of follow-up, 1,437 participants developed dementia. Proteomic signatures for PF and FI were independently associated with dementia risk (hazard ratios [HRs] up to 2.80). Stratification by signature quintiles showed clear gradients in both absolute and relative dementia risk. For all-cause dementia, cumulative incidence ranged from 1.19% to 5.27% (HR up to 3.29), and for vascular dementia, from 0.16% to 1.19% (HR up to 4.53). Similar trends were observed for Alzheimer's dementia. Mediation analysis indicated that proteomic signatures statistically accounted for 46%-53% of the association between frailty and dementia risk. Key proteins, including GDF15, HPGDS, ITGAV, SPP1, CHGA, and LGALS4, were identified as top contributors and mapped to immune-inflammatory, neuroimmune, and extracellular matrix pathways.

CONCLUSION: Frailty-related proteomic signatures and key proteins predict dementia risk and capture biological features beyond clinical frailty. These molecular markers may facilitate early risk stratification and support future research into prevention strategies.},
}

@article {pmid42468901,
year = {2026},
author = {Halabian, N and Park, C and Omoto, L and Bocca, LF and Palacios, G and Wu, K and Hamani, C and Rabin, J and Abrahao, A and Davidson, B and Lipsman, N and Meng, Y},
title = {Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.008},
pmid = {42468901},
issn = {1873-2402},
abstract = {Therapeutic focused ultrasound (FUS) leverages the non-invasive ultrasonic waves to modify the biological tissue. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), permitting passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses afflicting the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). We discuss the research developments to date and future directions.},
}

@article {pmid42468989,
year = {2026},
author = {Baraniuk, C},
title = {Alzheimer's drug lecanemab: FDA approves easier initial use, with "huge implications" for UK.},
journal = {BMJ (Clinical research ed.)},
volume = {394},
number = {},
pages = {e100318},
doi = {10.1136/bmj-2026-100318},
pmid = {42468989},
issn = {1756-1833},
}

@article {pmid42469165,
year = {2026},
author = {Ichimata, S and Hata, Y and Yoshida, K and Tanaka, R and Murayama, S},
title = {Clinicopathological and molecular heterogeneity of amyloid-β in unnatural deaths under 70 years: A forensic autopsy-based study.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70124},
doi = {10.1111/bpa.70124},
pmid = {42469165},
issn = {1750-3639},
support = {//Uehara Memorial Foundation/ ; },
abstract = {This study investigated the clinicopathological characteristics and molecular spectrum of amyloid-beta (Aβ) in unnatural deaths among relatively young individuals with moderate-to-severe Aβ deposition, including cases of early-onset Alzheimer's disease. A total of 856 forensic autopsy cases aged 40-69 years were analyzed. Detailed semiquantitative and quantitative immunohistochemical analyses were performed in the neocortex, striatum (caudate nucleus, putamen, and nucleus accumbens [NAc]), and amygdala using antibodies targeting multiple Aβ species (Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate-modified Aβ at the third glutamate residue [AβNp3E], and serine 8-phosphorylated Aβ), as well as phosphorylated tau. Ward's hierarchical cluster analysis was also performed. Thirty-three cases (eight females; 3.9%), including six early-onset Alzheimer's disease cases, were identified. Three cases exhibited genetic abnormalities (one with Down syndrome and two with presenilin 1 [PSEN1] mutations). Marked regional heterogeneity in Aβ molecular profiles was observed, particularly within the striatum. Notably, the NAc displayed a distinct pattern of Aβ deposition and occasional NAc-predominant cerebral amyloid angiopathy. Cases with cognitive impairment (CI) demonstrated more advanced Aβ and tau pathology than CI-negative cases; notably, interstitial Aβ42 and Aβ43 burdens were significantly elevated across all regions. Strikingly, siblings carrying the same PSEN1 mutation-one with CI and the other without-exhibited divergent pathological patterns. Although suicide accounted for approximately one-third of cases, a higher neocortical Aβ burden was associated with a lower frequency of suicide, and no significant difference in suicide rates was observed compared with cases lacking substantial Aβ deposition. Cluster analysis identified a subgroup characterized by relatively elevated striatal Aβ deposition, particularly AβNp3E. Collectively, these findings indicate that the severity of Aβ deposition is not directly associated with suicide. However, early involvement of the NAc may contribute to depressive states, and region-specific Aβ species-particularly Aβ42, Aβ43, and AβNp3E-may be associated with increased cognitive vulnerability in this age group.},
}

@article {pmid42469217,
year = {2026},
author = {Dodd, RB and Enomoto, M and Zhou, Y and Satoh, K and Zhang, Y and Chen, F and Acheson, B and Ghaffari, D and Sayn-Wittgenstein, E and Manning, JJ and Dukas, GV and Patel, R and Burguete, AS and Kralovec, MJ and Rashid, M and Hall, JL and Tamucci, KA and Chatila, Z and Liu, M and Lee, AJ and Vardarajan, BN and Taga, MF and Pollari, S and Rabinovitch, A and Rillahan, CD and Bobkov, AA and Sergienko, E and Meadows, W and Qamar, S and Randle, SJ and Johnson, CM and Sevalle, J and Griffin, J and Bohm, C and Ikura, M and Xian, X and Herz, J and Kelly, MA and West, J and Satapathy, S and Wilson, MR and Javitch, JA and Fraser, PE and Bennett, DA and De Jager, PL and Fishelson, Z and Frenkel, D and Asher, WB and Bradshaw, EM and George-Hyslop, PS},
title = {CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-75140-3},
pmid = {42469217},
issn = {2041-1723},
support = {203249/Z/16/Z//Wellcome Trust (Wellcome)/ ; 406915//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33[M] splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33[M] ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33[M], but not CD33[m]. We show that in human monocytes CD33[M]:CLU binding induces CD33[M] ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33[M] ectodomain fragment (sCD33[M]) - absent from CD33[m]-expressing cells - which could contribute to the role of CD33[M] in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33[M] axis, highlighting CD33[M] dimerization and ligand-binding sites as potential therapeutic targets.},
}

@article {pmid42469559,
year = {2026},
author = {Walker, L and Attems, J and Donaghy, P},
title = {Neuropathological correlates of imaging in dementia with Lewy bodies.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42469559},
issn = {1435-1463},
abstract = {Dementia with Lewy bodies (DLB) is a common yet underdiagnosed neurodegenerative dementia, characterised neuropathologically by nigrostriatal dopaminergic degeneration and widespread α-synuclein aggregation. Clinical diagnosis remains challenging due to marked heterogeneity in presentation and substantial overlap with Alzheimer's disease (AD), resulting in diagnostic delays and frequent misdiagnosis. The ability to identify underlying pathological processes ante-mortem is essential to improve diagnostic accuracy, refine prognosis, stratify patients for clinical trials, and ultimately enable personalised therapeutic approaches. Over recent decades, major advances have been made in the development of neuroimaging biomarkers that reflect key features in Lewy body disease pathology, many of which have informed diagnostic criteria. In addition to dopaminergic dysfunction and α-synuclein pathology, co-existing neuropathologies including amyloid-β, tau, neuroinflammation, and vascular changes are increasingly recognised as important modifiers of clinical phenotype and disease trajectory in DLB. This review summarises the current landscape of neuroimaging modalities in DLB and critically examines their relationships with confirmed neuropathological correlates. We discuss indicative biomarkers such as striatal dopamine imaging and [123]I-metaiodobenzylguanidine myocardial scintigraphy, alongside supportive imaging markers derived from structural magnetic resonance imaging and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). Emerging PET approaches targeting α-synuclein, as well as established amyloid and tau-PET techniques for assessing co-pathologies, are reviewed in the context of post-mortem validation studies. Finally, we consider Translocator protein PET imaging as a marker of neuroinflammation and highlight key methodological limitations and knowledge gaps. Together, these neuroimaging-pathological correlations provide critical insights into disease mechanisms and outline future directions toward earlier, biologically informed diagnosis and precision medicine in DLB.},
}

@article {pmid42469568,
year = {2026},
author = {Kaushik, S and Fatima, JE and Raheem, A and Barbhuiya, MA and Thirupathi, AT and Singh, LP and Khan, PA and Aparna, TN and Pramanik, S and Shahid, MAA},
title = {Nanomedicine targeting neuroinflammatory pathways in Alzheimer's disease: a new frontier in inflammopharmacology.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42469568},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative illness characterized by progressive cognitive impairment, synaptic compromise, and relentless neuroinflammation. Increasing evidence suggests that neuroinflammatory cascades orchestrated by microglial activation, astrocytic malfunction, cytokine hyperproduction, and inflammasome signalling are at the core of AD pathogenesis. Conventional anti-amyloid and cholinergic treatments are only symptomatic and neglect the inherent neuroimmune dysregulation. Nanomedicine is a revolutionary frontier in inflammopharmacology, which enables the accurate modulation of neuroinflammatory circuits and enhanced brain delivery of medicines. Nanocarriers designed by engineering, including liposomes, polymeric nanoparticles, dendrimers, and exosomes, allow for targeted delivery across the BBB, increase drug bioavailability, and provide controlled release. The nano-systems are capable of inhibiting pro-inflammatory signalling, such as NF-κB and MAPK pathways, reducing oxidative stress, and enhancing microglial M2 polarization and thus restoring neuronal homeostasis. Recent developments in surface-functionalized and stimuli-responsive nanoplatforms further enable active targeting through receptor-mediated pathways and theranostic imaging in real-time. Comparative studies show that interventions based on nanocarrier-based therapies enhance therapeutic efficacy and safety profiles in preclinical AD models. Future directions include integrating AI-driven nano-design, gene and siRNA delivery, and precision neuropharmacology to enable personalized anti-inflammatory therapies. Substantial progress, translational challenges remain regarding long-term biocompatibility, large-scale production, and clinical validation. Nanomedicine against neuroinflammatory pathways represents a new paradigm for Alzheimer's treatment, linking molecular pharmacology and sophisticated nanotechnology to next-generation neuroinflammatory medicine.},
}

@article {pmid42469606,
year = {2026},
author = {Low, A and Gunter, JL and Hu, M and Raghavan, S and Przybelski, SA and Schwarz, CG and Kantarci, K and Lowe, VJ and Petersen, RC and Graff-Radford, J and Jack, CR and Vemuri, P},
title = {Perivascular Spaces as Determinants of Amyloid, Tau, and Vascular Biomarker Progression.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78299},
pmid = {42469606},
issn = {1531-8249},
support = {R01 AG056366/NH/NIH HHS/United States ; R37 AG011378/NH/NIH HHS/United States ; U01 AG006786/NH/NIH HHS/United States ; R01 AG034676/NH/NIH HHS/United States ; U01 NS100620/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; },
abstract = {OBJECTIVE: Magnetic resonance imaging (MRI)-visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid-PET, and tau-PET, both cross-sectionally and longitudinally.

METHODS: We examined 2,229 participants across the aging-AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in-house algorithm. Amyloid on [[11]C]Pittsburgh Compound B (PiB)-PET and tau on AV1451-PET were measured. Cross-sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age- and sex-adjusted linear mixed effect (LME) models with natural splines and subject-wise 10-fold cross-validation.

RESULT: Three distinct associations were observed: (1) PVS in the basal ganglia (PVS-BG) was associated with greater WMH volume both cross-sectionally and longitudinally; (2) PVS-BG covaried with higher PiB standardized uptake value ratio (SUVR) cross-sectionally, with longitudinal trajectory associations limited to amyloid-negative individuals; (3) PVS in the centrum semiovale (PVS-CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA.

INTERPRETATION: Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS-BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS-BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS-CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026.},
}

@article {pmid42469846,
year = {2026},
author = {Tang, X and Chen, R and Xing, J and Huang, Q and Luo, L and Ouyang, C and Ma, F and Wen, J and Zhang, J and Kong, L and Cai, Y and Wang, Y and Cui, L},
title = {Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03956-3},
pmid = {42469846},
issn = {1742-2094},
support = {20252BAC200485//Natural Science Foundation of Jiangxi Province/ ; 2025R201//Zhanjiang Science and Technology Plan Talent Enclave Special Project/ ; 82101269//National Natural Science Foundation of China/ ; 82071190//National Natural Science Foundation of China/ ; 2024A1515011464//Natural Science Foundation of Guangdong Province, China/ ; 2024B1515230001//Natural Science Foundation of Guangdong Province, China/ ; GCC2021010//high-level talents scientific research start-up funds of the Affiliated Hospital of Guangdong Medical University/ ; GCC2022001//the high-level talents scientific research start-up funds of the Affiliated Hospital of Guangdong Medical University/ ; GJPY004//National-Level Talent Cultivation Funding Program of The Affiliated Hospital of Guangdong Medical University/ ; },
abstract = {BACKGROUND: Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system.

METHODS: Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD.

RESULTS: LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming.

CONCLUSION: Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.},
}

@article {pmid42469894,
year = {2026},
author = {Jiang, Z and Ding, Y},
title = {Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08662-5},
pmid = {42469894},
issn = {1479-5876},
support = {LQ24H160009//Zhejiang Provincial National Natural Science Foundation of China/ ; LHZY24H020002//Hangzhou Joint Fund of the Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Coffee is one of the most widely consumed beverages worldwide, yet its biological effects have often been attributed primarily to caffeine. Emerging evidence suggests that coffee contains a complex array of bioactive compounds, including chlorogenic acids, trigonelline, diterpenes, and melanoidins that collectively exert pleiotropic effects on cellular metabolism. However, a comprehensive framework linking the full spectrum of coffee-derived bioactives to mitochondrial health and chronic disease prevention is still lacking.

MAIN BODY: This review proposes an integrated perspective on coffee as a systemic "mitochondrial network optimizer." We present this model as an integrative framework and hypothesis rather than an established causal model. We synthesize molecular, pre-clinical, and clinical evidence suggesting that coffee bioactives converge on key regulatory nodes, namely the AMPK/SIRT1/PGC-1α axis, Nrf2/ARE antioxidant pathway, PINK1/Parkin-mediated mitophagy, and mitochondrial calcium signaling to coordinately enhance mitochondrial biogenesis, quality control, redox defense, and metabolic efficiency. These multi-targeted mechanisms provide a plausible biological basis for the consistent epidemiological associations between moderate coffee consumption and reduced risk of metabolic diseases (type 2 diabetes, non-alcoholic fatty liver disease), neurodegenerative disorders (Parkinson's, Alzheimer's), and cardiovascular conditions. Furthermore, we critically examine key determinants of response heterogeneity, including non-linear hormetic dose-response relationships, inter-individual variability (CYP1A2 genotype, gut microbiota, sex), and the impact of coffee processing and brewing methods on bioactive composition.

CONCLUSIONS: Collectively, these findings support the hypothesis that coffee may serve as a paradigm of polypharmacological dietary intervention that targets fundamental pathways of mitochondrial resilience. Moving beyond reductionist views centered on single compounds, we propose that the holistic effects of coffee are best understood through systems-level modulation of mitochondrial homeostasis. Future research should prioritize precision nutrition approaches stratified by genotype, microbiome, and metabolic phenotype, to translate these mechanistic insights into personalized dietary recommendations and the development of mitochondria-targeted nutraceuticals. We caution that this integrative framework requires direct validation in human causal studies.},
}

@article {pmid42469913,
year = {2026},
author = {Janahi, M and Lorenzini, L and Oxtoby, NP and Barkhof, F and Mokrab, Y and Schott, JM and Altmann, A and Initiative, FTADN},
title = {Multi-threshold polygenic risk improves hippocampal-based cognitive decline prediction.},
journal = {Genome medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13073-026-01722-x},
pmid = {42469913},
issn = {1756-994X},
support = {MR/T046422/1/MRC_/Medical Research Council/United Kingdom ; 733051106/ZONMW_/ZonMw/Netherlands ; ANR-19-JPW2-000//Agence Nationale de la Recherche/ ; 1191535//National Health & Medical Research Council, Australia/ ; 2019-2.1.7-ERA-NET-2020-00008//National Research, Development and Innovation Office, Hungary/ ; },
abstract = {BACKGROUND: Predicting cognitive decline from brain MRI is a central question in neuroscience. Hippocampal volume (HV) is a key cognitive biomarker, and normative models can be augmented with multimodal information. Here we augment normative models with genetic information and show improvements in cognitive decline prediction across multiple experimental setups.

METHODS: We improve normative models for HV by integrating multi-threshold polygenic scores (PGS) with demographic and imaging data using Gaussian Process Regression (GPR). Models were trained on 23,997 participants from UK Biobank (UKBB) and validated on 3,000 out-of-sample participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the European Prevention of Alzheimer's Disease (EPAD) cohorts.

RESULTS: Our genetically-informed models significantly strengthened associations across six experimental designs and 13 key neurocognitive measures, including Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Alzheimer's Disease Assessment Scale (ADAS), while enhancing prediction of future cognitive decline.

CONCLUSIONS: Together, these findings underscore the promise of integrating multi-threshold PGS with neuroimaging-based predictive models to improve prognostication and early intervention strategies for neurodegenerative diseases.},
}

@article {pmid42469972,
year = {2026},
author = {Li, X and Li, L and Ren, Y and Shi, L and Sun, M and Liu, Z},
title = {A bibliometric analysis of research trends and mechanisms of olfactory dysfunction in Alzheimer's diseases from 2008 to 2024.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49799},
pmid = {42469972},
issn = {1536-5964},
support = {2025JC-YBQN-1144//Project of Shaanxi Provincial Department of Science and Technology/ ; },
mesh = {*Alzheimer Disease/complications/physiopathology ; *Bibliometrics ; Humans ; *Olfaction Disorders/physiopathology/etiology ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Olfactory dysfunction (OD) and Alzheimer disease (AD) represent significant global public health challenges. Growing evidence underscores the need to clarify the neuropathological mechanisms underlying their association. Our study intends to analyze global research trends and overlapping molecular mechanisms underlying OD and AD.

METHODS: Reviews and articles on OD and AD published between 2008 and 2024 were extracted from the Web of Science Core Collection. CiteSpace and VOSviewer were applied to for the analysis and visualization of the publication outputs, as well as the distribution of countries/regions, institutions and authors, the journals output, keywords co-occurrence, and reference citations. Molecular targets and associated pathways were investigated by GeneCards, STRING, and Metascape databases.

RESULTS: One thousand nine hundred sixteen publications were identified, demonstrating steady growth in research output across 7006 institutions from 398 countries. The USA emerged as the top contributor, excelling in both publication output and citation impact. The University of Pennsylvania, University of California San Francisco, and Chinese Academy of Sciences stood out as the top influential institutions. Among 10,476 authors, Thomas Hummel from Technische Universität Dresden, Germany, emerged as the most prominent scholar. In terms of journals, Journal of Alzheimer's Disease leaded in publications in this field. Keywords including "Alzheimer's disease," "olfactory bulb," and "cognitive impairment" represent the current research focuses. A total of 1779 overlapping genes were identified between OD and AD. ACTB, AKT1, TP53, CTNNB1, and INS were identified as the most central regulatory genes. Enrichment analyses revealed involvement in PI3K-Akt, mitogen-activated protein kinases, and cyclic adenosine monophosphate signaling pathways, as well as biological functions related to signaling receptor activator activity, growth factor activity, and cytokine activity.

CONCLUSION: Our study uncovers the dynamic research trends on OD and AD, while we further identified shared molecular mechanisms underlying these 2 disorders. Early olfactory risk assessment, diagnosis, and intervention may serve as critical components in the prevention and management in AD.},
}

*Alzheimer Disease/complications/physiopathology
*Bibliometrics
Humans
*Olfaction Disorders/physiopathology/etiology
*Biomedical Research/trends

@article {pmid42469999,
year = {2026},
author = {Xu, D and Zhou, W and Qiu, H},
title = {Association between dietary antioxidant quality score and cognitive function in older adults: A cross-sectional study based on NHANES 2011-2014.},
journal = {Medicine},
volume = {105},
number = {29},
pages = {e49758},
doi = {10.1097/MD.0000000000049758},
pmid = {42469999},
issn = {1536-5964},
mesh = {Humans ; *Antioxidants/administration & dosage ; Cross-Sectional Studies ; Female ; Aged ; *Cognition/physiology/drug effects ; Nutrition Surveys ; Male ; *Diet ; Middle Aged ; *Cognitive Dysfunction/epidemiology ; Aged, 80 and over ; },
abstract = {The aim of this study was to examine the connection between the dietary antioxidant quality score (DAQS) and cognitive impairment in older adults. This cross-sectional study of 2713 older adults aged ≥ 60 years from the 2011 to 2014 National Health and Nutrition Examination Survey cohort evaluated cognitive performance at quartile thresholds using the digit symbol substitution test, the animal fluency test, and the consortium to establish a registry for Alzheimer disease word learning test. Vitamins A, C, E, zinc, selenium, and magnesium consumption were used to calculate the DAQS score. Multiple linear regression and logistic regression analyses were used to evaluate the association between DAQS and the cognitive capacities of senior citizens. In the fully adjusted model, higher DAQS was linked to less cognitive impairment (odds ratio = 0.34, 95% confidence interval: 0.22-0.53). According to our research, older adults' cognitive decline is adversely correlated with higher DAQS, and improving their antioxidant intake may help them improve cognitive function.},
}

Humans
*Antioxidants/administration & dosage
Cross-Sectional Studies
Female
Aged
*Cognition/physiology/drug effects
Nutrition Surveys
Male
*Diet
Middle Aged
*Cognitive Dysfunction/epidemiology
Aged, 80 and over

@article {pmid42461890,
year = {2026},
author = {Calandri, IL and Bocancea, DI and Allegri, RF and Suemoto, CK},
title = {Registry-Based Dementia Incidence in Argentina: A Nationwide, Decade-Long Analysis by Age, Sex, and Etiology.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-24},
doi = {10.1159/000553538},
pmid = {42461890},
issn = {1423-0208},
abstract = {BACKGROUND: National data on dementia incidence is scarce in low- and middle-income countries, limiting public health surveillance and planning. In Argentina, no nationwide estimates of dementia incidence exist despite rapid population aging. Administrative disability registries do not capture clinical disease onset; rather, they record certification events and therefore provide a registry-based proxy for population-level dementia surveillance in settings without prospective incidence cohorts.

METHODS: We conducted a population-based registry study using data from Argentina's National Registry of Persons with Disabilities between 2016 and 2022, excluding pandemic-disrupted years (2020-2021). Incident registry entries with dementia recorded as the primary cause of disability were identified using ICD-10 codes for Alzheimer's disease and related disorders (ADRD), vascular dementia, and other etiologies. Crude and age-standardized incidence (ASI) of dementia certification per 100,000 inhabitants were estimated by sex, age group, dementia subtype, and early- (<65 years) versus late-onset (≥65 years) dementia. Pre-specified sensitivity analyses quantified capture fraction against regional cohorts and adjusted temporal trends for an exogenous proxy of registry maturation.

RESULTS: In 2022, the registry-based crude dementia incidence was 47.7 per 100,000 inhabitants (95% CI: 46.6-48.7). Crude incidence was higher in women than men, whereas age-standardized incidence was comparable between sexes (48.1 vs. 45.5 per 100,000). Incidence increased steeply with age, from 0.9 per 100,000 at ages 40-45 to nearly 480 per 100,000 among individuals aged ≥95 years. ADRD predominated from approximately 55-60 years onward, while other etiologies were relatively more frequent at younger ages. Late-onset dementia incidence (≥65 years) was substantially higher than early-onset dementia (<65 years) (130.9 vs. 6.3 per 100,000). Provincial age-standardized rates varied from 4.7 to 137.7 per 100,000, and were strongly associated with care access metrics. Between 2016 and 2022, age-standardized incidence increased significantly (p<0.001); however, capture fractions of 6 to 12% relative to regional cohorts and a 45% attenuation of the temporal coefficient after adjustment for registry maturation.

CONCLUSIONS: This study provides the first nationwide characterization of registry-based dementia certification incidence in Argentina. Distinct age-, sex-, and etiology-specific patterns highlight different epidemiological scenarios for early- and late-onset dementia. Because these estimates reflect administrative certification rather than clinical disease onset and are subject to differential ascertainment, they should be interpreted as a lower bound of true incidence; nonetheless, they constitute a feasible and informative surveillance approach for countries lacking national clinical registries and can support health system planning and prevention strategies.},
}

@article {pmid42461977,
year = {2026},
author = {Zhu, C and Song, L and Mao, S and Li, K and Lin, X},
title = {Receptor-Ligand-Mediated Anchoring of Polyphenol Quantum Dots to Membrane Fragments for Precision Delivery in Alzheimer's Disease Therapy.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c10322},
pmid = {42461977},
issn = {1944-8252},
abstract = {Polyphenol-based carbon dots (PCDs) hold great promise for Alzheimer's disease (AD) treatment owing to their inherent antioxidant activity, ultrasmall size, and favorable blood-brain barrier (BBB) permeability. Nevertheless, rapid immune clearance and poor lesion targeting severely hinder their clinical translation. Conventional cell membrane coating is poorly compatible with ultrasmall PCDs, causing incomplete encapsulation, active site masking, and membrane protein inactivation. Herein, we fabricated a novel biomimetic nanostructure (MQCM) by anchoring mannose-modified quercetin nanodots (MQNDs) onto BV2 cell membrane fragments (CMFs) via specific mannose-CD206 receptor-ligand interactions. This unique binding strategy endowed MQCM with a high anchoring efficiency (84.3%) and improved structural stability. Distinct from conventional nonspecific membrane coating that shields active sites and impairs nanoparticle functionality, this design avoids such drawbacks and completely preserves the intrinsic bioactivity of MQNDs and membrane proteins. The optimized MQCM displays high BBB permeability (42.35%), precise BV2 targeting, and lesion-responsive drug release. BV2-derived CMFs prolong blood circulation and lesion retention of MQNDs, while the released MQNDs exert multiple anti-AD effects by regulating ROS homeostasis, inhibiting Aβ fibrillation, and promoting Aβ autophagy. Collectively, this integrated biomimetic system offers a precise AD therapeutic strategy and advances the clinical translation of PCD-based nanomedicines.},
}

@article {pmid42462262,
year = {2026},
author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M},
title = {Comparing Effectiveness of Antidepressants for Nursing Home Residents With Dementias and Depressive Symptoms.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70582},
pmid = {42462262},
issn = {1532-5415},
support = {5R01AG068450/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are frequently accompanied by depressive symptoms, which may accelerate cognitive decline and increase mortality. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed, yet comparative effectiveness evidence in nursing home residents with ADRD is scarce.

METHODS: We conducted a retrospective cohort study using linked CMS data (2011-2018) of long-stay nursing home residents aged ≥ 65 years with ADRD and baseline depressive symptoms who newly initiated an SSRI or SNRI. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9; self-report or observed) at baseline and 60-120 days after initiation. Outcomes were the change in PHQ-9 scores (continuous) and clinically meaningful improvement. Analyses used overlap propensity score and inverse probability of censoring weighted linear and log-binomial models with generalized estimating equations to account for clustering of nursing home residents. Intention-to-treat (ITT) analyses, as-treated, and subgroup analyses were conducted.

RESULTS: Among 19,397 SSRI initiators and 2581 SNRI initiators, 66.9% had mild depressive symptoms at baseline. Median time from initiation to follow-up assessment was 85 days. In ITT analyses, mean PHQ-9 change was -2.38 for SSRIs and -2.24 for SNRIs (adjusted difference: -0.15; 95% CI, -0.42 to 0.11); clinically meaningful improvement occurred in 55.2% versus 56.9% (risk difference: -1.57; 95% CI, -3.66 to 0.52). As-treated analyses yielded similar results, and findings were consistent across subgroups defined by baseline depression severity, cognitive function, dementia type, and sensitivity analyses.

CONCLUSIONS: SSRIs and SNRIs were similarly effective for depressive symptoms in nursing home residents with ADRD. Given this and modest improvement rates, antidepressant selection should be individualized, emphasizing safety and resident characteristics. Additional research is needed to inform the decision to treat or not to treat, specific medication selection, and when to stop treatment in this population.},
}

@article {pmid42462283,
year = {2026},
author = {Meng, W and Yang, Q and Xu, J and Huang, Y and Wang, C and Song, Q and Song, L and Bian, J and Ma, Q and Ma, A and Yin, R},
title = {Identifying sex-specific sub-phenotypes of Alzheimer's disease progression using longitudinal electronic health records.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106391},
doi = {10.1016/j.ebiom.2026.106391},
pmid = {42462283},
issn = {2352-3964},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a complex neurodegenerative disorder, with women comprising nearly two-thirds of individuals with AD. However, sex-specific heterogeneity in AD progression remains insufficiently understood. A data-driven approach is needed to characterise such heterogeneity from longitudinal electronic health records (EHRs).

METHODS: We developed a deep learning-based framework to uncover sex-specific AD sub-phenotypes using longitudinal EHRs from OneFlorida+ Clinical Research Consortium. We constructed temporal representations of these EHRs and employed an autoencoder architecture to generate latent embeddings, followed by clustering to derive sex-specific sub-phenotypes with associated progression patterns. We also performed statistical and survival analyses to unravel the characteristics of our identified sub-phenotypes.

FINDINGS: From 1665 individuals with AD (961 females, 704 males), we identified five major sex-specific sub-phenotypes of AD with distinct progression pathways and comorbidity patterns. Female-dominant sub-phenotypes presented later AD onset, longer disease duration, and enrichment of respiratory and neurological disorders. Male-dominant sub-phenotypes exhibited earlier onset, shorter duration, and higher prevalence of endocrine and metabolic conditions. Survival analysis showed significant differences in time to AD onset across sub-phenotypes.

INTERPRETATION: Our findings revealed distinct disease trajectories and comorbidity patterns between male- and female-dominant subgroups with AD. This study provides insight into sex-specific AD progression and demonstrates a data-driven framework for characterising disease heterogeneity using longitudinal EHRs.

FUNDING: This study was supported by grants from the Florida Department of Health, the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences, and the NIHNational Center for Advancing Translational Sciences.},
}

@article {pmid42462317,
year = {2026},
author = {Ban, Y and Miao, W and Jin, X and Chen, S and Lou, X and Wu, JL and Li, N},
title = {The underappreciated diversity of functional pigments in red yeast rice revealed by an integrated multi-engine mining strategy (IMMS).},
journal = {Food chemistry},
volume = {525},
number = {Pt 1},
pages = {150424},
doi = {10.1016/j.foodchem.2026.150424},
pmid = {42462317},
issn = {1873-7072},
abstract = {Red yeast rice (RYR) is a popular functional food, while its functional components remain severely understudied. This study developed an integrated multi-engine mining strategy (IMMS) ingeniously combining feature-based molecular networking, building blocks-based molecular networking, SIRIUS, PEAKS, and BUDDY to comprehensively analyze RYR components. Employing IMMS, 219 pigments (208 red, 6 orange, 5 yellow) and 104 peptides were first identified, including 185 potential new pigments, with red and yellow pigments showing higher contents. Notably, red pigments demonstrated optimal plasma exposure and brain distribution in rats after oral RYR. Bioactivity analysis first revealed that six typical pigments, especially red, suppressed oxidative stress and neuroinflammation related to Alzheimer's disease in L-Glu-induced HT-22 cells and LPS-induced BV-2 cells, potentially via the Keap1-Nrf2 and IDO1 pathways, respectively. These findings significantly expanded the pigment diversity and RYR components, facilitating the discovery of functional components and providing a foundation for RYR's development as an anti-Alzheimer's functional food.},
}

@article {pmid42462433,
year = {2026},
author = {Bernardes, LMM and Marquez, AS and do Prado Mascarenhas, FNA and de Freitas, LF and Ferreira, DC and Malta, SM and Moreira, AS and Mendonça, TP and Bernardo de Sousa, JN and Silva, ÍF and Correia, LIV and Martins, MM and Ferreira, RB and Zhu, A and Zhang, H and Adebiyi, O and Leung, AK and Espindola, FS and Leite, ML and Ueira-Vieira, C and Mendes-Silva, AP},
title = {Acetonic extract of Saskatoon berry attenuates amyloid-associated neurotoxicity in cellular and Drosophila melanogaster Alzheimer's disease models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {202},
number = {},
pages = {119774},
doi = {10.1016/j.biopha.2026.119774},
pmid = {42462433},
issn = {1950-6007},
abstract = {Saskatoon berry (Amelanchier alnifolia) is rich in polyphenols known to modulate oxidative stress and neuroinflammation, key mechanisms involved in Alzheimer's disease (AD), yet its neuroprotective potential in this context remains unexplored. Here, we investigated two Saskatoon berry extracts, acetonic and ethanolic, using integrated chemical, computational, cellular and in vivo approaches. Antioxidant activity was confirmed in multiple assays, with stronger radical scavenging and moderate reducing capacity. Chemical profiling revealed solvent-dependent differences in phenolic and flavonoid content. In neuroglial models, the ethanolic extract showed mild-cytotoxicity, whereas the acetonic extract exhibited a favorable safety profile. In an amyloid-beta-induced cellular model, the acetonic extract produced only modest effects on viability. Furthermore, fibroblasts assays showed increased total ATP under non-inflammatory conditions, whereas in the LPS-stimulated inflammatory model the extract increased mitochondrial membrane potential. In contrast, in vivo studies using Drosophila melanogaster AD models showed protective effects of the acetonic extract, including reduced ThT-reactive fluorescence and increased retinal thickness, while improved survival was observed in w[1118] flies. Gene expression analysis of flies' brain tissue showed altered expression of selected mitochondrial- and immune-related genes. The AD-like model showed increased expression of co1, nd1, tfam and dipt, which were significantly reduced following treatment. Overall, these findings identify Saskatoon berry as a novel natural source of bioactive compounds with anti-Alzheimer's potential and suggest that the in vivo protective effects may involve mitochondrial homeostasis and immune-related processes, warranting future mechanistic studies and neuronal-specific validation in more complex organisms.},
}

@article {pmid42462519,
year = {2026},
author = {Morsy, NA and El-Shiekh, RA and Ebrahium, MM and Srour, AM},
title = {Rational design and synthesis of dispiroindene-pyrrolidinedione scaffolds as multi-target directed ligands: potent AChE inhibitors with antioxidant activity and favorable biocompatibility in SH-SY5Y cells.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110245},
doi = {10.1016/j.bioorg.2026.110245},
pmid = {42462519},
issn = {1090-2120},
abstract = {Addressing the urgent need for multi-target therapies in Alzheimer's disease, we report the rational design and one-pot, multi-component synthesis of novel substituted dispiroindene-pyrrolidinedione scaffolds (4a-r). Systematic biological evaluation identified five lead compounds (4g, 4j, 4k, 4m, and 4p) with potent inhibitory activity. Derivative 4k emerged as the primary lead, exhibiting an IC50 for Acetylcholinesterase (AChE) of 2.58 ± 0.11 μM and a remarkable selectivity index of 15.71, significantly exceeding that of donepezil (4.37), the reference drug. Concurrently, the series demonstrated notable affinity for Butyrylcholinesterase (BChE), with several derivatives exhibiting submicromolar to low micromolar inhibition. Furthermore, these scaffolds demonstrated superior antioxidant potential; notably, compound 4p achieved an IC50 value of 25.23 ± 1.25 μM, demonstrating an approximate 5-fold increase in radical scavenging potency relative to ascorbic acid (128.20 μM). In vitro safety assays on SH-SY5Y human neuroblastoma cells confirmed excellent biocompatibility, with compound 4m displaying an IC50 of 125.00 ± 6.91 μM, nearly four times less toxic than donepezil (32.84 μM). Molecular docking validated these results, showing robust π-π stacking and halogen-based stabilization within the catalytic anionic site. These findings, supported by ADME profiles predicting high blood-brain barrier permeability, position the dispiroindene-pyrrolidinedione framework as a highly effective, low-toxicity, multi-functional candidate for the development of Alzheimer's disease therapeutics.},
}

@article {pmid42462634,
year = {2026},
author = {Wang, X and Tong, J and Wang, M and Du, B and Wang, H and Liu, H and Yang, X and Mu, R and Wang, K and Liu, X and Wang, Q},
title = {Amyloid-like nanofilm-decorated antifouling field effect transistor biosensor array for enhancing Alzheimer's disease diagnosis.},
journal = {Biosensors & bioelectronics},
volume = {312},
number = {},
pages = {119030},
doi = {10.1016/j.bios.2026.119030},
pmid = {42462634},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Compared to the limited specificity of single-biomarker detection, the combined detection of multiple biomarkers can significantly improve the accuracy of AD diagnosis. In this study, a field-effect transistor (FET) biosensor array integrating four independently functionalized regions was fabricated by modifying carbon nanotube (CNT) surfaces with amyloid bovine serum albumin (AL-BSA) nanofilm as an antifouling layer, enabling the simultaneous detection of multiple tau proteins. The proposed FET biosensor exhibited excellent anti-fouling performance while maintaining high sensitivity, with detection limits as low as 3.3 fg/mL, 0.17 fg/mL, 0.02 fg/mL, and 2.5 fg/mL for p-tau181, p-tau217, p-tau231, and t-tau, respectively. Evaluation of 35 clinical serum samples indicated that p-tau181 outperformed the other three tau proteins as an AD diagnostic biomarker. By further incorporating a support vector machine (SVM)-based machine learning algorithm and employing multi-biomarker co-detection, the accuracy of AD diagnosis can be improved to nearly 100%. This study provides a novel strategy for array FET biosensors with high clinical application potential for the precise detection of AD.},
}

@article {pmid42462667,
year = {2026},
author = {Yang, F and Chen, Y and Yan, Y and Zhao, R and Deng, L and Tian, D and Wang, Q and Xie, M},
title = {RVG-functionalized microglial membrane-coated cerium-gallic acid metal-organic frameworks for multi-target Alzheimer's therapy.},
journal = {Journal of colloid and interface science},
volume = {724},
number = {Pt 2},
pages = {141133},
doi = {10.1016/j.jcis.2026.141133},
pmid = {42462667},
issn = {1095-7103},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by aberrant β-amyloid (Aβ) aggregation, oxidative stress, neuroinflammation, and disrupted metal ion homeostasis, which limit the efficacy of conventional single-target therapies. To address these intertwined pathological processes, we developed a multifunctional nanotherapeutic platform based on a cerium-gallic acid bio-metal-organic framework (CeGA-MOF). Reversible Ce[3+]/Ce[4+] redox cycling enables efficient reactive oxygen species (ROS) scavenging, while gallic acid serves as both an organic ligand and metal chelator, inhibiting metal ion-mediated Aβ aggregation and alleviating oxidative stress-associated neurotoxicity, along with its intrinsic anti-inflammatory activity. To enhance in vivo stability and brain delivery, CeGA-MOF was coated with microglial membranes and functionalized with rabies virus glycoprotein (RVG) peptide, yielding a biomimetic nanosystem, CeGA-MOF/B/R. The microglial membrane provides immune evasion and inflammation-guided targeting, while RVG facilitates blood-brain barrier penetration. In vitro, CeGA-MOF/B/R effectively chelates Cu[2+], Zn[2+], and Fe[3+], suppresses metal ion-induced Aβ aggregation, and protects neurons. In APP/PS1 transgenic mice, it reduced cerebral Aβ, promoted anti-inflammatory microglial polarization, and improved learning and memory, highlighting its potential as a biomimetic nanoplatform for synergistic AD therapy.},
}

@article {pmid42463036,
year = {2026},
author = {Cheng, M and Zheng, X and Wei, YD and Ge, JF},
title = {Role of Abca7-related microglial responses in linking type 2 diabetes mellitus to Alzheimer's Disease progression: Evidence from single-cell transcriptomic analysis and experimental validation in animal and cell models.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179152},
doi = {10.1016/j.ejphar.2026.179152},
pmid = {42463036},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share overlapping pathological mechanisms characterized by neuroinflammation and metabolic dysfunction, yet the underlying mechanisms remain elusive. In this study, we aimed to investigate the potential involvement of Abca7 in the microglial responses linking AD and T2DM. Single-cell RNA sequencing (scRNA-seq) data from the hippocampi of db/db and db/m mice were analyzed to characterize cellular heterogeneity. To validate the bioinformatic findings, an AD mouse model was established by a single intracerebroventricular injection of Aβ1-42. Behavioral performances were observed, and the protein expression of Abca7 and typical neuropathological features of AD were detected. In parallel, in vitro studies were conducted using BV2 microglial cells exposed to Aβ1-42 following Abca7 knockdown. The scRNA-seq analysis revealed significant alterations in endothelial cells, microglia, and oligodendrocytes in db/db mice. Microglia emerged as central regulators of neuroinflammatory responses, with Abca7 identified as a hub gene linked to both T2DM and AD pathology. Consistently, the expression of Abca7 in the hippocampus of AD mice was markedly elevated and positively correlated with the cognitive impairments and Aβ/Tau pathology. Moreover, the knockdown of Abca7 could protect BV2 cells against Aβ-induced injuries and hyperactivation which could be partly ascribed to the suppression of NF-κB signaling and oxidative stress. Overall, these results suggest Abca7 may play a linking role in the microglial response between T2DM and AD, which is partly supported by in vivo and in vitro results of its effect on the hyperactivation of microglia in AD-like pathologies.},
}

@article {pmid42463181,
year = {2026},
author = {Kuznetsov, AV},
title = {Predicting biological age using an accumulated neurotoxicity biomarker for amyloid Beta oligomers.},
journal = {Mathematical medicine and biology : a journal of the IMA},
volume = {},
number = {},
pages = {},
doi = {10.1093/imammb/dqag005},
pmid = {42463181},
issn = {1477-8602},
abstract = {This study proposes using accumulated neurotoxicity, defined as the time integral of Aβ oligomer concentration, as a biomarker for neuronal aging. A relationship between biological age and accumulated neurotoxicity is proposed. Numerical analysis guided the development of a new analytical solution linking the biological and calendar ages of neurons. The effects of Aβ monomer and oligomer half-lives-key indicators of proteolytic efficiency-on biological age are examined. Both constant and age-dependent (exponentially increasing) half-life scenarios are considered. The findings indicate that increasing the half-life of Aβ monomers and oligomers with age accelerates biological aging. Reducing Aβ monomer production is shown to slow biological aging, with a linear relationship established between these two quantities. Additionally, biological age is found to depend linearly on the half-deposition time of Aβ oligomers into senile plaques. The model demonstrates that biological age is irreversible, providing a theoretical explanation for why plaque-clearing therapies cannot reverse established cognitive impairment. The model also demonstrates that biological age is path-dependent rather than state-dependent.},
}

@article {pmid42463287,
year = {2026},
author = {Maass, A and Garcia-Garcia, B and Behrenbruch, N and Schumann-Werner, B and Molloy, EN and Schwarck, S and Rullmann, M and Hochkeppler, A and Fischer, L and Büchel, AT and Bernal, J and Vockert, N and Incesoy, EI and Glanz, W and Butryn, M and Schulze, P and Baldauf, K and Stephens, AW and Schildan, A and Patt, M and Behnisch, G and Morgado, B and Esselmann, H and Seidenbecher, CI and Schott, BH and Wiltfang, J and Barthel, H and Sabri, O and Kreissl, MC and Düzel, E},
title = {Associations of [[18]F]PI-2620 Binding with Memory and Phosphorylated Tau 217 in Cognitively Unimpaired Older Adults.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271927},
pmid = {42463287},
issn = {1535-5667},
abstract = {[[18]F]PI-2620 is a second-generation tau PET tracer that may detect early tau accumulation in aging. We investigated whether temporal lobe [[18]F]PI-2620 binding is associated with age, sex, genetic Alzheimer disease (AD) risk, plasma biomarkers of AD (plasma phosphorylated tau 217 [p-tau217], Aβ1-42/Aβ1-40), astrogliosis (glial fibrillary acidic protein), and domain-specific cognition in cognitively unimpaired (CU) older adults. Methods: In this study, 166 CU older adults (mean age, 72 ± 7 y; females, 46%; apolipoprotein ϵ4 [APOE4] carriers, 23%) and 13 young adults underwent extensive cognitive testing, blood sampling, MRI, and dynamic [[18]F]PI-2620 PET (0-60 min postinjection). Associations of regional [[18]F]PI-2620 distribution volume ratio (DVR) with age, sex, APOE4 genotype, and plasma biomarkers were examined using region-of-interest and voxelwise analyses. Additional imaging markers of age-related pathology included hippocampal volume, medial temporal lobe thickness, white matter (WM) hyperintensities, perivascular spaces, and hippocampal perfusion (R1-derived maps). Associations among temporal lobe DVR, other imaging markers, and domain-specific cognitive performance (from factor analysis) were tested. Results: In older adults, temporal [[18]F]PI-2620 binding was higher in women (β = 0.543, P < 0.001) and APOE4 carriers (β = 0.395, P = 0.030) and was positively associated with plasma p-tau217 (β = 0.22, P = 0.008). Voxelwise analyses showed age-related increases in basal ganglia signal, whereas WM signal was higher in younger adults. In a multiple regression model, higher temporal DVR (β = -0.36, P = 0.003) and lower hippocampal volume (β = 0.22, P = 0.007) predicted worse episodic memory and, together with demographic factors, explained approximately 30% of the variance. Conclusion: Temporal [[18]F]PI-2620 binding is associated with genetic AD risk, plasma p-tau217, female sex, and episodic memory deficits in CU older adults, supporting its sensitivity to early tau pathology, while highlighting the need to consider potential WM binding.},
}

@article {pmid42463411,
year = {2026},
author = {Shi, Y and Liao, X and Yu, G},
title = {Advances in Tricyclic Compounds for the Treatment of Alzheimer's Disease.},
journal = {ChemMedChem},
volume = {21},
number = {14},
pages = {e70384},
doi = {10.1002/cmdc.70384},
pmid = {42463411},
issn = {1860-7187},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Animals ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder involving interconnected pathological pathways, including cholinergic dysfunction, Aβ deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and dysregulation of metal ion homeostasis. Recently, the "one drug, one target" paradigm has faced certain clinical limitations, driving a paradigm shift toward multi-target therapeutic strategies. In this context, tricyclic scaffolds, characterized by rigid fused-ring skeletons, excellent structural tunability, and favorable neuropharmacological properties, have emerged as promising scaffolds for developing multi-target AD therapeutics. These molecules can interact with multiple AD-related targets through stable π-π stacking and hydrophobic interactions. Some tricyclic scaffolds, such as tetrahydrocarbolines, share structural similarity with endogenous neurotransmitters, suggesting potential involvement in modulating cognitive and mood-related pathways, along with favorable BBB permeability and neuro-compatibility. Accordingly, this review begins by outlining the distinct pathological mechanisms underlying AD, followed by a summary of recent progress on tricyclic compounds, encompassing both single-target and multi-target-directed molecules, with an emphasis on structure-activity relationships and mechanisms of action, aiming to offer new insights and strategies for combating this devastating disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
Structure-Activity Relationship
Animals
*Cholinesterase Inhibitors/chemistry/pharmacology
Molecular Structure
Oxidative Stress/drug effects

@article {pmid42463545,
year = {2026},
author = {Trares, K and Duman, D and Beyer, L and Michaelian, JC and Stocker, H and Holleczek, B and Beyreuther, K and Schöttker, B and Gerwert, K and Brenner, H},
title = {Predictive value of plasma p-tau217 for Alzheimer's dementia compared to other blood-based biomarkers.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42463545},
issn = {1757-4684},
abstract = {Phosphorylated-tau (p-tau217) is a promising blood-based biomarker for Alzheimer's dementia (AD) in clinical settings. However, research from prospective cohort studies is sparse. We measured plasma p-tau217 levels in baseline blood samples of 779 participants in a population-based cohort of older adults followed over 17 years. Associations with AD were assessed and compared to those with previous measurements of p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Comparisons to the amyloid beta (Aβ) misfolding biomarker were performed in a subgroup analysis. P-tau217, NfL and GFAP showed strong associations with AD risk, especially within the first 9 years of follow-up, outperforming p-tau181. Over the later years of follow-up, the predictive accuracy of p-tau217 was significantly reduced. In contrast, the Aβ misfolding biomarker demonstrated superior performance especially as a preclinical indicator of the risk of AD many years before diagnosis. The combination of p-tau217 with NfL, GFAP, basic demographic and genetic information, as well as the misfolding biomarker yielded an AUC 0.86 for AD diagnoses over the entire 17-year follow-up period.},
}

@article {pmid42463666,
year = {2026},
author = {Bjørnholm, KD and Li, H and Del Gaudio, F and Mocci, G and Shao, W and Baldisseri, E and Rao, SB and Lindblad, C and Fletcher-Sandersjöö, A and Vázquez-Liébanas, E and Pietilä, R and Muhl, L and Jiang, R and Kalantzi, C and Cheung, J and Jin, S and Svensson, M and Lesnik Oberstein, SAJ and Syvänen, S and Mäe, MA and Torp, R and Lendahl, U and Karlström, H and Thelin, EP and Nilsson, P and Vanlandewijck, M},
title = {Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42463666},
issn = {2041-1723},
mesh = {Animals ; *Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/pathology/metabolism ; Disease Models, Animal ; Mice ; Humans ; *Brain Injuries, Traumatic/genetics/pathology/metabolism ; *CADASIL/genetics/pathology/metabolism ; Transcriptome ; Mice, Transgenic ; Male ; Brain/blood supply/pathology/metabolism ; Single-Cell Analysis ; },
abstract = {The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.},
}

Animals
*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/pathology/metabolism
Disease Models, Animal
Mice
Humans
*Brain Injuries, Traumatic/genetics/pathology/metabolism
*CADASIL/genetics/pathology/metabolism
Transcriptome
Mice, Transgenic
Male
Brain/blood supply/pathology/metabolism
Single-Cell Analysis

@article {pmid42463670,
year = {2026},
author = {Anwer, D and A, A and Marchi, A and Kerkhoven, E and Polster, A},
title = {Network-based discovery of regulatory drivers of cognitive decline in alzheimer's disease.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42463670},
issn = {2731-6068},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, yet its transcriptional regulatory architecture remains poorly understood. Here, we model sample-specific gene regulatory networks (GRNs) from dorsolateral prefrontal cortex transcriptomes of 87 individuals with AD and 67 non-cognitively impaired (NCI) controls and use a machine learning classifier to detect consistent disease-specific network features. This sample-specific network approach captures inter-individual variation in transcriptional regulation and revealed 22 key transcription factor-gene regulations that distinguish AD from NCI with 96% weighted accuracy. The key transcription factor-gene interactions were enriched in pathways central to AD pathology, including synaptic signalling, mitochondrial function, proteostasis, and neuroinflammation. Network analysis uncovered significant differences in regulatory connectivity between AD and controls, with ZNF225, ZNF849, and ZNF548 emerging as AD-specific regulatory hubs. Moreover, several key regulatory edges showed significant correlations with longitudinal cognitive decline, supporting their clinical relevance. Our findings highlight pervasive transcriptional dysregulation in AD, emphasizing sample-specific GRN modelling's value in uncovering regulatory mechanisms.},
}

@article {pmid42463907,
year = {2026},
author = {Yang, D and Guo, W and Wang, B},
title = {The Exercise-CTSS-AD Axis: a novel framework for understanding exercise-induced neuroprotection in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42463907},
issn = {1573-7365},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; Animals ; *Cathepsins/metabolism ; *Neuroprotection/physiology ; *Exercise/physiology ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Disease-modifying therapies for Alzheimer's disease (AD) targeting amyloid-β and tau have consistently failed, highlighting the urgent need for innovative therapeutic strategies. Cathepsin S (CTSS), a lysosomal cysteine protease upregulated in AD, functions as a "multifaceted disruptor" that interconnects neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ metabolic dysregulation. Although exercise is a validated non-pharmacological intervention that mitigates AD pathology, its multi-target molecular mechanisms remain elusive. Here, we propose and substantiate the "Exercise-CTSS-AD Axis" hypothesis, positing that exercise confers neuroprotection by suppressing CTSS through synergistic anti-inflammatory, anti-aging, and metabolic regulatory pathways. Exercise-induced myokines and clearance of senescent cells inhibit CTSS transcription, while AMPK-TFEB axis activation enhances lysosomal function to repress CTSS enzymatic activity. This systemic CTSS suppression preserves BBB integrity, ameliorates microglia-driven neuroinflammation, and restores Aβ homeostasis by reducing production and enhancing clearance. Our framework provides a unifying molecular explanation for the pleiotropic benefits of exercise, positions CTSS as a quantifiable biomarker for personalized exercise regimens, and supports an innovative combinatorial strategy: "Exercise + low-dose CTSS inhibitors" as a disease-modifying therapy for AD.},
}

*Alzheimer Disease/metabolism/therapy
Humans
Animals
*Cathepsins/metabolism
*Neuroprotection/physiology
*Exercise/physiology
Blood-Brain Barrier/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42463911,
year = {2026},
author = {Wang, Y and Xiong, X and Zhang, R and Xiao, L and Ruan, X and Ni, T and Liu, Z and Chen, J and Qin, S and Du, Z and Zhang, Y and Wu, L},
title = {Developmental priming of adult proteostasis and longevity by NuA4 complex activity in early life.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {42463911},
issn = {1460-2075},
support = {32271357//MOST | National Natural Science Foundation of China (NSFC)/ ; 32071151//MOST | National Natural Science Foundation of China (NSFC)/ ; 2022XHSJJ005//MOST | NSFC | NSFC-Zhejiang Joint Fund | | Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents/ ; },
abstract = {Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4 acetyltransferase complex activity enduringly enhances proteostasis and extends lifespan. Mechanistically, NuA4 reduction depletes H4K16ac, triggering a compensatory, early-life-biased, XBP-1-mediated unfolded protein response (UPR[ER]). This UPR[ER] activation remodels endoplasmic reticulum (ER) morphology and reprograms lipid metabolism, driving selective oleic acid (OA) accumulation. Crucially, this developmentally-installed OA reservoir confers lasting resilience against proteotoxic stress, an effect mimicked by OA supplementation. Together, these findings establish a chromatin-ER-lipid axis that developmentally primes adult proteostasis and suggest early-life interventions as a strategy to promote healthy aging and resilience to proteotoxic stress.},
}

@article {pmid42463967,
year = {2026},
author = {Xu, X and Liu, D and Sun, X and Yang, K and Lv, P and Lu, J and Ruan, W and Xia, X and Chen, J and Chen, Y and Wang, H and Wu, X and Ge, D and Yang, B and Wan, M and Liang, H and Lan, X and Gai, Y and Zhang, B},
title = {In vivo multimodal PET/MRI imaging and plasma biomarkers implicate glymphatic dysfunction linking neuroinflammation to tau pathology in the early Alzheimer's disease continuum.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42463967},
issn = {1619-7089},
support = {2022ZD0211800//Instituto Nacional de Ciência e Tecnologia Centro de Estudos das Adaptações da Biota Aquática da Amazônia/ ; },
abstract = {PURPOSE: Neuroinflammation is a key factor contributing to cognitive decline in Alzheimer's disease (AD). This study aims to investigate the mechanistic associations among neuroinflammation, glymphatic dysfunction, tau pathology, and cognitive decline in AD spectrum.

METHODS: The study included 355 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and a supportive cohort of 59 individuals from Wuhan Union Hospital (WHUH). Tau pathology was quantified using [18]F-AV1451 positron emission tomography (PET). Glymphatic function was estimated through diffusion tensor image analysis along the perivascular space (DTI-ALPS). Neuroinflammation was assessed via plasma glial fibrillary acidic protein (GFAP) in two cohorts and translocator protein (TSPO) PET imaging with [18]F-DPA-714 in supportive cohort. Correlation analyses and mediation models were employed to evaluate the directional relationships among tau deposition, inflammation, glymphatic function, and cognition.

RESULTS: Higher levels of inflammation were significantly associated with lower DTI-ALPS index (β = -0.171, P = 0.046), which in turn was associated with higher tau burden (β = 0.162, P = 0.010). Path analysis revealed significant indirect associations linking neuroinflammation to cognitive performance through glymphatic dysfunction and tau pathology, with total indirect effects of - 0.165 (95% CI, - 0.266 to - 0.105) in ADNI and - 0.143 (95% CI, - 0.386 to - 0.013) in WHUH. These findings support a hypothesized inflammation-glymphatic-tau pathway rather than a definitive causal cascade.

CONCLUSION: Our findings are consistent with a hypothesized inflammation-glymphatic-tau association in which greater neuroinflammation is linked to reduced glymphatic function and higher regional tau burden, particularly in preclinical and prodromal stages.

This study obtained ethical approval from the Institutional Review Committee of Nanjing Drum Tower Hospital (ChiCTR-BRC-17011316, date:20170506; ChiCTR1900022526, date:20190415).},
}

@article {pmid42464002,
year = {2026},
author = {Delaporte, M},
title = {Associations Between Occupational Trajectories at Ages 35-55 and Later-Life Cognition in Older Adults in Chile.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag142},
pmid = {42464002},
issn = {1758-5368},
abstract = {OBJECTIVES: As global rates of Alzheimer's Disease and Related Dementias (AD/ADRD) increase, understanding the factors that contribute to cognitive aging is crucial. This study examined the association between occupational skill trajectories between ages 35 and 55 and cognitive function among older Chilean adults aged 60 and above. It explored how different patterns of occupational trajectories relate to cognitive performance.

METHODS: The analysis used data from the Chile-Cog study, which applied the Harmonized Cognitive Assessment Protocol (HCAP) to a nationally representative sample of Chilean adults in 2019. These cognitive assessments were linked to detailed occupational histories from the Chilean Social Protection Survey (SPS). Using Sequence Analysis, occupational trajectories between ages 35 and 55 were classified into nine groups for women and six groups for men. Cognitive function was measured using a composite cognitive score based on the HCAP items. Linear regression models estimated the associations between occupational trajectory groups and cognitive outcomes, separately for women (n=1,009) and men (n=769).

RESULTS: Individuals with longer participation in middle- and high-skill occupations showed better cognitive performance at older ages, whereas prolonged periods in low-skill jobs or not employed were associated with lower scores. However, no strong evidence emerged on associations between specific trajectories of occupational mobility and cognitive outcomes.

DISCUSSION: The findings suggest that cumulative time in higher-skill occupations may be more important for cognitive aging than occupational mobility itself. This study contributes to understanding how occupational trajectories shape cognition in later life and offers insights for countries undergoing economic and demographic transitions.},
}

@article {pmid42464008,
year = {2026},
author = {Lim, S and Lee, Y and Yun, CS and Kim, K and Yun, CH and , },
title = {Change in Amyloid-β Deposition and Diffusion Tensor Image Analysis along the Perivascular Space Index in Incident Neurodegenerative Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78301},
pmid = {42464008},
issn = {1531-8249},
support = {//National Research Foundation of Korea (NRF)/ ; },
abstract = {OBJECTIVE: We investigated the longitudinal association between cognitive decline, amyloid-β deposition, and perivascular diffusivity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) index.

METHODS: This 2-year longitudinal study included 211 participants from the Alzheimer's Disease Neuroimaging Initiative, categorized into sustained cognitively normal, incident mild cognitive impairment, persistent mild cognitive impairment, and incident Alzheimer's disease (AD). The DTI-ALPS index and amyloid-β standardized uptake value ratio (SUVR) from amyloid positron emission tomography were obtained at baseline and follow-up. Linear mixed-effects models were used to examine longitudinal changes in the DTI-ALPS index and their associations with cognitive decline and amyloid-β accumulation. Multiple mediation analyses were performed to evaluate whether amyloid burden and gray matter atrophy mediated the relationship between changes in the DTI-ALPS index and cognitive performance. Additional analyses assessed the effect of baseline amyloid-β positivity.

RESULTS: The incident mild cognitive impairment and incident AD groups showed greater longitudinal declines in the DTI-ALPS index than the sustained cognitively normal group. Longitudinal reductions in the DTI-ALPS index were associated with greater cognitive decline and increased amyloid-β accumulation. Mediation analyses showed no significant indirect effects through SUVR or gray matter volume. Although baseline amyloid-β positivity alone was not associated with longitudinal DTI-ALPS changes, significant interactions with clinical progression were observed.

INTERPRETATION: Longitudinal alterations in the DTI-ALPS index are associated with cognitive decline and amyloid-β accumulation. These findings support the DTI-ALPS index as a non-invasive imaging marker reflecting disease progression in AD. ANN NEUROL 2026.},
}

@article {pmid42464060,
year = {2026},
author = {Tekin, BN and Kaya, S and Erkoç Ataoğlu, NE and Teleş, M},
title = {The Effect of Caregiver Burden on Healthy Lifestyle Behaviours of People Caring for Patients With Alzheimer's Disease: A Cross-Sectional Study.},
journal = {Scandinavian journal of caring sciences},
volume = {40},
number = {3},
pages = {e70295},
doi = {10.1111/scs.70295},
pmid = {42464060},
issn = {1471-6712},
mesh = {Humans ; *Alzheimer Disease/nursing ; Cross-Sectional Studies ; Male ; Female ; *Caregivers/psychology ; Aged ; *Healthy Lifestyle ; Middle Aged ; Aged, 80 and over ; Turkey ; },
abstract = {OBJECTIVES: This study aimed to determine the effects of caregiver burden on the healthy lifestyle behaviours of people caring for patients with Alzheimer's disease.

METHODS: The Caregiver Burden Inventory (CBI) and the Healthy Lifestyle Behaviour Scale-II (HLBS-II) were administered to caregivers of Alzheimer's disease patients who were admitted to the Neurology Department Dementia Outpatient Clinic of a university hospital in Ankara (n = 84). Independent sample t-test, one-way ANOVA, Pearson correlation and linear regression analysis were used in the study.

RESULTS: A moderate, negative and statistically significant correlation was found between CBI and HLBS-II (r = -0.40; p < 0.001). The effect of CBI on HLBS-II was significant even in the presence of control variables (b = -0.29; p < 0.05). The increase in social burden (b = -0.92; p < 0.05) and developmental burden (b = -0.65; p = 0.053) of the CBI dimensions caused a decrease in healthy lifestyle behaviours.

CONCLUSIONS: Effective home care for Alzheimer's patients requires caregivers to maintain their own good health. This study demonstrates that increased caregiver burden, particularly in social and developmental domains, negatively impacts their healthy lifestyle behaviours. Policies should focus on reducing this burden to enhance caregiver well-being and ensure sustainable home care.},
}

Humans
*Alzheimer Disease/nursing
Cross-Sectional Studies
Male
Female
*Caregivers/psychology
Aged
*Healthy Lifestyle
Middle Aged
Aged, 80 and over
Turkey

@article {pmid42464289,
year = {2026},
author = {Zhan, X and Liu, C and Yu, C and Lindblom, N and Deierborg, T and Kobro-Flatmoen, A and Gouras, GK and Wen, G},
title = {Passive amyloid-β immunotherapy in Alzheimer's disease: a multicellular clearance system beyond plaque removal.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42464289},
issn = {1750-1326},
mesh = {*Alzheimer Disease/therapy/immunology ; Humans ; *Amyloid beta-Peptides/immunology/metabolism ; Animals ; *Plaque, Amyloid/immunology/therapy ; *Immunotherapy/methods ; *Immunization, Passive/methods ; Brain/metabolism ; },
abstract = {Passive immunotherapy targeting amyloid-β (Aβ) has emerged as a major therapeutic strategy for Alzheimer's disease (AD), yet its clinical benefits remain modest and are frequently accompanied by vascular adverse events such as amyloid-related imaging abnormalities (ARIA). While the removal of extracellular Aβ plaques is associated with therapeutic efficacy, accumulating evidence suggests that additional cellular and vascular mechanisms may also contribute to complementary therapeutic outcomes alongside plaque removal. Recent studies show that Aβ antibodies are broadly distributed within the brain and interact with multiple neural and immune cell populations, rather than being limited to Aβ plaques. These observations support an expanded view of passive Aβ immunotherapy as a multicellular coordinated clearance process. Aβ antibodies engage diverse cellular and anatomical compartments, including neurons, glial cells, perivascular macrophages, peripheral immune cells, and meningeal lymphatic pathways, thereby influencing Aβ dynamics across intracellular and extracellular pools. Within this framework, therapeutic outcomes are influenced not only by plaque clearance but also by interactions between Aβ antibodies and cellular and anatomical compartments that regulate Aβ clearance and treatment-associated vascular response. This perspective may help explain variability in clinical efficacy and the emergence of vascular side effects, while also providing additional considerations for optimizing Aβ antibody design and therapeutic strategies.},
}

*Alzheimer Disease/therapy/immunology
Humans
*Amyloid beta-Peptides/immunology/metabolism
Animals
*Plaque, Amyloid/immunology/therapy
*Immunotherapy/methods
*Immunization, Passive/methods
Brain/metabolism

@article {pmid42464353,
year = {2026},
author = {Al-Awlaqi, A and Berckmans, L and De Waegenaere, S and Vanherle, S and Griffis, J and Dewachter, I and Verhoye, M and Adhikari, MH},
title = {Resting-state functional dynamics alterations relate to plasma amyloid markers and statistically explain memory impairments in the TgF344-AD model of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02146-w},
pmid = {42464353},
issn = {1758-9193},
support = {G045420N//Fonds Wetenschappelijk Onderzoek/ ; SAO-FRA 2020/027//Internationale Stichting Alzheimer Onderzoek/ ; 50751//Bijzonder Onderzoeksfonds UAntwerp/ ; },
abstract = {BACKGROUND: Resting-state functional MRI studies of Alzheimer's disease (AD) show lower functional connectivity (FC) of AD-relevant regions and resting-state networks in patients and transgenic rodent models at symptomatic stages. However, at early stages of the disease, both hyper and hypo connectivity has been reported. Traditional FC overlooks temporal fluctuations in connectivity and network dynamics at a short timescale captured by transient brain states such as co-activation patterns (CAPs). CAPs have been shown to be more sensitive than FC to detect early alterations in neurodegenerative diseases and therefore can shed light on hyper versus hypo connectivity observed at early stages. Moreover, how brain functional signatures of Alzheimer's disease are related to its behavioral and pathological markers and whether they have prognostic relevance remain scarcely investigated.

METHODS: We acquired high temporal resolution resting-state functional MRI data in the TgF344-AD model rats and age-matched wild-type animals at 4 and 10 months of age corresponding to the pre-plaque and plaque stages, respectively and delineated brain functional alterations using FC and CAPs in the model animals. We also assessed the levels of amyloid beta (Aβ) in blood and working and reference memory performance in the same animals at the plaque stage and investigated their statistical relationship with pre-plaque and plaque-stage changes in FC and CAPs.

RESULTS: TgF344-AD rats had significantly elevated blood Aβ levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network compared to wild-type animals at the plaque stage. FC at the pre-plaque stage did not differ between TgF344-AD and wild-type rats. TgF344-AD rats showed hyper- and hypo-activation in the default-mode-like-network and hippocampal regions at pre-plaque and plaque stages, respectively, in multiple CAPs. Blood Aβ levels were statistically explained more accurately by plaque-stage, than pre-plaque stage, FC values and CAP activations. CAP activations, especially at the pre-plaque stage, outperformed FC in accurate statistical explanation of memory impairments.

CONCLUSION: Our findings demonstrate pre-plaque stage hyperconnectivity not in the traditional, static measure of functional connectivity but in transient, dynamic brain states and that these early brain functional signatures have prognostic relevance for memory deficits in a translational rat model of Alzheimer's disease.},
}

@article {pmid42464410,
year = {2026},
author = {Malichova, F and Swann, P and Kigar, SL and Savinykh Yarkoni, N and Goddard, J and Lai, KO and Chouliaras, L and Surendranathan, A and Turner, L and Savulich, G and Bevan-Jones, R and Ashton, NJ and Blennow, K and Zetterberg, H and Needham, E and Jones, J and McEwan, WA and Rowe, JB and O'Brien, JT and Malpetti, M},
title = {Blood-based immunophenotyping of T cell profiles in patients with neurodegenerative disorders.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02144-y},
pmid = {42464410},
issn = {1758-9193},
abstract = {BACKGROUND: There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes.

METHODS: Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD = 20, DLB = 24, FTD = 19, CBS = 18, PSP = 58, controls = 35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction.

RESULTS: There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217.

CONCLUSIONS: This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell populations across neurodegenerative conditions may inform target development and patient stratification for new interventional trials.},
}

@article {pmid42464798,
year = {2026},
author = {Alluri, R and Kilari, EK and Pasala, PK and Kopalli, SR and Koppula, S},
title = {RETRACTED: Alluri et al. Repurposing Diltiazem for Its Neuroprotective Anti-Dementia Role Against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer's Disease-Type Rat Model. Life 2023, 13, 1688.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
doi = {10.3390/life16071175},
pmid = {42464798},
issn = {2075-1729},
abstract = {The journal retracts the article titled "Repurposing Diltiazem for Its Neuroprotective Anti-Dementia Role against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer's Disease-Type Rat Model" [...].},
}

@article {pmid42464964,
year = {2026},
author = {Dajani, I and Mahboob, A and Ibrahim, SS and Ibrahim, RS and Sedighi, M and Shirzadi, Z and Mahinrad, S and Sabatini, S and Khatoonabadi, AR and Prina, M and Castro, CB and Mantegna, JL and Akkari, PA and Hosseini, AA and Martins, RN and Burley, CV and Dunne, J and Stephan, BC and Sohrab, HR and Chaari, A},
title = {Dementia in the Middle East and North Africa: an integrative narrative review of epidemiology, risk structure, and health system implications.},
journal = {Journal of global health},
volume = {16},
number = {},
pages = {04181},
doi = {10.7189/jogh.16.04181},
pmid = {42464964},
issn = {2047-2986},
mesh = {Humans ; Africa, Northern/epidemiology ; Middle East/epidemiology ; *Dementia/epidemiology ; Risk Factors ; Prevalence ; },
abstract = {BACKGROUND: Dementia prevalence in the Middle East and North Africa (MENA) is projected to rise exponentially, with estimates suggesting increases of 367% by 2050. This region faces distinctive challenges, including rapid demographic transition, high rates of modifiable risk factors, and fragmented health systems. This paper examines region-specific risk factors and pooled prevalence rates of dementia across the MENA region.

METHODS: We conducted a narrative review of dementia risk factors in the MENA region, including analysis of population-attributable risk (PAR) estimates and pooled estimates of dementia prevalence among adults aged 50 years and older.

RESULTS: Dementia prevalence was estimated at 1.84% among individuals aged 50 years and older, increasing to 3.81% among those aged 60 years and older, with substantial variability across countries. Smoking (>30%), physical inactivity ( ~ 50%), and high burdens of diabetes, hypertension, and obesity were consistently associated with increased dementia risk. Additional region-specific drivers include nutritional transitions, gut dysbiosis, consanguinity, and environmental risk factors such as air pollution and climate-related heat stress. Critical barriers to prevention and care include limited research infrastructure, low health literacy, stigma, and inequitable health care access.

CONCLUSIONS: Dementia prevalence in MENA is rising rapidly, driven by demographic change and high exposure to modifiable risk factors that are relatively region-specific in terms of their contribution. Strengthening prevention, early detection, and equitable access to care should be regional health priorities.},
}

Humans
Africa, Northern/epidemiology
Middle East/epidemiology
*Dementia/epidemiology
Risk Factors
Prevalence

@article {pmid42465239,
year = {2026},
author = {Dong, R and Wang, M and Wang, GT and DeWan, AT and Leal, SM},
title = {LDSC regression-based heritability estimates can be biased when summary statistics are obtained from meta-analysis or imputed variants.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.05.736573},
pmid = {42465239},
issn = {2692-8205},
abstract = {MOTIVATION: Linkage disequilibrium score (LDSC) regression is a popular method to estimate heritability for complex traits using summary statistics and linkage disequilibrium (LD) reference panels, offering a practical alternative to methods requiring individual-level data. Despite its widespread use, LDSC regression can produce biased heritability estimates. The properties of LDSC regression were investigated using summary statistics from several large-scale Alzheimer's disease (AD) studies and a variety of LD reference panels. These heritability estimates were compared with those obtained from individual-level data.

RESULTS: When LDSC regression was applied to summary statistics obtained from meta-analysis, it led to an underestimation of heritability. This can occur if meta-analysis is used to combine studies of different ancestries leading to the caveat of the lack of an appropriate LD reference panel. Additionally meta-analyses often include studies with different phenotype definitions, that not only impacts heritability estimates but also makes them uninterpretable. Summary statistics generated from imputed variants, even those with high imputation accuracy, can lead to underestimation of heritability. For example, the heritability estimates for AD were reduced from 0.265 (se 0.148) to 0.160 (se 0.041) when imputed variants (INFO>0.9) were included compared to analyzing only genotype array variants. A decrease in heritability estimates was also observed when individual-level imputed variant data were analyzed using GCTA-GREML. Our findings highlight the caveats of estimating heritability using meta-analysis summary statistics or imputed data instead of genotyped or sequence data.},
}

@article {pmid42465252,
year = {2026},
author = {Balistreri, A and Gomulinski, M and Chapman, MR and Kelly, JW},
title = {The Microglial Protein sTREM2 Inhibits the Bacterial Functional Amyloid CsgA and Suppresses Amyloid-Dependent Biofilm Formation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.03.736422},
pmid = {42465252},
issn = {2692-8205},
abstract = {Protein misfolding and aggregation, including amyloid fibril formation, underlie a large class of human diseases including prominent neurological disorders such as Alzheimer's and Parkinson's disease. A small number of human proteins have been identified that inhibit amyloidogenesis. One such protein is sTREM2, a soluble receptor liberated from microglia, the resident macrophages of the central nervous system. The extracellular domain of TREM2 is shed upon proteolytic cleavage to create sTREM2, which has previously been shown to inhibit amyloid-β aggregation in vitro . TREM2 is also expressed by intestinal macrophages, which are known to directly bind the bacterial amyloid curli and mount cytokine responses upon exposure. Here we show that sTREM2 is a sub-stoichiometric inhibitor of CsgA amyloidogenesis, CsgA being the major protein component of curli that drives biofilm formation in uropathogenic Escherichia coli and many other proteobacteria. In vitro , sTREM2 potently and sub-stoichiometrically inhibited CsgA amyloidogenesis in a dose-dependent manner. Kinetic modeling indicated that sTREM2 slowed primary and secondary nucleation, rather than altering fiber elongation. When added exogenously to bacterial growth medium, sTREM2 significantly suppressed curli-dependent pellicle biofilm formation without affecting bacterial growth. These findings establish sTREM2 as a member of the small group of human proteins capable of inhibiting bacterial functional amyloidogenesis, suggesting that gut-resident TREM2-expressing macrophages, which are already known to interact with curli, may employ sTREM2 as a physiologically relevant defense against bacterial amyloid formation.},
}

@article {pmid42465255,
year = {2026},
author = {Giorgio, J and Morin, TM and Chen, HY and Berry, AS and Breakspear, M and Jagust, WJ},
title = {Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.736872},
pmid = {42465255},
issn = {2692-8205},
abstract = {Throughout the preclinical phase of Alzheimer's disease (AD) β-amyloid (Aβ) accumulates preferentially within the default mode network (DMN), yet the functional and behavioural consequences of this pathological burden remain poorly understood. Using task-based fMRI combined with Aβ, tau, and dopamine PET in cognitively normal older adults, we show that Aβ burden impairs learning independent of tau, but this learning performance is recovered with higher dorsolateral striatal dopamine synthesis capacity. Investigating the neural mechanisms that support this learning, we observe that Aβ positive individuals show attenuated DMN activity to error related feedback, a metric that relates to poorer learning. When estimating the effective connectivity during feedback, computational modelling reveals that Aβ induces dis-inhibition of the DMN during error processing. Critically, dopamine synthesis capacity in the dorsolateral striatum rebalances effective connectivity between the DMN and frontostriatal network, thereby opposing Aβ related disruption. These findings establish a systems-level framework in which Aβ impairs learning by disrupting dynamic DMN modulation during feedback, a disruption for which dopaminergic function can partially compensate. This suggests that learning in the presence of Aβ may be subserved by dopamine-dependent network rebalancing, a candidate mechanism of cognitive resilience to support learning in preclinical AD.},
}

@article {pmid42465266,
year = {2026},
author = {Tsantilas, KA and Riffle, M and Merrihew, GE and Wu, CC and Keele, GR and Maurais, A and Johnson, RS and Luciano, A and Robinson, L and Churchill, GA and MacCoss, MJ},
title = {Circulating extracellular vesicles in plasma carry accessible molecular signatures of aging in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.10.737625},
pmid = {42465266},
issn = {2692-8205},
abstract = {Cells release membrane-bound extracellular vesicles into the bloodstream laden with proteins that may reflect their physiological state. How this circulating EV proteome changes across life remains poorly understood. Identifying molecular signatures of aging in accessible biofluids could facilitate earlier intervention and monitoring of age-related disease. Many circulating aging proteome studies rely on affinity-based platforms which suffer from poor cross-species translation, ambiguous signal attribution, and inconsistent agreement between platforms. Here, we present a characterization of the aging plasma EV proteome from a cross-sectional cohort of 86 male and female C57BL/6J mice (5-31 months). We leveraged a species-agnostic EV enrichment (Mag-Net) and mass spectrometry to detect 2,575 protein groups from 15,969 peptides. Protein abundance heterogeneity increased with age and the abundance of 272 proteins were significantly correlated with chronological age including established senescence and frailty markers. Proteins increasing with age were enriched in genome maintenance pathways, while those decreasing were associated with the extracellular matrix organization and lipid metabolism. Notably, several of the strongest age-increased proteins converged on Alzheimer's and Parkinson's disease pathology. We observed sexual divergence in the aging EV proteome not previously characterized at this resolution. A proteomic clock built from this data accurately predicts chronological age, and peptide-level analysis reveals aging signals invisible at protein-level. These findings demonstrate that EV-enriched plasma proteomics can identify known aging markers, reveal novel sex-specific age-related changes, and generate predictive models of chronological age. This study provides a species-agnostic foundation for proteomic clocks that complement epigenetic approaches to monitor aging and evaluate healthspan.},
}

@article {pmid42465286,
year = {2026},
author = {Lai, HY and Kalavros, N and Chung, V and Kaplan, ES and Anastassiou, D and Cai, L and Chen, E and Vélez, IG and Gürsoy, G and Herrera, LJ and Li, X and Londin, E and Loher, P and Nazeraj, I and Ortuño, F and Yang, TO and Rigoutsos, I and Rojas, I and , and Andreoletti, G and Foschini, L and Heath, L and Oskotsky, T and Sirota, M and Stolovitzky, G and Travaglini, KJ and Zou, J and Gabitto, MI},
title = {The SEA-AD DREAM Challenge: Community benchmarking human and AI agent solutions for Alzheimer's disease neuropathology prediction from single-nucleus transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.02.736180},
pmid = {42465286},
issn = {2692-8205},
abstract = {Single-nucleus transcriptomic atlases offer an unprecedented opportunity to connect cellular molecular states with Alzheimer's disease (AD) neuropathology, but whether these profiles encode reproducible, predictive information about pathological burden remains unclear. We present the SEA-AD DREAM Challenge, an open, international, model-to-data competition built on the Seattle Alzheimer's Disease Brain Cell Atlas to predict Alzheimer's disease neuropathological severity from single-nucleus RNA-sequencing data. Participants developed containerized models to predict categorical neuropathological staging, including overall Alzheimer's disease neuropathologic change, Braak stage, Thal phase, and CERAD score, as well as quantitative amyloid-β and phospho-tau burden measured by 6E10 and AT8 immunohistochemistry. Across 17 eligible teams from 15 countries, the crowdsourcing framework enabled systematic comparison of diverse computational approaches and surfaced a broad landscape of modeling strategies and candidate predictive features. Top-performing methods achieved near-perfect prediction of categorical staging, with the best submission reaching a quadratic weighted kappa of 1.0 for the Overall AD Neuropathological Change score (ADNC), and competitive prediction of quantitative pathological burden in held-out data, with a best concordance correlation coefficient of 0.48. Post hoc perturbation analyses revealed that top categorical-stage predictions relied heavily on donor-level metadata-driven signals rather than transcriptomic features, whereas quantitative pathology prediction was more robust and supported by transcriptomic and cell-type-associated features with potential biological relevance to AD progression. The challenge also introduced the first AI Agent Track in a DREAM Challenge, providing an early benchmark for autonomous and human-guided agentic model development in single-cell neuroscience. This work demonstrates that single-nucleus transcriptomes encode substantial information about Alzheimer's disease pathology, establishes a reproducible benchmark for molecular neuropathology prediction, and highlights critical principles for designing privacy-preserving, leakage-aware community challenges using deeply phenotyped human brain data.},
}

@article {pmid42465304,
year = {2026},
author = {Bai, H and Liu, Y and Seluanov, A and Gorbunova, V},
title = {Age-Associated Behavioral Alterations in Laboratory-Housed Octodon degus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.737045},
pmid = {42465304},
issn = {2692-8205},
abstract = {UNLABELLED: Octodon degus are long-lived, diurnal, and highly social rodents increasingly used in studies of aging and neurodegeneration. However, behavioral profiles of aged laboratory-housed degus remain incompletely characterized, limiting the interpretation of aging-associated functional and molecular phenotypes in this species. Here, we evaluated age-associated changes in locomotor activity, open-field exploration, social novelty behavior, and manually scored ethological responses in young and old degus maintained under long-term laboratory housing conditions. Automated behavioral tracking was performed during open-field testing and three-chamber social behavior testing. During open-field testing, old degus showed increased locomotor activity compared with young animals, including greater total distance moved, higher mean velocity, increased moving frequency, and longer cumulative movement duration. Old degus also showed increased center-zone duration and reduced thigmotaxis score. Manual ethological scoring revealed increased rearing and fecal boli in old animals during open-field exposure. In the three-chamber social behavior assay, young degus showed higher investigation frequency toward the novel intruder than toward the familiar cagemate, whereas old degus showed a lower social novelty discrimination index compared with young animals. Sex-stratified analyses did not identify significant male-female differences within young or old groups for the major open-field or social novelty metrics examined. Together, these findings indicate that aging in laboratory-housed degus is associated with a mixed behavioral profile involving increased stress-related ethological responses and reduced social novelty preference reminiscent of dementia-like behavioral changes observed in Alzheimer's disease. This behavioral framework provides a practical reference for future studies examining behavioral heterogeneity and molecular correlates of brain aging in degus.

LAY SUMMARY: Octodon degus are long-lived, highly social rodents that are increasingly used to study aging and age-related neurodegenerative disorders. However, interpreting behavioral changes in aged degus requires a clear understanding of how aging affects activity, exploration, social behavior, and stress-related responses under laboratory housing conditions. In this study, we compared young and old degus using open-field testing, three-chamber social behavior testing, automated video tracking, and manual scoring of selected behaviors. Aged degus did not show a simple reduction in behavioral activity. Instead, they showed increased movement during behavioral testing, increased rearing behavior, greater exploration of the center of the open-field arena, and increased fecal output during open-field exposure. These findings suggest that aged degus show increased exploratory activity together with altered stress-related responses in a novel environment. Aged degus also showed reduced preference for investigating a novel social partner, consistent with a dementia-like cognitive impairment. Together, these results define a behavioral profile of aged laboratory-housed degus and provide a practical reference for future studies using this species to investigate aging, social behavior, and neurodegeneration-related phenotypes.},
}

@article {pmid42465306,
year = {2026},
author = {Mulholland, MM and Magden, ER and Scholtzova, H and Hopkins, WD},
title = {A Comparative Study of Plasma Biomarkers of Neurodegeneration in Rhesus Monkeys (Macaca mulatta) and Baboons (Papio anubis).},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.02.735676},
pmid = {42465306},
issn = {2692-8205},
abstract = {Many nonhuman primate species recapitulate the neuropathological features of sporadic Alzheimer's disease (AD) to varying degrees. As with humans, the assessment of AD-related pathology in nonhuman primates has historically relied on the use of postmortem brain tissues. In vivo alternatives, such as PET imaging tracers and fluid biomarkers, have been developed for use in humans but require further validation in nonhuman primates before replacing postmortem analyses. Here we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA [TM]) CNS Disease panel to compare age-related changes in plasma biomarkers in two nonhuman primate species (rhesus monkeys and baboons). In addition, we examined whether amyloid and tau biomarkers were associated with brain atrophy, as measured by gray matter volume. We found significant associations between age and multiple biomarkers of neurodegeneration for both species, as well as significant differences in the patterns of these associations between the two species. For the phosphorylated tau measures, though rhesus monkeys had higher values, baboons showed significant and stronger associations with age. By contrast, rhesus monkeys exhibited an earlier age-related decline in Aβ42/Aβ40 ratio than baboons. Finally, in both species, lower Aβ42/Aβ40 ratios were associated with lower gray matter volumes. This is the first systematic comparative study of age-related changes in neurodegeneration biomarkers in two closely related nonhuman primates using comparable age ranges and sample sizes, and the same multiplex assay. Future studies should examine longitudinal changes in these biomarkers as well as validate the plasma findings using cerebral spinal fluid.},
}

@article {pmid42465338,
year = {2026},
author = {Dooling, BR and Vielle, A and Lucero, EM and Rydland, C and Quang, D and Summers, R and Esquer, H and Coughlan, C and Galbraith, MD and Espinosa, JM and LaBarbera, DV and Chial, HJ and Potter, H and Ledreux, A and Johnson, NR},
title = {Trisomy 21 cerebral organoids exhibit Alzheimer's disease amyloid and apolipoprotein E co-pathologies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.735908},
pmid = {42465338},
issn = {2692-8205},
abstract = {Adults with Down syndrome (DS) develop Alzheimer's disease (AD) brain pathology by age 40 due to triplication of the Amyloid Precursor Protein (APP) gene on chromosome 21. Inheritance of the apolipoprotein E-e4 (APOE4) allele of the APOE gene on chromosome 19 remains the greatest genetic risk factor for AD in the typical population, yet its role in DS-associated AD (DS-AD) neuropathogenesis in people with DS is unclear. We generated human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, and cerebral organoids (COs) using cells from people with DS and from euploid individuals. Aged DS COs were smaller than aged euploid COs and showed robust amyloid-β neuropathology that was positively correlated with the levels of apoE expression. We then captured extracellular vesicles (EVs) from the conditioned media of COs and observed a decrease in the levels of secreted AD-related proteins, including amyloid, contained within the EVs and in the media from which the EVs were isolated. We also identified distinct neuronal and astrocytic gene expression signatures in DS COs relative to euploid COs, including a set of genes known to interact with both APOE and APP at the gene and/or protein levels. Lastly, we determined that, despite differences in the expression levels of the specific genes involved, several common pathways were upregulated in T21 hiPSC-derived neurons, astrocytes, and COs, including apoptosis, the endolysosome, and structural stabilization pathways. Taken together, our findings provide novel insights into molecular mechanisms that may contribute to DS-AD and indicate that apoE plays an important role in the disease process.},
}

@article {pmid42465384,
year = {2026},
author = {Fuchs, U and Schröder, S and Pena, T and Krüger, DM and Burkhardt, S and Schütz, AL and Sananbenesi, F and Fischer, A},
title = {The lncRNA Gm16685 / MITA1 modulates inflammatory astrocyte reactivity through PCBP2 associated regulation of IKKβ signaling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.03.736437},
pmid = {42465384},
issn = {2692-8205},
abstract = {Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of cellular identity and disease associated gene expression programs, yet their role in astrocyte reactivity remains poorly understood. Here, we profiled lncRNA expression in primary mouse astrocytes exposed to inflammatory activation paradigms that model microglia driven signaling. This identified a conserved set of activation responsive lncRNAs, among which Gm16685 emerged as one of the most strongly induced candidates. Gm16685 and its human homolog MITA1 were enriched in the nucleus, and MITA1 expression was increased in selected human datasets from Alzheimer's disease, Parkinson's disease and frontotemporal dementia patients. Functional depletion of Gm16685 attenuated inflammatory gene expression and several activation associated astrocyte phenotypes, including reactive oxygen species production, glutamate handling, phagocytic activity and proliferation. Time-resolved transcriptomic analysis indicated that Gm16685 is required for the timely induction of inflammatory response genes. Mechanistically, Gm16685 / MITA1 interacted with the RNA binding protein PCBP2, and Gm16685 depletion was associated with reduced PCBP2 protein abundance, altered splicing of Inhibitor of NF-κB Kinase Subunit Beta (IKKβ) and a shift in downstream inflammatory signaling. Together, our findings identify Gm16685 / MITA1 as a conserved lncRNA regulator of astrocyte reactivity and suggest that non-coding RNA dependent control of RNA binding proteins contributes to inflammatory signaling in neurodegenerative disease relevant contexts.},
}

@article {pmid42465390,
year = {2026},
author = {Zhan, J and Yang, CA and Nellis, M and Tan, Y and Smith, MR and Alvarez, J and Liang, D and Dunlop, A and Martin, G and Go, YM and Jones, DP},
title = {Development of a metabolomics-based index to monitor dietary effects on chronic inflammation: The Dietary Metabolomics Inflammation Index.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.06.736618},
pmid = {42465390},
issn = {2692-8205},
abstract = {BACKGROUND: The Dietary Inflammatory Index (DII) is widely used to assess the inflammatory potential of diet, but it relies on self-reported dietary assessment and does not directly capture individual differences in metabolism as an intermediate connection to inflammation. High-resolution metabolomics provides objective measurements that complement dietary assessment to support precision nutrition to control inflammation.

OBJECTIVE: We developed, tested, and applied a Dietary Metabolite Inflammatory Index (DMII) to assess diet-related chronic inflammation using metabolites measured by liquid chromatography-high-resolution mass spectrometry.

METHODS: DII was calculated using dietaryindex R package with Block Food Frequency Questionnaire (FFQ) data. To develop the DMII, chronic inflammation-related dietary metabolites corresponding to the DII food parameters were found through a literature review. Dietary metabolites were identified and quantified by authentic standards by our established laboratory procedures. DMII uses the same inflammatory effect scores as the DII. Three DMII versions were developed: concentration-based, median-based, and quintile-based DMII. Mean and standard deviation of 29 dietary metabolites were calculated by using 3025 human plasma samples from 3 studies. DMII was tested in the Center for Health Discovery and Well-Being cohort (CHDWB) and the Atlanta African American Maternal and Child cohort (ATLAA) using chronic inflammation biomarkers, including high-sensitivity C-reactive protein (hs-CRP), CRP, and IL-6. The median-based DMII was further applied to four Alzheimer's disease metabolomics datasets as a proof-of-concept application.

RESULTS: In the CHDWB study, concentration-based DMII had a weak positive correlation with Block FFQ-derived DII and strongly correlated with median-based and quintile-based DMII. In the same study, all three DMII versions had significant positive correlations with hs-CRP and IL-6. In the ATLAA study, only concentration-based DMII was positively associated with CRP and IL-6. Higher median-based DMII was associated with higher odds of Alzheimer's disease.

CONCLUSIONS: DMII provides a metabolomics-based framework for assessing diet-related chronic inflammation using metabolomics data. This metabolomics approach may complement self-reported dietary assessment to use diet and nutrition to help protect against chronic disease linked to inflammation.},
}

@article {pmid42465421,
year = {2026},
author = {Ambaw, Y and Nana, A and Zhuoning, L and Singh, S and Monetti, M and Miller, BL and Spina, S and Grinberg, LT and Seeley, WW and Walther, TC and Farese, R},
title = {Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.11.737778},
pmid = {42465421},
issn = {2692-8205},
abstract = {Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease's, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.},
}

@article {pmid42465448,
year = {2026},
author = {Dunlop, SR and Lincoln, SJ and Peng, Z and Graff-Radford, NR and Lachner, C and Day, GS and Tranovich, JF and Reichard, RR and Dickson, DW and Petersen, RC and Boeve, BF and Nguyen, A and Grinberg, LT and Graff-Radford, J and Algeciras-Schimnich, A and Murray, ME},
title = {Targeted proteomics of postmortem human brain reveals neurobiologic heterogeneity in Alzheimer's disease using NULISA technology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.735558},
pmid = {42465448},
issn = {2692-8205},
abstract = {BACKGROUND: Alzheimer's disease (AD) is clinicopathologically heterogeneous. A proportion of patients living with AD present clinically at a younger onset of cognitive symptoms before 65 years old and/or non-amnestic clinical syndromes. Neuropathologically, corticolimbic distribution of neurofibrillary tangle pathology occurs on a continuum with some cases having greater cortical tau pathology relative to limbic regions and others with relatively restricted accumulation in limbic structures. These patterns of corticolimbic tangle distribution are associated with clinical presentation and age at onset. This study sought to examine protein expression differences across the spectrum of clinicopathologic heterogeneity using the NULISA targeted proteomics platform.

METHODS: A series of thirteen neuropathologically diagnosed AD cases from Mayo Clinic prospectively followed research studies were selected to reflect heterogeneity of clinical syndromes and corticolimbic distribution of tangle pathology. Frozen postmortem brain tissue samples were isolated from inferior parietal cortex and homogenized in RIPA buffer for analysis using Alamar Biosciences' NULISA CNS disease 120 panel. Applying a conservative detection threshold of 75% level of detection for the novel application of NULISA in human brain, we evaluated levels of 69 of 129 protein targets across samples. We examined associations between age at onset cognitive symptoms and corticolimbic distribution of tangles (CLix) separately with individual protein targets using linear regression analysis.

RESULTS: AD cases with a younger age at onset had higher measured levels of ubiquitin, while older age was associated with higher levels of total tau, CRH, and NPTX2. Investigations of corticolimbic heterogeneity revealed AD cases with lower CLix score (i.e., cortical predominant distribution of tau) had higher measured p-tau181, p-tau231, ubiquitin, and p62. AD cases with higher CLix (i.e., relative cortical sparing) had higher levels of total tau, CRH, NPTX2, MDH1, and HBA1. Brain-derived total tau consistently showed a stronger association in both models.

CONCLUSION: This work demonstrates the utility of postmortem proteomics for investigating biomarkers associated with AD clinicopathologic heterogeneity. We observed proteomic differences in synapse integrity, tau post-translational modification, and ubiquitination associated with age at symptomatic onset and corticolimbic distribution of tangle pathology.},
}

@article {pmid42465460,
year = {2026},
author = {Kehmeier, MN and Choi, YD and Cullen, AE and Zimmerman, B and Leonhardt, T and Snyder, M and Cleveland, T and Setthavongsack, N and Woltjer, RL and Pike, MM and Alkayed, NJ and Walker, AE},
title = {APOE4 genotype and old age interact to impact cerebrovascular function, brain volume, and neuroinflammation in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.736860},
pmid = {42465460},
issn = {2692-8205},
abstract = {Old age and the apolipoprotein E ε4 (APOE4) genotype are two of the greatest risk factors for late-onset Alzheimer's disease (LOAD). However, the interaction between these is poorly understood, as most preclinical studies use young mice. Therefore, we assessed the interaction between APOE genotype and age across a comprehensive set of cerebrovascular and related outcomes. We performed in vivo imaging, ex vivo cerebral artery studies, behavioral tests, and molecular analyses in male and female homozygous APOE3 and APOE4 mice at ∼6 months (young) and ∼24 months (old). APOE4 interacted with old age to lead to deficits in brain volume and greater microglia content. Old APOE4 mice also exhibited greater cerebral artery vasoconstriction to endothelin-1 (ET-1) than old APOE3 mice, a response concomitant with age-and genotype-related differences in the expression of ET-1 receptors and endothelin-converting enzyme. While we found several interactions between age and APOE genotype, only age impacted cognitive function, cerebral artery endothelial function, and arterial stiffness. In summary, we found that brain volume, neuroinflammation, and ET-1-related outcomes were influenced by the interaction of APOE genotype and age, while other outcomes were affected only by age. As such, an altered ET-1 response and greater neuroinflammation may contribute to the increased risk for LOAD in APOE4 carriers.},
}

@article {pmid42465478,
year = {2026},
author = {Surabhi, S and Jenny, A},
title = {Actin nucleation promoting factors drive Arp2/3 dependent endosomal microautophagy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.09.737473},
pmid = {42465478},
issn = {2692-8205},
abstract = {Autophagy is a catabolic process that degrades damaged organelles and aggregation-prone proteins and plays key roles during development and in maintaining cellular homeostasis. It can be induced by stress including starvation, oxidative stress, or accumulation of misfolded proteins. Autophagy declines with age and there is great interest in manipulating autophagy to improve neurodegenerative diseases, as its stimulation shows promise to improve diseases including Huntington, Alzheimer, and Parkinson. Endosomal microautophagy (e-MI) is a type of autophagy in which cytosolic proteins are delivered to late endosomes and degraded upon incorporation into intraluminal vesicles of multivesicular bodies. Here, we report that the actin nucleation-promoting factors (NPFs) known to activate the Arp2/3 complex to promote branched actin assembly can alter the dynamics of e-MI. We found that upon stress exposure, overexpression of the NPFs WASp, Wash, or SCAR results in an expedited induction of e-MI. Strikingly, Wash is uniquely required for physiological e-MI induction implying that NPFs are not functionally redundant for e-MI. We show that the WASH complex regulates e-MI on late endosomes acting via Arp2/3 and thus likely branched actin. Surprisingly, the regulation of e-MI by Wash is independent of retromer that is known to recruit Wash to early endosomes for its role in recycling of membrane proteins and rather reflects a novel degradative aspect of Wash function. Taken together, we identified a novel function of NPFs as upstream regulators of e-MI that could be used to activate e-MI ectopically to improve aggregate clearance during neurodegeneration.},
}

@article {pmid42465485,
year = {2026},
author = {Ji, Y and Mandal, P and Liu, J and Hu, W and Colón, BD and Wan, C and Pan, RW and Guo, D and Zhang, L and Gu, X and Yang, Y and Huang, K and Shi, R and Qi, C and Yuan, C and Rochet, JC and Baloni, P and Liu, F and Xu, R},
title = {Patient-derived tau-seeded human neuronal chimeras recapitulate mature Alzheimer's tau pathology and uncover human-specific neuronal vulnerability.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.06.736894},
pmid = {42465485},
issn = {2692-8205},
abstract = {Tau pathology is a central hallmark of Alzheimer's disease (AD) and strongly correlates with cognitive decline, yet the development of tau-targeted therapies has been hindered by the inability of existing models to capture human-specific disease features, particularly the mature forms of AD tau pathology. Moreover, species-specific mechanisms underlying tau pathology remain poorly understood. Here, we establish a patient-derived tau-seeded human neuronal chimera model by transplanting human pluripotent stem cell (hPSC)-derived neural progenitor cells into neonatal mouse brains, followed by intracerebral injection of pathological tau seeds from postmortem AD brains. Human neurons matured in vivo and recapitulated adult human tau features, including all six isoforms with an approximately 1:1 3R:4R ratio. Upon seeding, aged human neurons without FTD mutations faithfully developed robust, mature AD tau pathology, including neurofibrillary tangles (NFTs) and neuropil threads composed of paired helical filaments (PHFs) and straight filaments (SFs) containing 3R and 4R tau, closely mirroring advanced-stage AD. This pathology accumulated and spread across anatomically connected regions, accompanied by neurodegeneration, elevated plasma pTau-217, and memory deficits. Strikingly, tau pathology was largely restricted to human neurons, revealing a pronounced human-specific vulnerability. Mechanistically, snRNA-seq showed that human neurons exhibited higher basal expression of tau-uptake genes and widespread synaptic suppression following tau exposure, whereas mouse neurons remained transcriptomically resilient. Finally, the familial AD mutation PSEN2 N141I exacerbated tau pathology and synaptic loss in human neurons. Together, this model recapitulates the molecular, structural, and functional hallmarks of mature AD tau pathology in human neurons in vivo and reveals intrinsic, species-specific vulnerability, providing a human-relevant in vivo platform for mechanistic studies and therapeutic development.},
}

@article {pmid42465495,
year = {2026},
author = {Liou, K and Thomopoulos, SI and Villalon Reina, JE and Yoo, H and Shuai, Y and Chehrzadeh, S and Arani, A and Borowski, B and Reid, RI and Vemuri, P and Jack, CR and Weiner, M and Jahanshad, N and Thompson, PM and Nir, TM},
title = {Comparing Harmonization Approaches for Protocol-Related Variability in Multisite Diffusion MRI Data.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.737018},
pmid = {42465495},
issn = {2692-8205},
abstract = {Diffusion MRI (dMRI) enables assessment of white matter microstructural abnormalities in Alzheimer's disease (AD), and multisite datasets enable more robust modeling of non-biological variation that can confound analyses. The Alzheimer's Disease Neuroimaging Initiative (ADNI) includes over 10 dMRI protocols, necessitating robust methods to model protocol-related variability when pooling data. Here, we compared three harmonization approaches: (1) mixed-effects models, (2) ComBat-GAM, and (3) eHarmonize, a reference-based lifespan method. We assessed their ability to reduce protocol-related variability in diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD) while preserving associations with cognitive impairment (CI), and amyloid-beta (Aβ) and tau PET burden in 1,086 ADNI3/4 participants. All approaches yielded more closely aligned FA/MD distributions across protocols. Associations with clinical indicators of CI were highly consistent across approaches, whereas PET associations were less widespread and more variable. Overall, multiple strategies effectively modeled protocol-related variability while preserving AD-related associations.},
}

@article {pmid42465681,
year = {2026},
author = {Gorbunova, G and Yashkin, AP and Kravchenko, J and Ukraintseva, S and Stallard, E and Yashin, A and Akushevich, I},
title = {Disease-specific drivers of sex- and locality-related disparities in life expectancy at age 65: two decades of progress before COVID-19.},
journal = {Innovation in aging},
volume = {10},
number = {8},
pages = {igag065},
pmid = {42465681},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: The distribution of life expectancy at age 65 (LE65) in the United States is characterized by profound sex- and locality-related disparities. Quantifying the disease-specific drivers of these disparities prior to the coronavirus disease 2019 (COVID-19) pandemic provides a critical baseline for understanding subsequent health shocks.

METHODS: Using CDC WONDER data (1999-2018) and Pollard's decomposition method, we analyzed cause-specific contributions to disparities in LE65, establishing a pre-pandemic baseline for trends in years of life lost (YLL) at age 65.

RESULTS: Sex-related disparities (YLLsex) narrowed, particularly in disadvantaged localities, driven by reductions in YLL from macrovascular diseases and lung cancer. Conversely, locality-related disparities (YLLloc) widened, especially for females, due to increasing YLL from Alzheimer's disease and the persistent impacts of diabetes, chronic lower respiratory diseases, and heart failure. This created a pre-existing landscape of vulnerability concentrated in low-LE states.

DISCUSSION AND IMPLICATIONS: The 2 decades before COVID-19 saw a critical divergence: progress in reducing sex-based gaps was offset by rapidly widening geographic disparities. The systemic failures that drove the increasing burden of chronic conditions in disadvantaged regions likely predetermined the populations most vulnerable to the pandemic's shock. Our findings highlight that building future resilience requires targeted investments to address these specific, pre-existing health challenges.},
}

@article {pmid42465697,
year = {2026},
author = {Wu, Y and Zhang, C and Yan, J and Lin, L and Tian, Y and Fu, Z and Sun, X},
title = {Glymphatic dysfunction in Alzheimer's disease: a systematic review and meta-analysis of the DTI-ALPS index as an imaging biomarker.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1832525},
pmid = {42465697},
issn = {1663-4365},
abstract = {INTRODUCTION: Although the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is widely utilized as a proxy for glymphatic function in Alzheimer's Disease (AD) research, its association with core AD pathological biomarkers remains inconclusive due to inter-study heterogeneity. This systematic review aimed to investigate associations between the DTI-ALPS index and AD biomarkers and to elucidate potential sources of heterogeneity.

METHODS: The study protocol adhered to PRISMA guidelines and was registered with PROSPERO (CRD420251266067). We systematically searched Web of Science, PubMed, and ScienceDirect from January 1, 2017 to September 18, 2025 for studies examining the relationship between the DTI-ALPS index and core AD biomarkers. Random-effects meta-analyses were conducted when studies employed comparable methodologies and reported effect sizes while narrative synthesis was performed otherwise. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) and the risk of bias was evaluated using the Risk of Bias in Systematic reviews (ROBIS) tool.

RESULTS: Thirty-six studies were included. Meta-analyses revealed significant correlations between the DTI-ALPS index (N = 22) and Aβ PET deposition (N = 9), MMSE (N = 15), and MoCA (N = 10) scores. Conversely, the association with tau PET deposition (N = 3) was not significant after adjusting for publication bias. Regarding clinical staging, indices were significantly lower in AD and mild cognitive impairment groups compared to controls but no difference was found between the two patient groups. Based on meta-regression and narrative synthesis results, we identified methodological variability and AD pathological complexity as primary sources of heterogeneity.

DISCUSSION: Consequently, we proposed the "GS Hub Integrative Framework." This framework posits that vascular, genetic, lifestyle, and environmental risk factors converge on glymphatic dysfunction (DTI-ALPS index) as a central hub, accelerating Aβ/tau accumulation, neurodegeneration, and cognitive decline. Future methodological standardization and refined patient stratification are essential for clinical translation.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251266067, identifier: CRD420251266067.},
}

@article {pmid42465698,
year = {2026},
author = {Almalki, DF and Alkabkabi, RA and Wayyani, RA and Alharthi, AS and Aljuhani, HA and Mahyub, RM and Bakhsh, HS and Alomani, AM and Almhmadi, NN and Aljohani, AA and Tawakul, AA},
title = {Chronic stress, cortisol dysregulation, and neurodegenerative vulnerability: mechanistic pathways linking HPA-axis dysfunction to Alzheimer's disease risk.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1883880},
pmid = {42465698},
issn = {1663-4365},
abstract = {Chronic psychological stress is increasingly recognized as a silent risk factor of long-term brain vulnerability and a potential modifier of neurodegenerative disease trajectories. The persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the consequent dysregulation of cortisol exert extensive influences on neural, immune, and metabolic pathways linked to cognitive decline and dementia. This review synthesizes current mechanistic and clinical evidence concerning the effects of chronic stress-induced HPA-axis dysfunction on neurodegenerative susceptibility and Alzheimer's disease risk. A structured narrative synthesis was conducted using literature from PubMed/MEDLINE, Scopus, and Web of Science, integrating multidisciplinary evidence from established biological and mechanistic domains. Present evidence suggests that prolonged exposure to glucocorticoids is associated with structural and functional alterations in the brain, including hippocampal atrophy, prefrontal cortical dysfunction, reduced synaptic plasticity, and increased amygdala activity. Chronic dysregulation of cortisol may result in neuroinflammation, disruption of the blood-brain barrier, induce mitochondrial dysfunction, and impair neuronal integrity. These interconnected mechanisms contribute to amyloid accumulation, tau pathology, and the progressive decline of neural resilience. Rather than serving as the root cause, chronic psychological stress can increase the likelihood of neurodegeneration by triggering complex interactions between the neuroendocrine and neuroimmune systems that accelerate the already existing pathological pathways toward neurodegeneration. Recognizing chronic stress as a potentially modifiable biological risk factor may improve early risk stratification and identification of HPA-axis dysregulation, ultimately driving preventive strategies targeting stress-related neurobiological pathways.},
}

@article {pmid42465724,
year = {2026},
author = {Zhang, C and Song, D},
title = {Implications of autolysosome- astrocyte-associated signature in the pathogenesis of Alzheimer's disease: evidence from artificial intelligence and multi-omics and clinical validation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1867831},
pmid = {42465724},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and neurofibrillary tangles. Dysfunctional cellular clearance mechanisms, particularly autophagy-lysosomal pathways, and reactive astrocytosis are prominent pathological features, yet their interrelationship remains poorly defined.

OBJECTIVE: This study aimed to decipher a novel co-expression molecular signature linking autolysosomal dysfunction and astrocyte reactivity in AD pathogenesis.

METHODS: We performed Limma, WGCNA and Xcell algorithms in AD patient hippocampus bulk profiles for enrichment of astrocyte and autolysosome (AA)-associated DEGs. Next, explainable machine learning and consensus clustering enables the identification of AA-associated diagnostic model and molecular subgroups for AD patients at bulk level. Besides, AA-associated central pathogenic factor was identified, and its corresponding biological implications for AD were assessed at AD patient hippocampus single-cell level in temporal and spatial manners. Next deep learning algorithm (Drugreflector) and molecular docking enriched natural compounds for the treatment of AD by targeting AA-associated hub gene. Finally, AD clinical peripheral blood samples were collected for estimation of hub gene expression patterns.

RESULTS: 5 AA-associated shared DEGs can elaborate diagnostic and patient stratification capacity for AD patients. HMGCR can be considered as astrocyte-distributed central pathogenic and Berberine-oriented therapeutic target for AD patients.

CONCLUSION: Our findings unveil AA-associated diagnostic model and molecular subgroups coupled with HMGCR center pathogenic and druggable role in AD, which represents an actionable clinical target for AD patients.},
}

@article {pmid42465730,
year = {2026},
author = {de Leeuw, DM and Duits, FH and Dicks, E and Vromen, EM and Teunissen, CE and Barkhof, F and van der Flier, WM and Visser, PJ and Tijms, BM},
title = {Neuroplasticity and immune system are related to altered grey matter networks: a cohort study in sporadic Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag257},
pmid = {42465730},
issn = {2632-1297},
abstract = {Grey matter network topology is altered in Alzheimer's disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer's dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer's disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired-A+, 88 mild cognitive impairment-A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer's disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P < 0.05) using the Gene Ontology database. Individuals across the Alzheimer's disease continuum had lower small-worldness coefficients compared with controls (ANOVA P < 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer's disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.},
}

@article {pmid42465741,
year = {2026},
author = {Zhang, R and Chen, K},
title = {Exercise-conditioned extracellular vesicles in Alzheimer's disease: a multi-organ signaling network linking peripheral adaptation to brain pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1856546},
pmid = {42465741},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Exercise/physiology ; *Brain/pathology/metabolism ; Signal Transduction ; Blood-Brain Barrier/metabolism ; Adaptation, Physiological ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which amyloid-β accumulation, tau pathology, chronic neuroinflammation, cerebrovascular impairment, and synaptic dysfunction act as interconnected rather than independent processes. Physical exercise is protective against several of these features, but how its peripheral effects produce coordinated changes in the brain remains only partly defined. Soluble exerkines explain part of this benefit, but they act individually, do not protect labile cargo such as RNA, and carry little information about their cell of origin. Extracellular vesicles (EVs) offer a complementary mechanism. By packaging diverse cargo within a membrane, they co-deliver several signals at once, protect labile cargo in transit, and carry a profile that partly reflects the state and origin of the releasing cell. In this review, we develop a multi-organ signaling framework in which exercise-conditioned EVs link peripheral exercise adaptation to AD-related brain pathology. We examine how exercise reshapes EV biogenesis, the circulating EV pool, and EV engagement with the neurovascular interface. We then map how exercise-conditioned EVs intersect with amyloid aggregation and clearance, tau propagation, neuroinflammation, blood-brain barrier integrity, and synaptic and neurogenic resilience, and which tissues contribute to the exercise-responsive EV pool. Several bottlenecks keep the field at the level of association rather than causation, including cargo heterogeneity, uncertain tissue-of-origin attribution, and the gap between describing cargo and demonstrating its function. This framework outlines a realistic, staged route from current associative evidence toward clinical application, in which exercise-conditioned EVs serve first as biomarkers of exercise responsiveness and later as engineered therapeutic platforms for AD.},
}

*Alzheimer Disease/metabolism/pathology/physiopathology
Humans
*Extracellular Vesicles/metabolism
Animals
*Exercise/physiology
*Brain/pathology/metabolism
Signal Transduction
Blood-Brain Barrier/metabolism
Adaptation, Physiological
Amyloid beta-Peptides/metabolism

@article {pmid42465883,
year = {2026},
author = {Park, J and Le Guen, Y and Peña-Tauber, A and Greicius, MD},
title = {Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.01.26356385},
pmid = {42465883},
abstract = {Most plasma proteomic studies in Alzheimer's disease (AD) compare cases and controls cross-sectionally, leaving unresolved which AD-associated proteins mark diagnostic states and which are linked to disease progression. Using longitudinal SomaScan profiling from the Global Neurodegeneration Proteomics Consortium (13,449 participants, 17,269 samples, 7,362 aptamers), we separated baseline AD differences from AD-specific change over time. Linear mixed-effects models requiring concordant baseline and AD-by-time effects defined a 30-protein signature. We prioritized proteins across five evidence domains: clinical progression, AD biomarker alignment, cerebrospinal fluid concordance, independent prospective replication in UK Biobank and genetic support from Mendelian randomization and rare-variant burden. Thirteen proteins were supported in two or more domains and six in three. EDA2R, HPGDS, ITGAV and CLEC3B converged across clinical, biomarker and prospective evidence. Signature proteins aligned more strongly with tau and neuronal-injury markers than with A β 42/40. ANTXR1 showed direction-concordant plasma pQTL Mendelian randomization and nominal rare-variant burden signals, supporting its prioritization within the longitudinal AD signature. By distinguishing diagnostic-state markers from progression-linked changes, this longitudinal, multi-domain approach prioritizes proteins for validation as markers of AD progression and for mechanistic and therapeutic follow-up.},
}

@article {pmid42465907,
year = {2026},
author = {Jordan, DM and Kritzer, E and Thompson, RC and Lund, AN and Patel, T and Buxbaum Grice, A and John, DA and , and , and , and Goate, AM and Glicksberg, BS and Golestani, N and Koromina, M and Renton, AE and Beckmann, ND},
title = {Genetic Associations with Temporal Modeling of Alzheimer's Disease Progression Supports a Novel Paradigm for Disease Risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.26356710},
pmid = {42465907},
abstract = {A major challenge in Alzheimer's disease (AD) research is predicting who will develop AD, how it progresses, and how to slow, prevent, or reverse progression. Here, we apply a data-driven timeline inference framework to sparse longitudinal blood metabolomics data to reconstruct AD timelines and derive individual-specific timeline progression rates. Inferred temporal locations for each metabolomics sample along the AD timeline closely track clinical severity, while timeline progression rates capture inter-individual differences in the speed of pathophysiological progression. Genome-wide association studies of timeline progression rate identify novel loci distinct from those in AD case-control studies, notably showing no effect of the major risk locus APOE . These findings support a multidimensional paradigm of AD risk in which disease potential and progression act as partially independent factors. By explicitly modeling disease dynamics, this work reveals genetic contributions not captured by traditional approaches and provides a framework for studying AD and other progressive disorders.},
}

@article {pmid42465939,
year = {2026},
author = {Reinhardt, A and Jiang, Z and Li, T and Tang, B and Qian, X and Huang, S and Ibrahim, JG and Li, Y and Zhao, B and Sullivan, P and Stein, J and Zhu, H},
title = {A spatially resolved genomic-molecular atlas of human white‑matter microstructure.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.06.26357381},
pmid = {42465939},
abstract = {Human white matter has been linked to inherited variation, circulating molecular state and brain disease, but these layers have rarely been mapped onto the same tract anatomy. Here we measured genetic effects along 6,090 atlas-aligned fiber pathways sampled at 609,000 locations in 72,185 UK Biobank participants, and integrated proteomic and metabolomic profiles within the same anatomical frame. Genetic effects were not whole-tract properties: each locus formed a spatial footprint along fiber trajectories, ranging from single locations to broad multi-tract patterns and reflecting regional polygenicity rather than tract heritability. This map identified 258, 186 and 298 previously unreported loci for fractional anisotropy, mean diffusivity and axial diffusivity; spatial patterns replicated in adults and 157 of 315 FA loci replicated in adolescence in ABCD. Mendelian randomization linked localized genetic effects to neurodegenerative and psychiatric traits, with Alzheimer's disease showing directional effects across 12 of 17 tracts. Multi-omic analyses identified 97 proteomic and 161 metabolomic associations, with the broadest signals from lipid metabolites including linoleic acid and phosphatidylcholines. The strongest lipid-metabolite and genetic signals converged in the corpus callosum, placing inherited variation, disease risk and systemic lipid metabolism on the same localized tract segments.},
}

@article {pmid42466090,
year = {2026},
author = {Medicine, CRIN},
title = {RETRACTION: A Severe Alzheimer's Disease Patient Improved by Intravenous Mesenchymal Stem Cell Transplant.},
journal = {Case reports in neurological medicine},
volume = {2026},
number = {},
pages = {9873498},
doi = {10.1155/crnm/9873498},
pmid = {42466090},
issn = {2090-6668},
abstract = {[This retracts the article DOI: 10.1155/2024/8353492.].},
}

@article {pmid42466122,
year = {2026},
author = {Liang, X and Ning, T and Wang, Y and Zhan, L},
title = {Integrating serum pharmacology, network pharmacology, and molecular biology analysis to reveal the mechanisms of Baihe Dihuang decoction in treating Alzheimer's disease.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1765044},
pmid = {42466122},
issn = {1664-302X},
abstract = {AIM: This study aimed to evaluate the potential neuroprotecive effects of Baihe Dihuang Decoction (BDD) in APP/PS1 double-transgenic (TG) mice and to investigate the role of the gut-brain axis (GBA) using an integrated approach combining serum pharmacology, network pharmacology, and molecular biology.

MATERIALS AND METHODS: The blood-borne bioactive components of BDD were initially identified using UPLC-Q-Orbitrap HRMS. Subsequently, network pharmacology was employed to prioritize key therapeutic targets and elucidate the primary pathways underlying the anti-Alzheimer's disease (AD) effects of BDD. The neuroprotective efficacy of BDD in TG mice was systematically evaluated using the morris water maze (MWM) test, histopathological observation (HE staining), transmission electron microscope (TEM) test, and ELISA-based inflammatory cytokine assays. The potential mechanisms were further elucidated by integrating network pharmacology with 16S ribosomal RNA (16S rRNA) sequencing. Finally, molecular docking and Western blotting (WB) were performed to validate the interactions within the identified pathways.

RESULTS: A total of 49 BDD-derived compounds were identified in serum samples. Network pharmacology revealed 116 common targets of BDD against AD. Remarkably, KEGG analysis highlighted 57 signaling pathways potentially involved in the anti-AD effects of BDD. Pharmacodynamic analysis showed that BDD ameliorated cognitive impairment in TG mice, mitigated pathological damage, and suppressed the release of IL-6, IL-1β, and TNF-α in the colon, brain, and serum. Moreover, 16S rRNA sequencing indicated that BDD modulated gut microbiota (GM) structure and restored intestinal flora imbalance in TG mice. Integrative analysis of network pharmacology and GM analysis identified several Key pathways (FoxO, MAPK, PI3K-Akt, HIF-1, Th17, IL-17, and Toll/Imd) and core anti-AD targets (TLR4, PTGS2, SIRT1, BDNF, NF-κB, STAT3, JAK2, EGFR, GSK3β, and CD86). Molecular docking results showed that the five complexes with the lowest docking scores (TLR4-salidroside, NF-κB-glabranin, TRKB-alantolactone, PTGS2-3'_4'_dihydroxyflavone, and SIRTI-abietic acid) exhibited strong binding affinity. QSAR and WB analyses further demonstrated the modulatory effects of BDD on these five core targets.

CONCLUSION: This study demonstrated that BDD effectively restored GM structure and ameliorated cognitive impairment in TG mice, thereby exerting therapeutic effects against AD. These findings support BDD as a potential traditional Chinese medicine (TCM) strategy for AD treatment.},
}

@article {pmid42466407,
year = {2026},
author = {Hammad, G and Seret, E and Schmidt, C and Vandewalle, G},
title = {Determinants of fractal motor activity regulation: insights from a large community-dwelling multi-ethnic population.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10237495/v1},
pmid = {42466407},
issn = {2693-5015},
abstract = {Background: Quantification of alterations in fractal motor activity regulation (FMAR) has the potential to improve early detection of Alzheimer's disease. To improve the clinical relevance of such marker, our analysis aims to investigate potential determinants such as age, sex, physical activity and race and ethnicity in a large community-dwelling multi-ethnic cohort of older Asian, Black, Hispanic and White individuals. Methods: We analysed week-long actigraphy recordings from 1508 older adults (55 to 90 years) of the MESA Sleep dataset. Long-range correlations in activity levels, a marker of fractal regulation, were assessed via a scaling exponent extracted with a Detrended Fluctuation Analysis over two different time ranges. Bayesian linear models were used to compare scaling exponent values between ethnic groups and test their associations with various determinants, such as age, sex and physical activity levels. Results: We found opposite effects of age on FMAR at both short and long time scales, respectively (ßAge=0.014, 95% C.I. [0.009,0.019] and ßAge=-0.015, 95% C.I. [-0.026,-0.005]), as well as differences between women and men at long time scales (ßSexMen=+0.028, 95% C.I. [0.012,0.044]). We also confirmed that higher activity levels were linked to less degraded FMAR (ßMDA=0.007, 95% C.I. [0.003,0.011] at short time scales and ßMDA=0.032, 95% C.I. [0.024,0.041] at long time scales). Finally, we observed that Black and Hispanic participants, as well as Asian participants, exhibiting lower values in scaling exponents at short and long time scales, respectively (ßBlack=-0.026, 95% C.I. [-0.035,-0.017], ßHispanic=-0.018, 95% C.I. [-0.027,-0.009] and ßAsian=-0.065, 95% C.I. [-0.091,-0.039]), compared to White participants. Conclusion: Using a large multi-ethnic cross-sectional dataset, our analysis provided support and clarified the interaction effect of age and sex on FMAR. It also confirmed, in humans, the influence of activity levels on FMAR observed in rodents and demonstrated for the first time that FMAR alterations are modulated by race and ethnicity.},
}

@article {pmid42466408,
year = {2026},
author = {Zhao, F and Puerta, R and Wang, Y and Beckett, E and García-González, P and Valero, S and Sanz, P and Kautz, T and Cavazos, JE and Fernandez, MV and Cano, A and Seshadri, S and Boada, M and Garbarino, VR and Ruiz-Laza, A and Gnpc, TGNPC},
title = {Lactoferrin Levels in Cerebrospinal Fluid Exhibit Differential Associations with Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9678397/v1},
pmid = {42466408},
issn = {2693-5015},
abstract = {Lactoferrin has been proposed as a minimally invasive biomarker for Alzheimer's disease (AD), but its relationship with established AD pathology remains uncertain. We analyzed paired cerebrospinal fluid (CSF) and plasma SOMAscan proteomic profiles from 1,367 participants in the ACE Alzheimer Center Barcelona cohort, focusing on two lactoferrin-targeting SOMAmers, Seq.14755.4 (LTF1) and Seq.2780.35 (LTF2). LTF1 and LTF2 showed distinct distributions and weak concordance across fluids, indicating that they should not be treated as interchangeable lactoferrin measures. In CSF, LTF2 was associated with lower Aβ42 and AD biomarker-defined status, whereas LTF1 showed subgroup-dependent associations with tau markers that were partly influenced by major CSF proteomic axes and reference-gene adjustment. Neither CSF nor plasma LTF signals predicted conversion from mild cognitive impairment to dementia. GNPC analyses supported the non-interchangeability and compartment specificity of LTF signals and identified a reproducible plasma LTF2-centered network enriched for innate immune and granule biology. These findings suggest that lactoferrin-related signals are assay-, compartment-, and network-context dependent rather than standalone AD biomarkers.},
}

@article {pmid42466706,
year = {2026},
author = {Zheng, C and Li, F and Wang, R and Li, B and Jiao, J and Yuan, K and Wang, Z and Li, T and Deng, Y and Wang, Z and Peng, J and Gao, C and Rong, S},
title = {The relationship between low-sodium salt substitutes and cognitive function among middle-aged and older adults: The Chinese Square Dance Cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468778},
doi = {10.1177/13872877261468778},
pmid = {42466706},
issn = {1875-8908},
abstract = {BackgroundPrevious studies have indicated that high sodium intake is associated with poorer cognitive function, and low-sodium salt substitutes (LSSS) can reduce sodium intake.ObjectiveWe hypothesized that the use of LSSS is linked to better cognitive performance.MethodsIn this cross-sectional study, participants reported using LSSS or regular salt via questionnaire. Cognitive function was evaluated using Auditory Verbal Learning Test (AVLT), Verbal Fluency Test (VFT), Digit Symbol Substitution Test (DSST), and Trail Making Test-B (TMT-B). Z-scores were utilized to standardize the results, with composite z-score reflecting global cognitive function. Mild cognitive impairment (MCI) was determined by Petersen's criteria, and subclassified into amnestic MCI (aMCI) and non-amnestic MCI (naMCI). Multiple linear regression and logistic regression analyses were performed to assess the associations of the use of LSSS with cognitive function and MCI.ResultsAmong 4201 participants (median age 64 years, 85.91% female), 639 (15.21%) self-reported using LSSS. Compared to those who used regular salt, the use of LSSS was associated with higher composite z-score, VFT, and DSST, with β values (95%CIs) of 0.10 (0.05, 0.15), 0.16 (0.08, 0.24), and 0.17 (0.10, 0.23), respectively. The prevalence of MCI was 8.29% in the LSSS group and 12.80% in the regular salt group, the use of LSSS was related to lower odds of naMCI (OR = 0.63, 95%CI: 0.41, 0.96).ConclusionsOur findings indicate that the use of LSSS was related to better cognitive performance and lower odds of naMCI, suggesting that replacing regular salt with LSSS may be a promising dietary strategy for cognitive aging worthy of further investigation.},
}

@article {pmid42466721,
year = {2026},
author = {Marinelli, L and Puce, L and Diotti, D and Currà, A and Vestito, L and Mori, L and Ponzano, M and Cervia, A and Cotellessa, F and Schenone, C and Monacelli, F and Trompetto, C},
title = {Clinical dissociation and electromyographic convergence of paratonia in cognitive impairment including Alzheimer's disease: Evidence for a shared central inhibitory mechanism.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468799},
doi = {10.1177/13872877261468799},
pmid = {42466721},
issn = {1875-8908},
abstract = {BackgroundDespite a shared conceptual framework linking both components to impaired inhibitory control, clinical evidence suggests that facilitatory and oppositional paratonia are not equally related to cognitive deterioration, with facilitatory paratonia showing a stronger association with cognitive impairment. Whether this apparent divergence reflects true neurophysiological differences or arises from limitations intrinsic to clinical assessment remains unclear. Electromyography (EMG)-based assessment offers a direct approach to quantify involuntary muscle activation and reduce measurement-related confounding factors.ObjectiveTo determine whether the reported clinical divergence between facilitatory and oppositional paratonia reflects distinct neurophysiological mechanisms or is primarily driven by measurement-related factors.MethodsEighty-six participants (46 cognitively impaired and 40 cognitively healthy) underwent clinical and EMG-based assessment of paratonia during passive elbow movements. Associations with global cognitive status (Mini-Mental State Examination) and discriminative performance between cognitively impaired and healthy subjects were evaluated.ResultsClinically assessed facilitatory paratonia showed stronger associations with cognitive status and better discriminative performance than oppositional paratonia. In contrast, EMG-based assessment revealed comparable associations with cognitive status and similar discriminative performance for both paratonia components.ConclusionsEMG assessment reveals a neurophysiological convergence between facilitatory and oppositional paratonia, supporting a shared central inhibitory mechanism. Our findings indicate that the apparent clinical distinction between facilitatory and oppositional paratonia does not reflect a true pathophysiological separation, but is largely driven by limitations inherent to clinical assessment. In this context, facilitatory paratonia emerges as the most informative bedside marker of cognitive impairment.},
}

@article {pmid42466724,
year = {2026},
author = {Grueso, S and Sánchez-Benavides, G and Santos-Santos, M and Subirats, L and Prados, F and Grau-Rivera, O and Calabria, M},
title = {Bilingualism and cognition: The impact of age of acquisition, language use, and proficiency in cognitively unimpaired older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469525},
doi = {10.1177/13872877261469525},
pmid = {42466724},
issn = {1875-8908},
abstract = {BackgroundThe positive effect of bilingualism as a cognitive reserve factor in aging remains inconclusive, with inconsistencies often stemming from treating bilingualism as a dichotomous variable rather than a dynamic, multidimensional experience.ObjectiveTo investigate the impact of bilingualism on cognition in cognitively unimpaired older adults, focusing on age of language acquisition (AoA), proficiency, and usage throughout life.MethodsData from 2415 participants (aged 45-74) from the Alzheimer's and Families (ALFA) study were analyzed. Cognitive assessments included the Mini-Mental State Examination to assess global cognition, semantic verbal fluency for semantic lexical retrieval, Memory Binding Test for verbal episodic memory, and WAIS-IV subtests for processing speed (Coding), visual-spatial reasoning (Visual Puzzles), non-verbal abstract reasoning (Matrix Reasoning), verbal short-term memory and attention (Digit Span Forward) and working memory (Digit Span Backward and Sequencing). We defined three groups based on AoA (Early/Late) and proficiency (High/Low) of Catalan: 1) Early High-Proficiency bilinguals (n = 1559); 2) Late High-Proficiency bilinguals (n = 537) and 3) Late Low-Proficiency bilinguals, primarily Spanish-dominant (n = 319).ResultsEarly and Late High-Proficiency bilingual groups outperformed Late Low-Proficiency bilinguals in verbal semantic fluency and processing speed. Additionally, Early High-Proficiency bilinguals scored significantly higher in verbal short-term memory than both Late AoA groups.ConclusionsThe effects of bilingualism are domain-specific and primarily driven by high proficiency and active language use rather than AoA alone. These findings suggest that maintaining high L2 proficiency throughout the lifespan contributes to cognitive reserve, enhancing attentional control and processing speed in healthy aging.},
}

@article {pmid42466729,
year = {2026},
author = {Huoponen, S and Kettunen, J and Mežinska, S and Haaranen, A and Malm, T and Jolkkonen, J},
title = {Nurses' Attitudes Toward Innovative Neurotherapies in Memory Disorders: A Pilot Study.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {7},
pages = {e71015},
doi = {10.1002/cns.71015},
pmid = {42466729},
issn = {1755-5949},
support = {357769//Research Council of Finland/ ; },
mesh = {Humans ; *Memory Disorders/therapy/drug therapy ; Female ; *Attitude of Health Personnel ; Pilot Projects ; Male ; *Nurses/psychology ; Finland ; Surveys and Questionnaires ; Adult ; Middle Aged ; *Health Knowledge, Attitudes, Practice ; },
abstract = {BACKGROUND: As the aging population increases, the prevalence of Alzheimer's disease and other memory disorders increases, and emerging neurotherapies offer new hope, yet little is known about nurses' knowledge and perspectives on these innovations, despite their critical role in patient care. This study aimed to investigate nurses' attitudes, expectations, concerns, and perspectives toward innovative therapies for memory disorders.

METHODS: A multiple-choice questionnaire (24 items) in Finnish was developed to explore nurses' views. The questionnaire was distributed via email to nursing homes in the Wellbeing Services County of North Savo, Finland, in autumn 2024. Composite scores for perceived benefits, perceived barriers, enabling factors, professional role-related responsibilities, and worries were generated for statistical analyses.

RESULTS: A total of 132 nurses responded to the survey, most of whom were practical nurses working in nursing homes. Overall familiarity with innovative neurotherapies was low, and many participants indicated that they were not at all familiar with these treatments. Opinions on the future role of such therapies in managing memory disorders varied, with some considering them significant or moderately important. Several respondents also expressed serious concerns regarding the efficacy and potential side effects of these therapies. Regression analyses showed that lower composite outcome scores were consistently associated with being a social and healthcare student, being somewhat familiar with innovative neurotherapies, and, in some models, with shorter work experience or specific workplace settings. However, adjusted R[2] values ranged from 0.09 to 0.18, indicating that demographic and professional background factors explained only a modest proportion of variance in the composite outcomes.

CONCLUSION: Nurses currently have limited familiarity with innovative neurotherapies, but there is cautious optimism about their future role in treating memory disorders, including Alzheimer's disease.},
}

Humans
*Memory Disorders/therapy/drug therapy
Female
*Attitude of Health Personnel
Pilot Projects
Male
*Nurses/psychology
Finland
Surveys and Questionnaires
Adult
Middle Aged
*Health Knowledge, Attitudes, Practice

@article {pmid42467046,
year = {2026},
author = {Makita, K and Nishihara, T and Arakaki, Y and Ohida, T and Goto, K and Kutsuna, N},
title = {Hospital Budget Impact and Provider-Side Economic Evaluation of Lecanemab and Donanemab Under Japan's National Fee Schedule: A Head-to-Head Linear Model.},
journal = {Value in health regional issues},
volume = {},
number = {},
pages = {101675},
doi = {10.1016/j.vhri.2026.101675},
pmid = {42467046},
issn = {2212-1102},
abstract = {OBJECTIVES: The study aimed to assess the provider-side financial viability of antiamyloid disease-modifying therapies for early Alzheimer's disease in Japan, we developed a linear hospital-provider model that separates a short inpatient diagnostic phase from an outpatient infusion phase.

METHODS: Using public National Health Insurance tariffs, official 2025 drug prices, and workflow-based labor costing with time-driven activity-based costing, we estimated per-case outpatient margins and program-level break-even case volumes. Scenarios examined fee-for-service versus diagnosis procedure combination/per-diem payment system hospitals, magnetic resonance imaging surveillance intensity, purchase discounts, wage growth, routine-workflow staff time, and the scheduled 15% lecanemab price reduction effective November 1, 2025.

RESULTS: At 1.5 T with no assumed wage growth, donanemab yielded positive outpatient margins from + 37,670JPY at no purchase discount to + ¥110 777 at a 2.6% discount. Lecanemab at 50 kg yielded -¥9048 at no discount and broke even at a discount of 0.304% before the scheduled price reduction and 0.358% after it. At 55 to 60 kg, the equal-discount threshold at which lecanemab overtook donanemab shifted from about 6.2% before the price reduction to 20.9% after it. Sensitivity analyses showed purchase discounts were the dominant driver, whereas labor and workflow inputs affected lecanemab more because it requires more infusions per year.

CONCLUSIONS: Under Japan's fee schedule, both therapies were financially viable across typical purchase-discount ranges in scenario analyses, but findings should be interpreted as provider-margin estimates rather than comparative clinical judgments.},
}

@article {pmid42467182,
year = {2026},
author = {Imabayashi, E and Morris, A and Iaccarino, L and Arora, AK and Kamiki, E and Lu, M},
title = {[18]F-flortaucipir PET imaging: Biodistribution in the Japanese population and diagnostic accuracy by Japanese readers.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42467182},
issn = {1864-6433},
support = {Eli Lilly and Company//Eli Lilly and Company/ ; Avid Radiopharmaceuticals//Avid Radiopharmaceuticals/ ; },
abstract = {OBJECTIVE: [18]F-flortaucipir (Tauvid™) is an [18]F-labeled diagnostic positron emission tomography (PET) radiopharmaceutical, which was developed to detect tau pathology in the brain and to estimate the density and/or distribution of aggregated tau neurofibrillary tangles for patients being evaluated for Alzheimer's disease (AD). The objective of this article is to report findings from two studies. The primary objective of the first (dose and biodistribution) study was to investigate the consistency of [18]F-flortaucipir PET biodistribution between Japanese and non-Japanese individuals. In the second (reader) study, the comparability of visual reads performed by Japanese and US expert readers who followed the same training program was evaluated.

METHODS: This article reports findings from two separate studies and datasets. In the dose and biodistribution study, whole-body distribution of [18]F-flortaucipir was assessed (N = 9). Standardized uptake value ratios, normalized to the entire cerebellum, were calculated, and whole-body effective dose was calculated using a 73.7 kg bodyweight model. In the reader study (Study A27; I7E-AV-A27), five Japanese physicians visually interpreted 60 PET scans randomly selected from a previous US reader study (Study FR01; NCT03901092). Scan positivity was determined based on increased activity of [18]F-flortaucipir in posterolateral temporal, occipital, or parietal/precuneus regions with or without frontal activity. Each scan was visually interpreted by all Japanese readers, who determined whether scans were consistent with an AD or non-AD pattern. Concordance between Japanese and US readers who underwent the same training on the interpretation of [18]F-flortaucipir PET images was then evaluated (reader study primary endpoint).

RESULTS: The biodistribution of [18]F-flortaucipir was consistent between Japanese and non-Japanese individuals. When interpreting [18]F-flortaucipir PET images to distinguish between AD versus non-AD patterns, Japanese and US readers who underwent the same training showed 100% agreement on the majority reads, with a Cohen's Kappa value of 1.

CONCLUSIONS: [18]F-flortaucipir whole-body biodistribution for Japanese individuals was consistent with that of non-Japanese individuals. After completing the same training, Japanese readers showed high concordance with US readers on the interpretation of [18]F-flortaucipir PET images to distinguish between AD and non-AD patterns. Data and scans were from previous studies registered with ClinicalTrials.gov (registration numbers: NCT04474405; NCT03901092).},
}

@article {pmid42467190,
year = {2026},
author = {Siriwattanasathien, Y and Yotmanee, P and Lehboon, K and Chokchaisiri, R and Nunparn, K and Chunglok, W and Suksamrarn, A},
title = {Isolation, modification, structure-activity relationship (SAR) and molecular docking studies of isoflavones from Derris scandens as potent dual AChE/BuChE inhibitors.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {},
number = {},
pages = {},
pmid = {42467190},
issn = {1554-8120},
support = {Contract No. 10/2025//Walailak University Graduate Scholarship/ ; DBG6180030//The Thailand Research Fund/ ; },
abstract = {The stems of Derris scandens are rich sources of isoflavonoids including a new isoflavone and nine known isoflavones. Some isolated isoflavones exhibited considerable acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) inhibitory activities. Preliminary SAR studies have indicated that one of the essential structural requirements for a 5,7,4'-trioxygenated isoflavone to exhibit high ChE inhibitory activities is the presence of prenyl group(s). Structural modifications of the isoflavone 5 to ester and ether derivatives did not enhance the ChE inhibitory potential. Molecular docking studies have indicated that, if the isoflavone structure is more flexible, the better binding of isoflavone molecule to the receptor should be achieved. The more flexible dihydro analog of the prenyl moiety was therefore prepared from the isoflavone 5 to give corresponding dihydro analog 19 and the tetrahydro analog 20. It was found that the dihydro analog 19 was the most active analog for AChE and BuChE inhibitions, with the IC50 values of 0.41 ± 0.07 µM and 0.64 ± 0.01µM, respectively. It was 3.3- and 4.8-fold, respectively, more active than galanthamine. In addition, the dihydro analog 19 exhibited lower cytotoxicity toward Vero and RAW 264.7 cells than the isoflavone 5. Molecular docking studies indicated that 19 could simultaneously interact with the PAS, AS and CT of AChE and BuChE. The presence of an isopentyl group on isoflavone ring B is necessary for the dihydro analog to exhibit anti-ChE activity. Hence, an isoflavone with an isopentyl group on ring B, a prenyl group on ring A and suitable hydroxy groups on the aromatic ring could be a possible lead candidate for a dual-target-directed ligand for the treatment of Alzheimer's disease.},
}

@article {pmid42467268,
year = {2026},
author = {Feder, B and Polli, G and Laurenzi, S and Righetti, S and Tessari, B and Terruzzi, S and Papagno, C},
title = {A novel writing to dictation test to investigate lexical and sublexical processes: Italian normative data and preliminary clinical feasibility in Mild Cognitive Impairment and Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42467268},
issn = {1590-3478},
mesh = {Humans ; Male ; *Cognitive Dysfunction/diagnosis/psychology/physiopathology ; Female ; *Alzheimer Disease/diagnosis/psychology ; Aged ; *Neuropsychological Tests ; Italy ; Aged, 80 and over ; Feasibility Studies ; Reproducibility of Results ; Middle Aged ; *Writing ; },
abstract = {Writing abilities can be interpreted within dual-route models, which distinguish lexical and sublexical processes. The present study aimed to validate a novel writing to dictation test to assess both lexical and sub-lexical spelling abilities in an Italian population. A sample of 392 healthy participants provided robust normative data, revealing significant effects of age, education, and sex on spelling performance. Test-retest analyses indicated satisfactory reliability and minimal learning effects. The clinical feasibility of the test was explored in patients with amnestic Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). MCI patients mainly showed selective difficulties in spelling words with unpredictable orthography, suggesting early lexical impairment, whereas AD patients exhibited more severe and heterogeneous deficits involving both lexical and sublexical processes. Qualitative error analysis revealed multiple dysgraphic patterns, particularly in the AD group. Spelling performance did not significantly correlate with other cognitive domains, which may suggest a relative specificity of writing impairment. While the test provides a useful tool for assessing spelling abilities and characterizing writing to dictation disorders in neurodegenerative conditions, limitations related to sample stratification and socio-demographic representation were noted. The study underscores the importance of including standardized writing to dictation assessments in neuropsychological evaluations.},
}

Humans
Male
*Cognitive Dysfunction/diagnosis/psychology/physiopathology
Female
*Alzheimer Disease/diagnosis/psychology
Aged
*Neuropsychological Tests
Italy
Aged, 80 and over
Feasibility Studies
Reproducibility of Results
Middle Aged
*Writing

@article {pmid42467293,
year = {2026},
author = {Hassan, MA and Al Amin, M and Sweilam, SH and Abohassan, M and Krishnan, K and Gupta, JK and Jahnavi, P and Vodeti, R and Radha, R and Gupta, PS and Reddy, KTK},
title = {Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42467293},
issn = {1568-5608},
abstract = {Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.},
}

@article {pmid42467720,
year = {2026},
author = {Piotrowski, SL and Li, X and Fitzpatrick, CE and Tucker, A and Lee, A and Leibovitch, E and Monaco, MCG and Grosskopf, AK and Peterson, R and Dwyer, JE and Warner, A and Starost, MF and Simpson, RM and Sukoff Rizzo, SJ and Silva, AC and Allen-Worthington, K and Narver, H and Krug, LT and Jacobson, S},
title = {Callitrichine herpesvirus 3 in the common marmoset is a model of Epstein-Barr virus infection and associated lymphoma.},
journal = {PLoS pathogens},
volume = {22},
number = {7},
pages = {e1014450},
doi = {10.1371/journal.ppat.1014450},
pmid = {42467720},
issn = {1553-7374},
abstract = {Herpesviruses, such as Epstein-Barr virus (EBV), are thought to potentially play a significant role in multiple disease processes, including neoplasia, multiple sclerosis (MS), and more recently, Alzheimer's disease (AD). Animal models remain vital tools for understanding these diseases and developing therapeutics. Callitrichine herpesvirus 3 (CalHV-3) was identified in the early 2000s in the common marmoset (Callithrix jacchus). Although phylogenetically related to human EBV, the biological similarities between CalHV-3 and EBV have not been thoroughly characterized. Over 450 marmosets from five biomedical research colonies in the United States were screened for CalHV-3 using droplet digital PCR (ddPCR). Peripheral blood mononuclear cells (PBMCs) were magnetically separated to determine viral loads in B-cell selected and B-cell depleted populations. A CalHV-3 infected cell line was reactivated to determine gene expression profiles using quantitative-Reverse Transcription PCR (q-RT-PCR). Archived cases of lymphoma in the marmoset were immunophenotyped by immunohistochemistry (IHC). In the neoplastic tissue, CalHV-3 viral loads were measured by ddPCR, and viral transcripts were visualized using RNAscope. The prevalence of CalHV-3 in these research colonies ranged from 19-63%. The virus was detected longitudinally in PBMCs and saliva. Infected marmosets had CalHV-3 viral loads enriched in B-cells. All cases of B-cell lymphoma in the marmoset were positive for CalHV-3 DNA, with transcripts of EBV latent and lytic gene homologs detected in neoplastic tissue. Like EBV, CalHV-3 is characterized by persistent infection, shedding in saliva, B-cell tropism, latent and lytic gene expression profiles, and lymphomagenesis in a subset of infected animals. These results further suggest that CalHV-3 in the common marmoset may serve as a translational model of EBV infection and associated diseases.},
}

@article {pmid42467872,
year = {2026},
author = {Grill, JD and Graff-Radford, J},
title = {The Promise and Peril of Alzheimer Disease Prevention.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218348},
doi = {10.1212/WNL.0000000000218348},
pmid = {42467872},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/prevention & control/diagnosis ; },
abstract = {Interventions to delay or prevent Alzheimer disease dementia hold the promise of sizable personal and public benefit. The nomenclature, research designs, and interpretation of results for studies assessing prevention outcomes, however, are inconsistent and would benefit from greater consensus about the necessary requirements for specific intervention claims. Moreover, the public space includes substantial media attention, direct-to-consumer diagnostics, and marketing of unproven interventions for brain health and dementia prevention. This article outlines these issues in hopes of catalyzing further consensus building and alerting professional and regulatory agencies to these topics.},
}

Humans
*Alzheimer Disease/prevention & control/diagnosis

@article {pmid42467931,
year = {2026},
author = {Kim, Y and Lee, G and An, S and Park, H and Kim, H and Kim, J and Kang, S and Kim, S and Kwon, D and Park, J and Hwang, Y and Kim, S and Yuan, X and Jeong, J and Lee, H and Kim, HK and Kim, J},
title = {Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76658},
doi = {10.1002/advs.76658},
pmid = {42467931},
issn = {2198-3844},
support = {NRF-2022R1A6A1A03053343//Ministry of Education, Republic of Korea/ ; RS-2025-02223734//Korea Health Industry Development Institute (KHIDI)/ ; RS-2024-00433755//Ministry of Science and ICT and Ministry of Health and Welfare, Republic of Korea/ ; },
abstract = {The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), driving Aβ accumulation, tau pathology, and synaptic dysfunction. Allele-specific correction of APOE4 represents a promising therapeutic strategy to mitigate disease progression. In this study, we developed an APOE4-specific prime editing strategy based on an optimized APOE4-targeting pegRNA, enabling precise and efficient conversion of the APOE4 allele to the lower-risk APOE3 variant. We found that PE7 targeting the APOE4 allele achieved robust and specific editing without detectable off-target effects. This correction reduced ApoE4 protein levels and attenuated key AD-related pathologies, including Aβ42 accumulation, tau phosphorylation, and activation of the ERK1/2 pathway in APP/APOE4 knock-in (KI) mice. Notably, PE7 treatment enhanced neuronal survival and improved cognitive performance in these mice. Furthermore, in human induced neurons derived from APOE3/4 heterozygous AD patient fibroblasts, PE7 consistently corrected the APOE4 allele and suppressed both amyloid- and tau-associated pathologies. These findings establish PE7-mediated APOE4 correction as a precise and efficient therapeutic genome-editing strategy with translational potential for sporadic AD.},
}

@article {pmid42468094,
year = {2026},
author = {Feng, Q and Song, Y and Pan, Z and Liu, W and Xu, H and Wang, L and Cheng, H and Wang, P and Chen, G},
title = {Heterostructure nanozyme-synergistically modulated electrochemiluminescence/photoelectrochemical sensing platform for detection of Alzheimer's disease biomarkers in plasma samples.},
journal = {Biosensors & bioelectronics},
volume = {312},
number = {},
pages = {119004},
doi = {10.1016/j.bios.2026.119004},
pmid = {42468094},
issn = {1873-4235},
abstract = {In this work, a PtPd/CeO2 heterostructure nanozyme-synergistically modulated ternary ZnS/CdS/Bi2Se3 electrochemiluminescence/photoelectrochemical (ECL/PEC) aptasensor was designed for simultaneous detection of amyloid-β peptides (Aβ1-40 and Aβ1-42), as the key plasma biomarkers of Alzheimer's disease (AD). Benefiting from the bimetallic alloy effect and the support-active component synergy, PtPd/CeO2 heterostructure efficiently accelerated interfacial electron transfer, leading to both an improved catalytic reaction kinetic rate and enhanced adsorption and activation of reactants. Ternary ZnS/CdS/Bi2Se3 achieved photocurrent self-enhancement via synergistic bandgap excitation and multi-interface charge transfer effects among its components, thereby significantly boosting the response signals of both ECL and PEC. Through the integration of aptamer-mediated specific target recognition and toehold-triggered strand displacement reaction (TSDR)-based signal amplification, this aptasensor realized the simultaneous detection of Aβ1-42 and Aβ1-40. Notably, practical validation of the aptasensor for Aβ1-42/Aβ1-40 ratio detection in actual plasma specimens demonstrated the feasibility of minimally invasive liquid biopsy with high patient compliance and great potential for large-scale screening and early diagnosis of AD.},
}

@article {pmid42468111,
year = {2026},
author = {Bittner, T and Lopera, F and Rios-Romenets, S and Schiffman, C and Clayton, D and Hibar, D and Kollmorgen, G and Dolton, M and Poon, V and Nguyen, J and Giraldo-Chica, M and Acosta-Baena, N and Espinosa, A and Villegas, G and Muñoz, C and Serna, L and Alvarez, S and Protas, H and Luo, J and Sohankar, J and Chen, Y and Ghisays, V and Malek-Ahmadi, M and Ashton, NJ and Denkinger, MN and Cai, Y and Xu, YR and Ostaszewski, B and Selkoe, DJ and Alexander, RC and Quiroz, YT and Su, Y and Chen, K and Doody, RS and Langbaum, JB and Tariot, PN and Sink, KM and Reiman, EM},
title = {Baseline and placebo-related imaging, cerebrospinal fluid, plasma biomarker, and cognitive findings in unimpaired PSEN1 E280A mutation carriers and non-carriers in the Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia Trial.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106390},
doi = {10.1016/j.ebiom.2026.106390},
pmid = {42468111},
issn = {2352-3964},
abstract = {BACKGROUND: The Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease (ADAD) Colombia Trial evaluated the biological, cognitive, and clinical effects of crenezumab, an anti-oligomeric and monomeric amyloid-beta (Aβ) monoclonal antibody, in 30-60-year-old PSEN1 E280A mutation carriers without cognitive impairment from the world's largest ADAD kindred, finding no significant treatment effects on Alzheimer's disease progression. This article describes baseline biomarker, cognitive, and clinical measurements and placebo-related longitudinal changes in the randomised prevention trial's mutation carrier and non-carrier groups.

METHODS: Crenezumab and placebo-treated mutation carriers and placebo-treated non-carriers were assessed using amyloid and fluorodeoxyglucose positron emission tomography (PET), magnetic resonance imaging, plasma, and optional tau PET and cerebrospinal fluid (CSF) biomarker, cognitive, and clinical measurements over 5-8 years.

FINDINGS: 94% of the 252 kindred members (85 crenezumab-treated mutation carriers, 84 placebo-treated carriers, and 83 placebo-treated non-carriers) completed the trial. 55% of the carriers had baseline PET evidence of substantial Aβ plaques. 32.9% and 6.8% of amyloid PET-positive and PET-negative carriers, respectively, 36.5%, 13.2%, and 0% of pTau217-positive, pTau217-intermediate, and pTau217-negative carriers, respectively, and no non-carriers became cognitively impaired over the next 5 years. Carriers were distinguished from non-carriers by several baseline and longitudinal Aβ, tau, neurodegenerative, and inflammatory biomarker measures, but not by CSF oligomeric Aβ measurements.

INTERPRETATION: Despite the absence of significant treatment effects, these findings and the trial itself continue to inform the course of preclinical ADAD, advance Alzheimer's disease prevention research, and provide a shared resource of data and samples for the field (ClinicalTrials.gov ID: NCT01998841; trial completed).

FUNDING: National Institute on Aging, Banner Alzheimer's Institute, Genentech, Inc., and F. Hoffmann-La Roche Ltd.},
}

@article {pmid42468194,
year = {2026},
author = {Castro, MM and Pavón, RA and Moroni, AD and Melcon, M and Menite, NE and Villafañe, G and Genaro, AM and Palumbo, ML},
title = {Reduced serum IL-6 as a potential peripheral marker of amnestic mild cognitive impairment: A pilot study.},
journal = {Medicina clinica},
volume = {166},
number = {9},
pages = {107540},
doi = {10.1016/j.medcli.2026.107540},
pmid = {42468194},
issn = {1578-8989},
abstract = {INTRODUCTION AND OBJECTIVE: Mild cognitive impairment (MCI) represents an intermediate state between age-related cognitive changes and early stages of dementia. People with amnestic subtype (aMCI) show higher risks of progression to dementia due to Alzheimer's disease. In this pilot study, the aim was to investigate whether cytokines could be potential peripheral markers associated with MCI.

METHODS: Women were recruited in Junín city, Buenos Aires, Argentina. Their cognitive performance was evaluated using a neuropsychological battery. Serum levels of IFN-γ, IL-1β, IL-2, IL-4 and IL-6 were analyzed by ELISA, and the type 2/type 1 balance was determined. Correlations between both parameters, as well as within-group analysis cytokines levels were evaluated.

RESULTS: After cognitive evaluation, participants were classified as healthy controls (HC: n=14) or as aMCI (n=7). IL-6 levels were significantly decreased in the aMCI group compared with HC (p=0.047). IFN-γ showed no robust correlations within the HC group but presented a strong negative correlation with IL-2 (p=0.005) and IL-4 (p=0.052) in aMCI. Several correlations were found between cytokine levels, the type 2/type 1 balance and neurocognitive tests.

CONCLUSIONS: We concluded that IL-6 decreased levels, altered correlation in cytokine profiles, together with performance on the neuropsychological battery, may serve as potential blood-markers of amnestic mild cognitive impairment.},
}

@article {pmid42456517,
year = {2026},
author = {Liao, R and Jin, H and Guo, Y and Jiang, X and Liu, Y and Yu, T and Li, H and Yin, P},
title = {A dual-recognition ratiometric fluorescent probe for selective imaging of cysteine in Alzheimer's disease models.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {363},
number = {Pt 2},
pages = {128448},
doi = {10.1016/j.saa.2026.128448},
pmid = {42456517},
issn = {1873-3557},
abstract = {Alzheimer's disease (AD) is strongly associated with redox imbalance and metabolic dysregulation, in which cysteine (Cys), an essential biothiol and endogenous antioxidant, plays a key role in neuronal redox homeostasis. However, selective and ratiometric imaging of Cys in AD-related biological systems remains challenging because of interference from structurally similar biothiols and complex pathological microenvironments. Herein, we developed probe 1, a coumarin-based dual-recognition ratiometric fluorescent probe for selective Cys imaging. Probe 1 displayed a rapid, sensitive, and distinct ratiometric fluorescence response toward Cys with a pronounced emission blue-shift. Owing to its dual-recognition design, probe 1 exhibited excellent selectivity for Cys over homocysteine, glutathione, and other biologically relevant species, as well as good photostability, low cytotoxicity, and favorable biocompatibility. Probe 1 enabled reliable visualization of endogenous and exogenous Cys in living cells and was further applied to monitor Cys fluctuations in zebrafish and AD mouse models. These results demonstrate that probe 1 provides an effective ratiometric imaging tool for tracking Cys-related redox alterations in AD-associated biological systems and offers a useful platform for exploring the role of Cys metabolism in AD progression.},
}

@article {pmid42456683,
year = {2026},
author = {Bouzigues, A and Grassi, M and Cantoni, V and Premi, E and Bellini, S and Binetti, G and Logroscino, G and Russell, LL and Ferry-Bolder, E and Foster, PH and van Swieten, JC and Jiskoot, LC and Seelaar, H and Sanchez-Valle, R and Laforce, R and Graff, C and Galimberti, D and Vandenberghe, R and de Mendonça, A and Di Fede, G and Santana, I and Gerhard, A and Langheinrich, T and Levin, J and Nacmias, B and Otto, M and Bertoux, M and Lebouvier, T and Ducharme, S and Butler, C and le Ber, I and Bruffaerts, R and Solje, E and Kinnunen, M and Krüger, J and Finger, E and Tartaglia, MC and Masellis, M and Rowe, JB and Synofzik, M and Moreno, F and Ghidoni, R and Migliaccio, R and Rohrer, JD and Borroni, B and , },
title = {Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study.},
journal = {The Lancet. Neurology},
volume = {25},
number = {8},
pages = {731-740},
doi = {10.1016/S1474-4422(26)00197-3},
pmid = {42456683},
issn = {1474-4465},
mesh = {Humans ; *Frontotemporal Dementia/genetics/mortality/diagnosis ; Retrospective Studies ; C9orf72 Protein/genetics ; tau Proteins/genetics ; Female ; Male ; Middle Aged ; Aged ; Cohort Studies ; Progranulins/genetics ; Mutation ; Kaplan-Meier Estimate ; },
abstract = {BACKGROUND: What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation.

METHODS: In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method.

FINDINGS: Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level.

INTERPRETATION: Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed.

FUNDING: Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.},
}

Humans
*Frontotemporal Dementia/genetics/mortality/diagnosis
Retrospective Studies
C9orf72 Protein/genetics
tau Proteins/genetics
Female
Male
Middle Aged
Aged
Cohort Studies
Progranulins/genetics
Mutation
Kaplan-Meier Estimate

@article {pmid42456853,
year = {2026},
author = {Chang, J and Gao, PY and Gao, Y and Wu, ZY and Wang, ZB and Chen, O and Kulick, ER and Zhao, G and Tang, Y},
title = {Mental health, biological aging, and lifestyle mediate the associations between social determinants of health and dementia.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.07.036},
pmid = {42456853},
issn = {2090-1224},
abstract = {INTRODUCTION: Social determinants of health (SDoH) encompass non-medical factors including economic stability, education, social engagement, and environmental conditions that significantly influence health outcomes. Comprehensive evaluation of weighted SDoH scores and their underlying mechanisms in dementia risk remains limited.

OBJECTIVES: To investigate longitudinal associations between SDoH and dementia risk, and explore mediating pathways through mental health, biological aging, lifestyle, and inflammation using directed acyclic graph theory.

METHODS: We constructed a weighted SDoH score encompassing seven components across four domains: economic stability, education, social contact, and environmental factors. Cox models assessed dementia risk across SDoH tertiles. Mediation analyses examined pathways through mental health, biological aging, lifestyle, and inflammatory markers. Life expectancy differences were calculated using flexible parametric survival models.

RESULTS: A total of 359,419 UK Biobank participants (mean age: 56.26 years; 52.53% female) with a median follow-up of 13.46 years were included. We found that participants with favorable SDoH levels had a lower risk of developing all-cause dementia (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.53-0.60), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.68), and vascular dementia (HR, 0.48; 95% CI, 0.41-0.55) compared to those with unfavorable SDoH levels. SDoH emerged as the 2nd most important factor affecting dementia risk after age. The associations between SDoH and incident dementia were mediated by mental health, biological aging, and lifestyle factors. Specifically, depression, frailty, PhenoAge, and smoking mediated 24.00%, 13.60%, 6.33%, and 2.82% of the association, respectively. At age 65, participants with dementia who had favorable SDoH levels had an average life expectancy of 0.909 (95% CI 0.002-1.816) years longer than those with unfavorable SDoH levels.

CONCLUSION: Favorable SDoH levels significantly reduce dementia risk, with mental health, biological aging, and lifestyle serving as key mediating pathways, emphasizing the importance of comprehensive social interventions for dementia prevention.},
}

@article {pmid42456864,
year = {2026},
author = {Séguy, L and Guyon, L and Corvaisier, S and Maurel, M and Verdié, P and Herbinet, R and Pluart, LL and Dehouck, L and Sevin, E and Fenart, L and Gosselet, F and Lagadu, S and Née, G and Fréret, T and Since, M and Delépée, R and Dallemagne, P and Lisowski, V and Groo, AC and Malzert-Fréon, A},
title = {Enhancing brain delivery of tegaserod for Alzheimer's disease: a pharmaceutical comparison of two nanocarrier-based strategies.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127181},
doi = {10.1016/j.ijpharm.2026.127181},
pmid = {42456864},
issn = {1873-3476},
abstract = {Tegaserod is a serotonin receptor agonist with potential neuroprotective properties for Alzheimer's disease. Due to its low druggability profile and to avoid detrimental side effects, a brain-targeted formulation is required. Nanocarriers targeting the blood-brain barrier (BBB) with a shuttle peptide, such as peptide-22, or enabling direct nose-to-brain delivery were considered as valuable approaches. This study aimed to compare two types of lipid-based nanocarriers and determine the best formulation for intravenous (IV) or intranasal (IN) administration. Tegaserod-loaded nanoemulsions and liposomes were successfully developed, improving the solubilization of tegaserod in injectable formulations. Their properties were optimized for the IV route, and the two formulations were compared in terms of granulometric properties, stability, stealth properties, and transport across a human model of the human BBB. Based on these evaluations, peptide-22-decorated tegaserod-loaded nanoemulsions were the most promising for IV administration. In addition, tegaserod-loaded nanoemulsions or liposomes were incorporated in a gelling formulation with properties optimized for the IN route, focusing on gelation temperature, osmolarity, and pH. Due to its rheological profile and behavior at room temperature, gel-embedded liposomes emerged as the most suitable formulation for the IN route. The successful development of these nanocarriers will facilitate further preclinical evaluation of tegaserod in Alzheimer's disease.},
}

@article {pmid42456879,
year = {2026},
author = {Taei, AA and Karimani, F and Kaveh, N and Khodabakhsh, P and Dehaqani, MA and Dargahi, L},
title = {Forty-hertz auditory stimulation restored hippocampal-prefrontal synchrony and attenuated hippocampal hyperexcitability in an STZ-induced Alzheimer's model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115931},
doi = {10.1016/j.expneurol.2026.115931},
pmid = {42456879},
issn = {1090-2430},
abstract = {Dysfunction of neuronal networks such as aberrant excitability and disrupted oscillatory activity, especially within theta and gamma bands, in memory-related areas including the hippocampus and prefrontal cortex, is increasingly recognized as an important contributor to cognitive impairment in Alzheimer's disease (AD). In this context, targeting network dysfunction via gamma sensory entrainment, such as 40 Hz auditory stimulation, has emerged as a promising non-invasive therapeutic approach; however, the therapeutic mechanisms by which 40 Hz auditory stimulation ameliorates network-level deficits remain poorly understood. We studied the effects of long-term 40 Hz auditory stimulation in STZ-induced AD rats on the hippocampal-prefrontal network activity. Daily auditory stimulation was applied for 21 days, and its impact was assessed using electrophysiological recordings, behavioral testing, histological staining, and molecular analyses. STZ-treated rats exhibited impaired theta-gamma coupling, reduced hippocampal-prefrontal theta coherence, increased interictal epileptiform discharges, and significant deficits in spatial memory. These network abnormalities were associated with Aβ accumulation, tau hyperphosphorylation, altered expression of insulin/PI3K/Akt pathway-associated genes, and reduced expression of neurogenesis-related markers. Remarkably, 40 Hz auditory stimulation reversed many of these impairments: it restored functional connectivity and cross-frequency coupling, reduced epileptiform activity, improved memory performance, attenuated Aβ and tau pathology, partially normalized insulin/PI3K/Akt pathway-associated gene expression, and upregulated genes related to adult neurogenesis. Our findings indicated that 40 Hz auditory stimulation can effectively target both neural circuit dysfunction and molecular markers of AD, highlighting its potential as a simple, accessible, and multifaceted therapeutic strategy.},
}

@article {pmid42456960,
year = {2026},
author = {Yang, F and Zhao, Y},
title = {Di(2-ethylhexyl) phthalate exposure aggravates amyloid-beta-induced toxicity in transgenic AD Caenorhabditis elegans via lysosomal dysfunction and oxidative stress.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {116276},
doi = {10.1016/j.fct.2026.116276},
pmid = {42456960},
issn = {1873-6351},
abstract = {Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and environmental contaminant. DEHP exposure has been linked to neurotoxicity in Alzheimer's disease (AD), yet the underlying mechanisms remain unclear. Here we found that DEHP exacerbated amyloid-beta (Aβ)-induced toxicity in transgenic AD Caenorhabditis elegans (C. elegans) models. Meanwhile the accumulation of SQST-1 was increased, indicating that the autophagic flux was impaired. Consistently, Aβ deposition was elevated in DEHP-treated AD C. elegans. Further investigation revealed that DEHP treatment resulted in lysosomal dysfunction accompanied by a significant decrease in lysosome number. The expression of hlh-30, a key transcription factor involved in lysosomal biogenesis, as well as its downstream lysosome-related genes, including cup-5, vha-17, and lmp-1, was reduced by DEHP. Moreover, hlh-30 RNAi abolished the exacerbation of Aβ toxicity by DEHP, indicating that the modulation of hlh-30 was a critical mechanism underlying the effects of DEHP. Additionally, DEHP aggravated oxidative stress in AD C. elegans, while the antioxidant N-acetylcysteine alleviated lysosomal impairment and reduced Aβ deposition, suggesting that the elevated oxidative stress was a key contributor to DEHP-induced lysosomal dysfunction and autophagy impairment. These findings highlight lysosomal impairment as a key mechanism contributing to DEHP-exacerbated toxicity in AD models, and suggest the possibility of using antioxidants to prevent DEHP-induced toxicity.},
}

@article {pmid42457037,
year = {2026},
author = {Fernando, MG and Sullivan, K and Simons, M and Squillace, A and Kiat, H and Martins, RN},
title = {Nutritional Strategies Targeting Glucose Metabolism to Slow Cognitive Ageing: A Scoping Review of Human Trials.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101434},
doi = {10.1016/j.ajcnut.2026.101434},
pmid = {42457037},
issn = {1938-3207},
abstract = {Cerebral glucose hypometabolism is a hallmark of cognitive aging and Alzheimer's Disease (AD), underscoring the need for nutritional strategies that support brain energy metabolism. This scoping review synthesized evidence from human interventions evaluating alternative energy substrates and nutrients that support cerebral energy metabolism and their effects on cognition in older-adults. The review followed PRISMA-ScR guidelines. MEDLINE, EMBASE, and Scopus were searched for studies published during 2014-2024, involving adults aged ≥60 years, with Mild Cognitive Impairment (MCI), AD, subjective cognitive decline, or normal cognition. Thirty-two studies were included, investigating Medium Chain Triglycerides (MCTs), ketogenic diets, omega-3 fatty acids, amino acids, histidine-containing dipeptides, serotonin precursors, and dietary fat modification. Cognitive outcomes were global and domain-specific measures including memory, executive function, and attention, while other outcomes included functional capacity, neuroimaging markers, inflammation, mood, and quality-of-life. Omega-3 supplementation showed mixed evidence with cognitive benefits reported particularly in MCI populations receiving higher DHA doses and longer intervention durations (≥1 g/day, ≥6 months). Ketogenic/MCT-based strategies improved cognitive function in MCI and early-AD, with effects tied to plasma ketone levels; however, benefits were not consistently observed. Limited evidence suggested that anserine/carnosine supplementation may improve verbal memory and executive function, particularly in adults aged ≥70 years and APOE4 carriers. L-arginine improved global cognition in frail hypertensive older-adults, while tryptophan and amino acid interventions demonstrated domain-specific or age-dependent effects, rather than consistent improvements. Findings were heterogeneous across interventions and populations. Cognitive benefits were most evident in early disease-stages, with sufficient dosing and adherence. Several studies reported favourable biomarker, inflammatory, metabolic, or quality-of-life outcomes despite limited cognitive effects. Overall, nutritional strategies targeting brain energy metabolism show promise for supporting cognitive health. However, substantial heterogeneity, small sample sizes, short intervention durations, and inconsistent cognitive outcomes limit the strength of the evidence. Future research should prioritise biomarker-based, longer-term, and multimodal approaches to clarify efficacy and clinical applicability.},
}

@article {pmid42457038,
year = {2026},
author = {Dhana, K and Aggarwal, NT and Ventrelle, J and Voigt, RM and Liu, X and Agarwal, P and Tangney, C and Arfanakis, K and Sacks, FM and Barnes, LL},
title = {Adherence to the MIND Diet and Longitudinal Changes in Global Cognition: A Post-Hoc Analysis of the MIND Trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101433},
doi = {10.1016/j.ajcnut.2026.101433},
pmid = {42457038},
issn = {1938-3207},
abstract = {BACKGROUND: A three-year randomized trial comparing the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet with a control diet found no significant differences in cognitive outcomes by intervention assignment, potentially due to variability in dietary adherence.

OBJECTIVE: We examined whether adherence to the MIND diet, validated using plasma nutrient biomarkers, was associated with longitudinal changes in global cognition.

METHODS: The MIND trial enrolled 604 community-dwelling adults aged 65-84 years without cognitive impairment at baseline. MIND diet adherence was quantified as the change in MIND scores from baseline, with higher values indicating greater adherence, and validated using blood levels of antioxidant nutrients, including lutein-zeaxanthin and β-carotene. Participants were classified into categories of no, moderate, or substantial improvement in MIND diet score. Linear mixed-effects models with random intercepts and slopes were used to estimate annual changes in global cognition.

RESULTS: Of 590 participants (mean age 70.3 years and 65% females) included in the analysis, 116 (19.7%) showed no improvement, 224 (38.0%) modest improvement, and 250 (42.3%) substantial improvement in their MIND diet score. Compared with participants with no change in MIND score, those with greater improvement (mean absolute increase of 4 points on the 0-14 scale) demonstrated a significant annual increase in global cognitive composite scores (β = 0.035; 95% CI: 0.006, 0.064), along with higher plasma lutein-zeaxanthin (β = 0.088; 95% CI: 0.038, 0.137) and β-carotene (β = 0.075; 95% CI: 0.001, 0.150). Modest improvement was not associated with significant changes in cognitive function. The associations between changes in MIND score and cognition were not modified by dietary intervention arm (p-for-interactions > 0.167).

CONCLUSIONS: Participants with greater increases in MIND diet scores from baseline, indicating higher adherence, showed significant improvements in global cognitive function compared with those whose scores did not increase during the trial. Clinical Trial Registry (clinicaltrials.gov) number: NCT02817074.},
}