@article {pmid42010440,
year = {2026},
author = {Kawabata, K and Shima, S and Ohdake, R and Bagarinao, E and Mizutani, Y and Tatebe, H and Koike, R and Kasai, A and Ueda, A and Ito, M and Hata, J and Ishigaki, S and Toyama, H and Tokuda, T and Takashima, A and Watanabe, H},
title = {VR-based path integration predicts individual risk of rapid cortical decline: a one-year longitudinal study in cognitively unimpaired adults.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42010440},
issn = {1758-9193},
support = {JP22dk0207055//Japan Agency for Medical Research and Development/ ; JP21wm0425016//Japan Agency for Medical Research and Development/ ; JPJS00420240019//Japan Society for the Promotion of Science/ ; },
abstract = {BACKGROUND: Path integration (PI) is a navigational computation that can be affected by aging and Alzheimer’s disease (AD). Virtual-reality PI (VR-PI) preferentially engages medial temporal circuits and can reveal subtle changes that occur prior to overt impairment. Nevertheless, the longitudinal association between PI performance and structural brain changes remains unclear.

METHODS: In a 1-year longitudinal cohort of 71 cognitively unimpaired adults, we assessed baseline VR-PI performance (PI error and angular error), AD-related plasma biomarkers (p-tau181 and glial fibrillary acidic protein [GFAP]), and longitudinal cortical thickness and volume from MRI scans acquired one year apart, to examine whether baseline PI performance was associated with both plasma biomarkers and subsequent structural brain changes. Linear mixed-effects (LME) models were used to assess whether baseline PI performance predicted time-dependent regional thinning and atrophy.

RESULTS: Greater baseline PI error was associated with greater longitudinal cortical thinning and volume decline in the parahippocampal gyrus, middle temporal gyrus, posterior cingulate cortex, and caudal middle frontal gyrus. Similar spatial patterns were observed for angular error, indicating consistent associations across PI measures. Sensitivity analyses using extended models that additionally included either APOE ε4 status or the baseline age × time interaction, as well as analyses restricted to participants aged ≥ 40 years, did not materially alter the pattern of results. Both baseline PI error and angular error were associated with plasma p-tau181 (r = 0.38 for both, 95% confidence interval [CI]: 0.16–0.56), and PI error was associated with GFAP levels (r = 0.36, 95% CI: 0.14–0.55). Receiver operating characteristic (ROC) curve analyses showed that baseline PI error best discriminated individuals with accelerated parahippocampal thinning (10% threshold; cross-validated AUC = 0.87).

CONCLUSIONS: Baseline VR-PI performance was associated with longitudinal cortical thinning and volume decline in AD-vulnerable regions, along with additional associations with plasma p-tau181 and GFAP levels. VR-PI performance may reflect both molecular (blood biomarker) and structural (MRI) signatures preceding overt clinical impairment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02056-x.},
}

@article {pmid42229579,
year = {2026},
author = {Wang, D and Fan, J and Wang, T and Tang, F and Yao, Q and Ye, X and Qi, X and Tian, M and Lin, X and Shi, J},
title = {Cerebellar rTMS ameliorates cognitive impairment in Alzheimer's disease: A randomized trial.},
journal = {Brain stimulation},
volume = {19},
number = {4},
pages = {103138},
doi = {10.1016/j.brs.2026.103138},
pmid = {42229579},
issn = {1876-4754},
abstract = {BACKGROUND: Developing effective neuromodulatory therapies for Alzheimer's disease (AD) is a critical unmet need. While repetitive transcranial magnetic stimulation (rTMS) shows promise, its optimal targets and mechanisms remain incompletely understood. The cerebellum, a key modulator of large-scale brain network dynamics, represents a novel therapeutic target for addressing the distributed cognitive network dysfunction in AD.

OBJECTIVE: This study aimed to evaluate the cognitive efficacy and safety of cerebellar rTMS in AD and to elucidate its potential mechanism of action through the lens of structural network topology.

METHODS: In this randomized, double-blind, sham-controlled trial, patients with AD were assigned to receive active or sham rTMS targeting the bilateral cerebellar Crus II region. Cognitive assessments were conducted at baseline, post-treatment (4 weeks), and at a 12-week follow-up. Diffusion tensor imaging (DTI) was employed to analyze changes in whole-brain structural network topology.

RESULTS: Compared to the sham group, the active rTMS group demonstrated significantly greater improvement in global and domain-specific cognitive function at 4 weeks, with benefits sustained at the 12-week follow-up. Response rates on the MMSE and MoCA were also significantly higher in the active group. Neuroimaging revealed that active rTMS enhanced global network efficiency, indicated by significant increases in global/local efficiency and clustering coefficient, alongside a decreased characteristic path length, signifying an optimization toward small-world topology. Furthermore, treatment selectively enhanced nodal efficiency within core hubs of the default mode, frontoparietal, and salience networks. Critically, these structural improvements correlated with cognitive gains; increased nodal efficiency in the precuneus and posterior cingulate cortex was associated with improved episodic memory and visuospatial function.

CONCLUSION: Cerebellar rTMS is a safe and effective intervention that confers sustained cognitive benefits in AD. Its therapeutic mechanism likely involves the reinforcement of structural connectivity and enhanced integrative capacity within supraordinate cognitive networks, particularly the default mode network, via cerebello-cortical pathways.},
}

@article {pmid42229590,
year = {2026},
author = {Reddy-Mazzitello, RM and Alexander, J and Skawratananond, S and Sehar, U and Mukherjee, U and Brownell, M and Ballada, S and Reddy, PH},
title = {Associations Between Posttraumatic Stress and Comorbidities of Traumatic Brain Injury and Substance Use Disorders with Alzheimer's Disease in Older Veterans: A Narrative Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103188},
doi = {10.1016/j.arr.2026.103188},
pmid = {42229590},
issn = {1872-9649},
abstract = {Posttraumatic stress disorder (PTSD) exhibits high rates of comorbidity with Substance Use Disorders (SUDs) and Traumatic Brain Injury (TBI), especially in older adults who are subject to the effects of psychological trauma due to combat exposure, health-related and psychosocial outcomes, and aging. This narrative review explores the associations between PTSD and comorbidities of psychoactive substance abuse and traumatic brain injuries on the incidence of Alzheimer's disease (AD) in veterans aged 55>, according to existing literature. The account of genetic predisposition in reference to the presence of the Apolipoprotein e4 gene was also considered. Biomarkers of AD, including beta-amyloid and phosphorylated tau levels in cerebrospinal fluids (CSF), were analyzed in PTSD, TBI and SUD conditions. This review was conducted as a narrative summary utilizing three separate search engines. Inclusion of data was primarily determined by a single reviewer with a randomized 10 percent of 49 selected studies cross screened by a second reviewer. Two additional independent reviewers incrementally cross- checked the 49 included studies at full-text stages for accuracy and consistency. The literature review found that PTSD and comorbidities of TBI and SUD may share increased incidence of AD and related dementia, however, a causal relationship cannot be implied. Conflicting results on CSF biomarker trends for each comorbidity and complications arising from genetic predispositions indicate a need for future studies to clarify the relationship between PTSD comorbidities on the onset of AD. Expanded biomarker analysis has not yet been assessed. Implications of this review may lead to alternative treatment and care methods for older adults/veterans suffering from psychological impairment to prevent the formation of comorbidities and lower existing elevated risks for AD onset and progression.},
}

@article {pmid42229706,
year = {2026},
author = {Alqahtani, SM and Afzal, M and Afzal, O and Alabbas, A and Phalak, P and Goyal, K},
title = {Platelet-derived extracellular vesicles as neurodegenerative disease biomarkers.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121130},
doi = {10.1016/j.cca.2026.121130},
pmid = {42229706},
issn = {1873-3492},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are increasingly prevalent worldwide and have not yet been adequately diagnosed, especially because they require minimally invasive, non-invasive techniques. Although established blood-based biomarkers, such as plasma p-tau217, neurofilament light chain (NfL), and GFAP, have shown clinical utility, limitations in sensitivity and scalability remain. Platelets, anucleate cytoplasmic fragments originating from megakaryocytes, are the primary producers of extracellular vesicles in the peripheral blood. These vesicles contain disease-specific cargo, including amyloid-β, α-synuclein, tau, disease-associated glycoproteins, and microRNAs (miRNAs) derived from platelets. Recent findings suggest that the cargo of platelet-derived extracellular vesicles (pEVs) may be associated with neurodegenerative changes linked to disease severity. However, validation through a prospective multicenter study is necessary. A systematic narrative review was performed by searching the PubMed, Scopus, and Web of Science databases with the keywords "platelet-derived extracellular vesicles," "platelet microvesicles," "neurodegeneration," and "biomarkers" (inception through April 2026). This review discusses the biogenesis of pEV, their composition in relation to blood markers, and their pathomechanistic roles, such as platelet-mediated blood-brain barrier disruption, neuroinflammation, and misfolded protein seeding. The diagnostic evidence of pEV-associated cargo in neurodegenerative diseases is critically evaluated and contextualized with current blood markers. Key preanalytical considerations, including the selection of anticoagulants, isolation procedures, storage conditions, and the number of freeze-thaw cycles, as well as analytical considerations, such as flow cytometric calibration, single-vesicle resolution, and multiplexed platforms, are examined for their applicability in clinical laboratory settings. The emphasis is on reporting according to the MISEV and the harmonization between laboratories. The limitations of this study are the small heterogeneous cohorts, lack of preanalytical handling standardization, ex vivo platelet activation artifact, and lack of external validation.},
}

@article {pmid42229733,
year = {2026},
author = {Kumari, N and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and HariKrishnaReddy, D},
title = {From capillaries to cognition: decoding neurovascular unit dysfunction and cerebrovascular contributions in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118107},
doi = {10.1016/j.bcp.2026.118107},
pmid = {42229733},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD), classically defined by abnormal amyloid-β and tau aggregation, is now also understood to profoundly disturb the brain's cerebrovascular system and the integrity of the neurovascular unit (NVU). An ever-growing body of evidence points to NVU dysfunction and neurovascular unit deficits as major contributors to AD pathology. NVU comprises neurons, glial cells, endothelial cells, and pericytes, which together orchestrate cerebral blood flow in the CNS and help maintain the structural and functional integrity of the blood-brain barrier (BBB). Its disruption increases neuronal damage and impairs clearance mechanisms in AD. Interactions between pericytes, astrocytes, smooth muscle cells, neurons, microglia, and NVU endothelial cells support cerebral perfusion, BBB integrity, and metabolic homeostasis. Major pathophysiological events involved in the development of early BBB leakage and neurovascular uncoupling in AD include endothelial impairment, breakdown of tight junctions, thickening of the basement membrane, degeneration of pericytes, and astrogliosis. Activated astrocytes and microglia further exacerbate NVU injury by releasing inflammatory mediators and ROS. Numerous molecular signaling cascades, including PI3K/Akt/mTOR, MAPK/ERK, and NF-κB pathways, are implicated in mechanistic interplay among metabolic perturbations, neuroinflammatory responses, and vascular endothelial damage. Emerging NVU-targeted therapeutic strategies include anti-inflammatory, antioxidant, and vasculoprotective drugs intended to restore BBB integrity, preserving neurovascular coupling, and promoting the removal of amyloid-β. This review synthesizes preclinical and clinical evidence elucidating mechanisms by which capillary-level perturbations lead to cognitive decline, while discussing therapeutic interventions aimed at restoring NVU integrity and preserving BBB architecture. The delineation of cerebral involvement in AD provides support for a potential for timely diagnosis and innovative approaches for treatment.},
}

@article {pmid42229832,
year = {2026},
author = {Singh, VB and Gupta, S and Sella, RN},
title = {Engineered EV-mediated delivery of an anti-amyloid peptide provides neuroprotection in an in vitro Alzheimer's disease model.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127043},
doi = {10.1016/j.ijpharm.2026.127043},
pmid = {42229832},
issn = {1873-3476},
abstract = {Alzheimer's disease is driven in part by amyloid-β (Aβ) aggregation, oxidative stress, and progressive neuronal dysfunction. Despite various attempts, therapeutic translation remains limited by inefficient delivery of bioactive molecules to neuronal cells. This study presents a surface-engineered extracellular vesicle (EV) platform designed for targeted peptide delivery, assessing its neuroprotective efficacy in an in vitro model of Alzheimer's disease. EVs were obtained from NIH/3T3 cells expressing Lamp2b-RVG and were surface-modified with the β-sheet breaker peptide H102 through CP05-CD63 affinity binding. ATR-FTIR, SERS Raman spectroscopy, high-resolution transmission electron microscopy, nanoparticle tracking analysis, zeta potential measurements, and EV marker profiling demonstrated successful peptide conjugation and vesicle integrity. Aggregated Aβ25-35 was utilized to assess neuronal toxicity in NGF-differentiated PC-12 cells. Peptide-modified EV demonstrated effective, time-dependent cellular uptake and significantly improved cell viability while decreasing membrane damage and intracellular reactive oxygen species levels in comparison to Aβ-treated controls. Treatment with Peptide-modified EV normalized the expression of key genes associated with Alzheimer's, such as APP, Bax, Sirt1, and Stat1, suggesting a coordinated modulation of amyloidogenic, apoptotic, oxidative, and inflammatory pathways. The results indicate that surface-engineered EVs facilitate efficient neuronal delivery of therapeutic peptides and offer multi-level cytoprotection against Aβ-induced neurotoxicity. This study emphasizes the capability of peptide-decorated EV as a multifunctional nanocarrier system for the treatment of Alzheimer's disease.},
}

@article {pmid42229860,
year = {2026},
author = {Nguyen, MN and Ryu, TH and Lee, JS and Hong, SH and Yoon, SE and Kim, YJ and Yu, K},
title = {Engrailed, a target of the miR-92 family, attenuates Tau accumulation and associated memory deficits in Drosophila.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {120169},
doi = {10.1016/j.bbamcr.2026.120169},
pmid = {42229860},
issn = {1879-2596},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated Tau protein. While microRNAs (miRNAs) have emerged as critical regulators of gene expression and potential biomarkers for AD, their role in Tau pathology remains incompletely understood. In this study, we investigated the role of the miR-92 family and its downstream targets in modulating Tau-induced neurodegeneration using the Drosophila model. Overexpression of miR-311, miR-312, and miR-313, members of the miR-92 family, exacerbated Tau-induced phenotypes. We identified deltex (dx) and engrailed (en) as miR-92 target genes with genetic screening with in silico target prediction. Overexpression of en or EN2, a human ortholog of en, reduced Tau protein levels in Drosophila and human neuroblastoma cells, respectively. Furthermore, overexpression of en attenuates Tau-associated memory deficits in Drosophila. These findings suggest that the engrailed gene is an evolutionarily conserved regulator of Tauopathy and highlight the utility of the Drosophila AD model for identifying genetic modulators with therapeutic potential in AD.},
}

@article {pmid42230361,
year = {2026},
author = {Barba, L and Steinacker, P and Halbgebauer, S and Oeckl, P and Landwehrmeyer, B and Weishaupt, J and Verde, F and Ticozzi, N and Silani, V and Levin, J and Schönecker, S and Kornhuber, J and Prudlo, J and Schroeter, ML and Fassbender, K and Fliessbach, K and Diehl-Schmid, J and Jahn, H and Lauer, M and Dorst, J and Rosenbohm, A and Abu-Rumeileh, S and Anderl-Straub, S and Söntgerth, M and Böhm, F and Wiltfang, J and Otto, M},
title = {Serum neurofilaments for motoneuron and dementia diseases: a German multicenter cohort study.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42230361},
issn = {1432-1459},
support = {JCS24/02//Martin Luther Christian University/ ; CS22/06//Martin-Luther-University Halle-Wittenberg/ ; RF-2021-12374238)//Ministero della Salute/ ; TelDem//Sächsische Aufbaubank/ ; 100757914//EFRE InfraProNet/ ; },
abstract = {BACKGROUND: Serum neurofilament light and heavy chains (sNfL and sNfH) have been assessed as neuronal markers for amyotrophic lateral sclerosis (ALS) and dementias. Whereas sNfL has robust literature, systematic studies on sNfH are lacking. Here, we aimed to assess the diagnostic value of sNfH in comparison to sNfL in a broad range of neurodegenerative disorders.

METHODS: We measured with immunoassays sNfH and sNfL in patients recruited in the multicenter German Frontotemporal Lobar Degeneration (FTLD) Consortium (n = 340) and in a single-center German cohort (n = 290). We assessed the diagnostic accuracy of serum biomarkers for ALS and dementia subtypes and their relationship with cognitive impairment.

RESULTS: sNfH and sNfL were significantly increased in ALS (n = 90) vs. controls (n = 109) and ALS mimics (n = 56, p < 0.001), with sNfL showing higher discriminative accuracy (AUC = 0.94-0.95) than sNfH (AUC = 0.87-0.88). sNfH/sNfL ratio did not improve the diagnostic performance. Both markers were elevated in patients with dementia (n = 289) vs. controls (p < 0.001). sNfL was higher in behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and Creutzfeldt-Jakob disease (CJD) than in Alzheimer's disease (AD), whereas sNfH was similar in AD, PPA and bvFTD. sNfL, but not sNfH, was correlated with cognitive impairment at baseline and cognitive decline at follow-up in AD and bvFTD.

CONCLUSIONS: sNfH and sNfL are elevated in motoneuron and dementia disorders. sNfH showed good discriminative accuracy for ALS, which was slightly lower than that of sNfL. sNfL, but not sNfH, showed prognostic value for assessing cognitive decline in dementia.},
}

@article {pmid42230432,
year = {2026},
author = {Liao, Y and Ye, S and Zhao, L and Zhou, M and Wen, Y and Zhu, Y and Huang, J and Zhang, L and Zhang, X and Guo, P and Xie, Y},
title = {Gain-of-function Modulation of TREM2 and its Impact on Amyloid-β and Tau Pathologies in Alzheimer's Disease: A Systematic Review and Meta-analysis of Animal Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42230432},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, hyperphosphorylated Tau accumulation, and chronic neuroinflammation, with microglial function playing a crucial role in modulating these pathological cascades. The microglial receptor TREM2 has emerged as a key regulator of microglial responses to AD-related pathology, and gain-of-function strategies targeting TREM2 have shown substantial therapeutic potential in preclinical models. However, outcomes of these strategies on Aβ and Tau pathologies have exhibited marked heterogeneity across studies, and no systematic integration of the relevant evidence so far. This deficiency has substantially hindered the rational development and clinical translation of TREM2-targeted therapeutic strategies. The objective of this study is to evaluate the effects of TREM2-targeted interventions on Aβ and Tau pathologies in AD animal models. A systematic search of PubMed, Embase, and Cochrane Library identified studies using AD animal models with TREM2-targeted interventions and reporting Aβ or Tau outcomes. This review was registered in PROSPERO (CRD420251131147). A total of 12 studies were included, with overall moderate risk of bias, mainly due to inadequate randomization and blinding. In APP/PS1 mice, TREM2 overexpression significantly reduced Aβ plaque number (SMD = - 0.87; 95% CI, - 1.28 to - 0.47) and plaque area (SMD = - 0.98; 95% CI, - 1.46 to - 0.50), with more pronounced effects observed in younger mice (≤ 7 months), where reductions in insoluble Aβ42 were also observed; phosphorylated Tau levels decreased as well. TREM2 agonist antibodies also reduced Aβ plaque number (SMD = - 2.03; 95% CI, - 2.83 to - 1.24). However, effects on Aβ plaque area, insoluble and soluble Aβ isoforms levels were inconsistent. Antibody treatment also attenuated Tau pathology and Aβ pathology in certain models, including 5XFAD mice or Tau transgenic mice. In addition, both TREM2 overexpression and agonist antibodies could reverse the cognitive impairment of AD animal models. This systematic review and meta-analysis provides the first comprehensive synthesis of preclinical evidence supporting TREM2 gain-of-function modulation as an AD therapeutic strategy targeting both Aβ and Tau pathologies. Our findings reveal that therapeutic efficacy is governed by disease stage, model pathological complexity, and intervention mode. These insights highlight the need for developing stage-specific and pathology-stratified strategies in translational research, establishing TREM2 as a condition-dependent yet promising immunotherapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
Humans
Disease Models, Animal

@article {pmid42230841,
year = {2026},
author = {Grande, G and Valletta, M and Gasparini, F and Vetrano, DL and Canevelli, M and Bacci, JR and Qiu, C and Marengoni, A and Blasi, MT and Xu, H and Fratiglioni, L and Mielke, MM},
title = {Brain pathology in relation to somatic diseases: Exploring the body-brain crosstalk.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70119},
pmid = {42230841},
issn = {1365-2796},
support = {//StratNeuro/ ; //Karolinska Institutet Strategic Research Area in Neuroscience/ ; //Karolinska Institutet Committee for Research/ ; //Stiftelsen Dementia/ ; },
abstract = {Several somatic diseases have been consistently linked with an increased dementia risk. However, the underlying neuropathological substrates remain poorly characterized. This narrative review aims to summarize evidence on the association between common age-related somatic conditions (i.e., heart diseases, type 2 diabetes, kidney disease, liver diseases, lung disease, and anemia) and neuropathological findings, encompassing both Alzheimer's disease (AD)-related pathology (amyloid and tau deposition) and non-AD co-pathologies (i.e., neuronal loss, neuroinflammation, cerebrovascular lesions, and non-AD proteinopathies). We conducted a PubMed search for human studies examining these associations using postmortem data, brain imaging, or cerebrospinal fluid biomarkers. Evidence was qualitatively synthesized and graded according to its strength. Strong and consistent associations were observed between most examined somatic diseases and global neuronal loss or brain atrophy, as well as cerebrovascular lesions. In contrast, evidence associating these conditions with amyloid and tau pathology was limited and inconsistent. No studies systematically examined neuroinflammation or non-AD proteinopathies in relation to somatic diseases. Together, the available evidence suggests that somatic diseases are unlikely to primarily drive AD pathology but instead contribute to brain damage through a combination of non-AD processes, particularly cerebrovascular injury and diffuse neuronal loss. These findings highlight the need to increase our knowledge of "mixed dementia" and move beyond a purely brain-centric view of dementia, especially in older adults with complex clinical profiles.},
}

@article {pmid42230953,
year = {2026},
author = {Schlachetzki, Z and Langford, O and Zammit, MD and Donohue, MC and Zhou, X and Sukreet, S and Abdel-Latif, S and Braunstein, JB and Rissman, RA and Rafii, MS},
title = {Exploring automated plasma phospho-tau217 assays for the diagnosis of Down syndrome-related Alzheimer's disease.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01709-0},
pmid = {42230953},
issn = {2730-664X},
abstract = {BACKGROUND: Individuals with Down syndrome (DS) develop a genetic form of Alzheimer's disease (AD) due to an extra copy of chromosome 21, which contains the APP gene. Blood-based biomarkers of AD are becoming increasingly adopted in research and clinical practice. These tests hold promise for diagnosing AD in DS once validated.

METHODS: In this exploratory study, we assessed plasma phospho-tau217 (p-tau217) in participants (n = 39) from the NIH Trial Ready Cohort - Down syndrome (TRC-DS), using predefined amyloid-PET cutoffs. Plasma p-tau217 was measured via two fully automated assays: C2N Diagnostics' PrecivityAD2 mass spectrometry and Fujirebio's Lumipulse immunoassay. The primary outcome was β-amyloid AD pathology, defined by amyloid PET > 18 centiloids.

RESULTS: Both p-tau217 assays showed high accuracy: AUCs of 0.94 (95% CI 0.84, 1.00) for Lumipulse and 0.91 (95% CI 0.77, 1.00) for C2N, with sensitivities of 0.88 (95% CI 0.62, 1.00), specificities of 0.90 (95% CI 0.77, 1.00) and 0.94 (95% CI 0.84, 1.00), and overall accuracies of 0.90 (95% CI 0.79, 0.97) and 0.92 (95% CI 0.82-1.00), respectively, when using maximized Youden index cutpoints.

CONCLUSION: These preliminary results are comparable to composite plasma measures. In summary, automated p-tau217 tests offer strong potential for routine AD screening in individuals with DS.},
}

@article {pmid42230965,
year = {2026},
author = {Jörg, M and Walz, L and Nathal, S and Kristen, M and Lietz, C and Müller, M and Nguyen, VTT and Ruffini, N and Winz, ML and Gerber, S and Endres, K and Helm, M and Friedland, K},
title = {Sex-specific regulation of angiogenin in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42230965},
issn = {1476-5578},
support = {TRR319 RMaP (Project Id 439669440) TPB05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; TRR319 RMaP (Project Id 439669440) TP A05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease that inhibits apoptosis by generating 5'-tRNA fragments, is a candidate whose expression and regulation in AD is not understood. Here, we investigated ANG expression and regulation using AD cell and animal models, postmortem human brain tissue, and transcriptomic datasets (n = 645). We found that ANG is dysregulated in AD in a sex-dependent manner, altering downstream levels of 5'-tiRNA[Gly-GCC]. Our analysis revealed female-specific molecular subtypes, absent in males: Subtype 1 featured low ANG levels with increased inflammation and neuronal death; subtype 2 exhibited higher ANG expression and intermediate pathology; subtype 3, marked by the highest ANG levels, showed reduced inflammation, slower cognitive decline, and extended survival. These findings position ANG as a key modulator of neuroinflammation and apoptosis in AD, highlighting its potential as a treatment strategy.},
}

@article {pmid42230978,
year = {2026},
author = {Zeng, ZM and Han, SS and Liu, Q and Zeng, CD and Jia, X and Bi, J and Liu, LC and Gao, TA and Liang, L and Cheng, FX},
title = {Hierarchical organization of tau topography across the Alzheimer's disease continuum integrates amyloid, connectome, and intrinsic molecular vulnerability.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10388-5},
pmid = {42230978},
issn = {2399-3642},
abstract = {Tau pathology defines the Alzheimer's disease (AD) continuum and is spatially heterogeneous, yet the roles of amyloid-β (Aβ), connectome architecture, and intrinsic molecular vulnerability remain unclear. Here we integrated Aβ- and tau-PET, diffusion MRI, resting-state fMRI, and transcriptomic maps across the AD continuum. We found that tau pathology followed a hierarchical spatial gradient that progressively stratified by Aβ and clinical stages. Across the AD continuum, Aβ covariance and structural and functional connectivity were associated with tau covariance, and their derived propagation signatures further recapitulated regional tau burden, explaining substantial spatial variance. A residual tau pattern not captured by the modeled propagation signatures was further identified and was associated with reproducible transcriptional gradients involving intracellular signaling, synaptic programs, mitochondrial bioenergetics, and post-transcriptional regulation, with stage-specific shifts in biology. Importantly, tau geometry related to epicenter segregation and perivascular diffusion and mediated their associations with clinical expression. These findings position tau topography as an integrative marker coupling Aβ, connectivity, and intrinsic molecular vulnerability, and indicate that tau geometry is related to the link between network organization and cognitive decline.},
}

@article {pmid42230995,
year = {2026},
author = {Koch, Z and Nandi, SP and Licon, K and Bujarrabal-Dueso, A and Meyer, DH and Saeed, S and Perampalam, P and Dick, FA and Schumacher, B and Alexandrov, LB and Ideker, T},
title = {DREAM repressive activity links somatic mutation, lifespan and disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42230995},
issn = {2662-8465},
support = {U54 CA274502/CA/NCI NIH HHS/United States ; U54 CA274502/CA/NCI NIH HHS/United States ; P41 GM103504/GM/NIGMS NIH HHS/United States ; P41 GM103504/GM/NIGMS NIH HHS/United States ; },
abstract = {The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM-associated activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM-associated activity (quantified from the expression of genes transcriptionally repressed by DREAM) and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM-associated activity have decreased mutation rates. Second, DREAM-associated activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM-associated activity in individuals with Alzheimer's disease predicts late disease onset and decreased risk for severe neuropathology. Finally, DREAM knockout in mice protects against mutation accumulation, reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in the brain. These findings position DREAM as a key regulator of aging.},
}

@article {pmid42231099,
year = {2026},
author = {Zarnashan, A and Fazli, F and Talebi, V and Patel, DI},
title = {Exercise Lowers Hepatic Amyloid β Concentrations in Alzheimer's Rodent Model.},
journal = {Medicine and science in sports and exercise},
volume = {},
number = {},
pages = {},
doi = {10.1249/MSS.0000000000004043},
pmid = {42231099},
issn = {1530-0315},
abstract = {PURPOSE: This study aims to investigate the effects of voluntary exercise on liver levels of amyloid β (Aβ) and serum concentrations of LRP1, focusing on peripheral clearance in a rat Alzheimer's disease model.

METHODS: Forty male Wistar rats (aged 4-6 weeks) were randomly divided into four groups: Healthy control, Alzheimer's disease (Alz), control + exercise (Con-Ex) and Alzheimer's disease + exercise (Alz-Ex). Alzheimer's disease was induced by an intraventricular STZ injection and the disease was confirmed with the shuttle box test. Rats randomized to the exercise intervention were given continuous access to a running wheel of 12 weeks. At the end of the study memory (Morris Water Maze), serum LRP1 level and liver Aβ40 were measured. Data were analyzed by one-way ANOVA and Tukey's post hoc test.

RESULTS: The results of the study indicate that compared to Alz voluntary exercise significantly improved Morris Water Maze performance (Alz: 153.2 ± 19.95; Alz-Ex:106.8 ± 18.89; p<0.001) and decreased liver concentration of Aβ40 (Alz: 40.06 ± 6.17; Alz-Ex: 25.12 ± 2.92; p<0.001) levels similar to non-exercising control animals. Serum concentrations of LRP1 were not impacted by exercise.

CONCLUSIONS: These results suggest that voluntary wheel running may positively reduce hepatic concentrations of Aβ40 in Alzheimer's disease independent of changes in circulating LRP1. Further research is needed to better understand the role of exercise in assisting in clearing Aβ40 in this model.},
}

@article {pmid42231420,
year = {2026},
author = {Han, WB and Liu, XD and Tang, CF and Zheng, J and Xu, TL and Xu, NJ and Sun, S},
title = {Persistent PirB cleavage drives Golgi-directed trafficking deficits underlying neurodegeneration.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42231420},
issn = {2047-9158},
support = {32571164//National Natural Science Foundation of China/ ; 32030042//National Natural Science Foundation of China/ ; 32271009//National Natural Science Foundation of China/ ; 2021ZD0202801//STI2030-Major Projects/ ; },
abstract = {BACKGROUND: Extensive research evidence indicates that neuronal immune receptors play a critical role in Alzheimer's disease (AD). However, it remains unclear how these receptors convert extracellular signals into cellular pathological changes. Proteolytic cleavage of membrane receptors serves as an unconventional pathway for reprogramming cellular functions, and the cleaved fragments often play important roles within the cell. Whether immune receptors mediate their effects in AD through this cleavage-dependent signaling mechanism remains to be clarified.

METHODS: We performed proteomic screening of human cerebrospinal fluid to identify cleaved membrane proteins. Cleavage events were validated in postmortem AD brains, primary neurons, and APP/PS1 mice by immunoprecipitation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and immunofluorescence. Functional impacts were assessed through cathepsin D maturation assays, Retention Using Selective Hooks (RUSH) systems, live imaging of axonal transport, and behavioral tests (e.g., Barnes maze and fear conditioning). Therapeutic potential was evaluated by inhibiting the paired immunoglobulin-like receptor B (PirB) cleavage and overexpression of the GAT domain of Golgi-associated, gamma adaptin ear-containing, ARF binding protein 3 (GGA3).

RESULTS: This study identified a pathogenic proteolytic pathway in AD patients and mouse models, which cleaves PirB, a mouse ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), upon Aβ exposure, generating a C-terminal fragment (PirB-CTF) that accumulated in the Golgi apparatus via retrograde transport. PirB-CTF bound to the GAT domain of GGA3, disrupting Golgi transport, impairing lysosomal maturation, and compromising anterograde synaptic vesicle transport. Inhibiting PirB cleavage or overexpressing GGA3-GAT restored Golgi function, reduced Aβ plaque burden and tau phosphorylation, and rescued memory deficits.

CONCLUSION: Our study revealed a non-canonical pathway in which proteolytic cleavage repurposes PirB into an intracellular disruptor of Golgi trafficking, directly coupling immune receptor activation to organelle dysfunction in AD. The PirB-CTF/GGA3 interface represents a promising therapeutic target for mitigating trafficking deficits and cognitive decline in neurodegenerative disorders.},
}

@article {pmid42231842,
year = {2026},
author = {Wiechmann, D and Günes, A and Kerz, E and Qiao, Y and Köhne, M and Sprick, U},
title = {Connected-speech digital biomarkers for monitoring transcranial pulse stimulation in Alzheimer's disease: A pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456294},
doi = {10.1177/13872877261456294},
pmid = {42231842},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) lacks effective disease-modifying therapies and scalable, ecologically valid biomarkers to monitor treatment response. Transcranial pulse stimulation (TPS) is an emerging non-invasive neuromodulation technique with potential to attenuate cognitive decline. Sensitive digital endpoints are needed to quantify intervention-related changes.ObjectiveTo develop and validate connected-speech-derived digital biomarkers as a longitudinal framework for monitoring TPS treatment response in AD.MethodsIn this open-label, single-arm pilot study, 32 patients with AD were compared to cognitively healthy controls. A three-stage framework was implemented: (1) machine-learning classification using linguistic features to derive a parsimonious biomarker panel; (2) construction of a Speech Composite Index (SCI) calibrated against the CERAD total score (CTS); and (3) longitudinal SCI tracking in a sub-cohort receiving TPS.ResultsThe classifier discriminated AD from controls with an AUROC of 0.879 and an F1-score of 0.825. The SCI showed strong convergent validity with global cognition (CTS: r = 0.76, p < 0.001; MMSE: r = 0.76, p < 0.001) and executive function (Stroop interference: r = -0.51, p = 0.015). Longitudinal modeling demonstrated a significant positive deviation from a CERAD-based progression reference (β_time = 0.057 z-units/month, p = 0.013), indicating relative stabilization of speech performance. Individual trajectories were heterogeneous (range -0.053 to +0.336) without significant demographic associations.ConclusionsConnected-speech-derived digital biomarkers can serve as scalable longitudinal endpoints for neuromodulatory interventions in AD. The SCI captures treatment-related dynamics and may support response stratification. Further validation in larger, sham-controlled multicenter studies is needed to establish clinical utility and specificity to TPS.},
}

@article {pmid42231856,
year = {2026},
author = {Chen, M and Xie, Q and Yi, F and Ma, J and Lu, S and Ouyang, H and Qin, Y and Yang, S and Wei, W and Liu, Y},
title = {Secoisolariciresinol diglucoside ameliorates Alzheimer-like lesions by increasing MKP-1.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450557},
doi = {10.1177/13872877261450557},
pmid = {42231856},
issn = {1875-8908},
abstract = {BackgroundSecoisolariciresinol diglucoside (SDG), a phytoestrogen, has been demonstrated to exert anti-inflammatory and neuroprotective effects. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) serves as a critical negative regulator of MAPK signaling pathways, and the MAPK signaling pathways play a significant role in the pathogenesis of Alzheimer's disease (AD). However, it remains unclear whether SDG ameliorates Alzheimer-like lesions by regulating the MAPK pathway through increasing MKP-1.ObjectiveWe aimed to investigate the impact of SDG on the Alzheimer-like lesions of AD mice and its mechanisms.MethodsThree-month-old 5×FAD mice were treated with SDG (50 mg·kg-1·d-1, i.g.) for 2 months. Learning and spatial memory function was assessed with the behavioral test. Immunofluorescence and Thioflavine-S staining was assessed with the levels of amyloid-β (Aβ) plaques in the cortex and hippocampus. Western blot was performed to evaluate the level of learning memory-related proteins, hyperphosphorylated tau, APP-related proteins, and MAPK phosphorylation. Besides, knockdown of MKP-1 in N2A/APP cells to investigate whether SDG regulates the MAPK signaling pathway by increasing MKP-1.ResultsWe found that SDG significantly enhanced learning and spatial memory while recovering PSD95, PKA-Cα, and synaptophysin levels in 5×FAD mice. SDG reduced Aβ plaques, tau phosphorylation at Ser 199/214/262/396 and Thr 231, alleviated the phosphorylation of MAPKs (JNK, ERK1/2, P38), and increased p-GSK-3β (Ser9), while decreased activation of microglia (Iba-1) and astrocytes (GFAP). Moreover, knockdown of MKP-1 in N2A/APP cells inhibited the regulatory effect of SDG on APP, ERK1/2 and JNK.ConclusionsSDG ameliorates Alzheimer-like lesions may be related with increasing MKP-1.},
}

@article {pmid42231857,
year = {2026},
author = {Rashidi-Ranjbar, N and Churchill, NW and Jerkic, M and Zomorrodi, R and Rotstein, O and Schneider, R and Andreazza, AC and Rajji, TK and Graham, SJ and Munoz, DG and Fornazzari, L and Lim, L and Norris, M and Schweizer, TA and Fischer, CE},
title = {A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive, metabolic, and neuroimaging outcomes of a pilot randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453911},
doi = {10.1177/13872877261453911},
pmid = {42231857},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).MethodsWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.ResultsAdherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.},
}

@article {pmid42231859,
year = {2026},
author = {Tsutsui, S and Stepanchuk, AA and Stys, JP and Black, SAG and Templeton, GW and Greiner, R and Stys, PK},
title = {Fluorescence spectroscopy and machine learning methods for detection of Alzheimer's disease from circulating white blood cells.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453512},
doi = {10.1177/13872877261453512},
pmid = {42231859},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common cause of dementia whose prevalence is projected to increase significantly in the coming decades. The recent advent of disease modifying therapies is a welcome development; however, it is also now apparent that early treatment maximizes the benefits of these drugs. Therefore, it is important to develop reliable methods of disease detection, preferably from an easily accessible matrix such as blood.ObjectiveTo develop a method for detecting AD from circulating white blood cells using spectral confocal microscopy.MethodsUsing K114-stained wild type and 5xFAD transgenic mouse cortical sections as proof-of-principle, spectral imaging of K114 fluorescence coupled with a signal processing/machine learning pipeline (spectral wavelet decomposition, dimensionality reduction, support vector machine classifier) can reliably distinguish non-plaque background parenchyma in the two strains. We then performed immunoprecipitation of Aβ from peripheral blood mononuclear cells (PBMCs) obtained from non-neurological controls and histopathologically-proven AD cases. We spectrally imaged the immunobeads labeled with K114, then used similar machine learning methods to classify control versus AD samples.ResultsNormal-appearing non-plaque 5xFAD background was reliably distinguished from wild type mouse brain. We could also classify AD with a high degree of reliability (area under the receiver operating curve = 0.95, p = 6.1e-5) and predict neuropathological scores from these blood elements (R = 0.89).ConclusionsOur spectral imaging method, together with automated machine learning analysis of spectral micrographs, using readily obtainable PBMCs from blood, represents a potentially useful approach for detection of AD in living subjects.},
}

@article {pmid42231879,
year = {2026},
author = {Nibila, Y and Sivagami, M},
title = {Artificial intelligence techniques for classification of Alzheimer's disease using neuroimaging data: a review.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1748985},
pmid = {42231879},
issn = {2624-8212},
abstract = {Alzheimer's disease (AD) is a gradually advancing brain disorder marked by memory impairment. The incurable, progressive nature of the disease leads to the dementia stage. Treatment is effective in the early stage, and it can be controlled but not cured. Artificial Intelligence (AI) learning models are used in medical science to detect and classify diseases into specific categories. Features are extracted from medical images and trained using AI learning models to perform an accurate diagnosis of AD. Recent advancements in machine learning (ML) and deep learning (DL) models have demonstrated significant potential in identifying AD across various data modalities, including neuroimaging, genetic information, and clinical assessments. This study focuses on the application of advanced ML and DL techniques in the identification and classification of AD, including regression models, decision trees, random forests, support vector machines (SVMs), k-nearest neighbors (KNNs), ensemble models, convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). Each model is analyzed for its strengths, limitations, and performance metrics, with particular emphasis on the importance of data preprocessing and augmentation techniques to improve model accuracy and robustness. The review highlights that multimodal approaches, particularly the fusion of MRI and PET data, enhance classification accuracy compared to single-modality models. Additionally, transfer learning techniques have shown promise in overcoming data limitations by leveraging pretrained models. The review also highlights the critical role of evaluation metrics in assessing model performance, emphasizing the need for a diverse set that includes accuracy, precision, recall, F1-score, and Cohen's Kappa. The study identifies gaps in the current literature, including underreporting of certain metrics and the need for more comprehensive evaluations, and provides recommendations for future research. Finally, this study discusses the challenges and opportunities in the field, including improving model generalizability, enhancing interpretability, advanced data preprocessing and augmentation, integration with clinical workflows, and multimodal data fusion. This review provides consolidated information that may be useful for researchers, clinicians, and data scientists, offering insights into current trends, challenges, and future research directions in AI-driven AD detection.},
}

@article {pmid42232055,
year = {2026},
author = {Puja, A and McNeel, R and Xu, R and Zhu, S and Hansman, D and Du, J},
title = {Early proteomic signatures of Alzheimer's disease in the retina and brain of 3xTg-AD mice.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1827348},
pmid = {42232055},
issn = {2296-634X},
abstract = {INTRODUCTION: Visual dysfunction and retinal structural changes can occur early in Alzheimer's disease (AD), but the molecular basis of these early alterations remains unclear.

METHODS: We performed quantitative proteomic profiling of the retina and brain from 4-week-old triple-transgenic AD (3xTg-AD) mice carrying human PS1M146V, APPSwe, and tauP301L mutations, prior to detectable retinal morphological abnormalities.

RESULTS: Retinal morphology was normal in 4-week-old 3xTg-AD. Proteomic analysis identified 92 significantly altered proteins in the retina and 130 in the brain, with eight proteins overlapping between tissues. These overlapping proteins included three hemoglobin subunits and five proteins involved in protein homeostasis and vesicular transport. The retinal proteome was characterized by reduced vision-related proteins, altered small-molecule transporters, and decreased levels of proteins involved in mitochondrial energetics. In the brain, prominent changes were observed in mitochondrial proteins, including respiratory chain components and mitochondrial ribosomal subunits, as well as proteins linked to autophagy and synaptic vesicle pathways.

DISCUSSION: These findings identify early, common and tissue-specific proteomic changes in the retina and brain of 3xTg-AD mice prior to detectable retinal structure abnormalities. The data indicate early changes in proteins related to mitochondrial function and intracellular transport and support the use of retina as an accessible tissue for detecting preclinical AD pathology.},
}

@article {pmid42232071,
year = {2026},
author = {Sochan, L and Archibald, J and Weber, AM},
title = {Does the brain's E:I balance really shape long-range temporal correlations? Lessons learned from 3T MRI.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42232071},
issn = {2837-6056},
abstract = {A 3T multimodal MR study of healthy adults (n = 18; 10 female; 21.3-53.4 years) was performed to investigate the relationship between functional magnetic resonance imaging (fMRI) long-range temporal correlations and excitatory/inhibitory balance (via single voxel magnetic resonance spectroscopy measurements of glutamate and γ -aminobutyric acid (GABA)). The study objective was to determine whether the Hurst exponent (H)-an estimate of self-correlation and signal complexity-of the blood oxygen level-dependent signal was correlated with the excitatory-inhibitory (E:I) ratio. E:I has been proposed to serve as a control parameter for brain criticality-the theory that the brain operates near a critical point between order and disorder, optimizing information processing and adaptability-which H is believed to be a measure of. Thus, understanding whether H and E:I are indeed correlated would clarify this relationship. Moreover, findings in this domain have implications for neurological and neuropsychiatric conditions with disrupted E:I balance, such as autism, schizophrenia, and Alzheimer's disease. From a practical perspective, H is easier to accurately measure than E:I ratio at 3T MRI. If H can serve as a proxy for E:I, it may serve as a more practical clinical biomarker for this imbalance and for neuroscience research in general. The study collected functional MRI and magnetic resonance spectroscopy data during rest and movie watching. H and E:I (glutamate/GABA) were not found to be correlated. H was found to increase with movie watching compared with rest, while E:I did not change between conditions. This study represents the first attempt to investigate this connection in vivo in humans. We conclude that, at 3T and with our particular methodologies, no association was found. We end with lessons learned and suggestions for future research.},
}

@article {pmid42232224,
year = {2026},
author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD},
title = {Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1818660},
pmid = {42232224},
issn = {1663-4365},
abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs. 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (< 1 year) to 0.25 (> 6 years). Risk reduction was greatest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.},
}

@article {pmid42232578,
year = {2026},
author = {Xue, X and Liu, L and Tan, Z and Zhou, L and Li, S and Yan, W and Liu, X and Ye, M and Li, X and Ren, H},
title = {Associations of novel visceral obesity indices (METS-VF and BRI) with dementia: the role of metabolic mediators and genetic susceptibility.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1800772},
pmid = {42232578},
issn = {2296-861X},
abstract = {BACKGROUND: Visceral obesity-related indices may capture metabolically adverse adiposity more effectively than conventional obesity measures, but their comparative associations with dementia risk and the potential roles of metabolic dysfunction and genetic susceptibility remain insufficiently characterized.

METHODS: In this prospective cohort study, 327,368 dementia-free participants from the UK Biobank were included. Body roundness index (BRI) and metabolic score for visceral fat (METS-VF) were first validated against imaging-derived visceral fat measures and then examined for their associations with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia using Cox proportional hazards models and restricted cubic spline analyses. Additional analyses assessed subgroup effects, sensitivity, multicollinearity, incremental explanatory value beyond BMI and waist circumference (WC), metabolomic mediation, genetic susceptibility, and longitudinal changes in anthropometric and metabolic markers before dementia diagnosis.

RESULTS: During follow-up, 8,768 participants developed dementia. METS-VF and BRI showed the strongest correlations with imaging-derived visceral adiposity among the tested obesity indices. Higher METS-VF levels were associated with increased risks of all-cause dementia, vascular dementia, and AD, with significant nonlinear threshold effects. BRI was also positively associated with all three dementia outcomes, although its association with AD was attenuated after full adjustment but remained statistically significant. The association between METS-VF and AD was particularly evident among individuals with low to intermediate genetic risk. Exploratory mediation analyses suggested that metabolic dysfunction may partly explain the observed associations between visceral obesity indices and dementia-free survival time. Among participants who subsequently developed dementia, WC and fasting blood glucose increased before diagnosis, whereas BMI remained relatively stable.

CONCLUSION: Visceral obesity, particularly as captured by METS-VF, was independently associated with increased dementia risk. These findings support moving beyond BMI-centric obesity definitions and highlight visceral adiposity-related metabolic dysfunction as a potential focus for dementia risk stratification and prevention research.},
}

@article {pmid42232611,
year = {2026},
author = {Zawar, I and Zhu, S and Quigg, M and Kapur, J and Lam, AD and Sarkis, RA and D'Abreu, A and Manning, C and Fletcher, PT},
title = {Mesial temporal shape asymmetry as a neuro-imaging correlate of epilepsy in mild cognitive impairment and dementia.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag179},
pmid = {42232611},
issn = {2632-1297},
abstract = {Epilepsy is a common comorbidity of Alzheimer's disease (AD) and related dementias (ADRD). Both epilepsy and ADRD affect the mesial temporal structures in volume and morphology. Nonetheless, mesial temporal shape and volume asymmetry remain understudied in persons with dementia and mild cognitive impairment, collectively called persons with cognitive impairment (PWCI) and co-morbid epilepsy. We investigated hippocampal and amygdalar left-to-right shape and volume asymmetry in AD (AD_Epi) and non-AD (nonAD_Epi) with co-morbid epilepsy. This multicentre study included participants from 39 US Alzheimer's disease centres from 9/2005 to 12/2021. We categorized participants into group 1: PWCI with epilepsy (subclassified into AD_Epi and nonAD_Epi); group 2: PWCI without epilepsy (subclassified into AD_NoEpi and nonAD_NoEpi); and group 3: healthy controls (HC). We used a fixed-ratio, optimal propensity score matching to match group 1 participants to groups 2 and 3. Matching was based on age, sex and type of dementia (AD versus nonAD) for group 2 and age and sex for group 3. We used FreeSurfer for MRI segmentation of hippocampi and amygdalae. For volume asymmetry, we subtracted the right volume from the left and divided it by the total volume of the structure (right + left). For shape asymmetry, we calculated a 512-point shape model using left and flipped right hippocampi and, similarly, a 256-point shape model for amygdalae. Next, we calculated the point-by-point shape asymmetry between left and right hippocampi and amygdalae in a normal direction for each participant. Multivariable linear models were used to compare volume and shape asymmetry among groups after adjusting for age, sex, total intracranial volume and dementia severity. We compared AD_Epi versus AD_NoEpi, nonAD_Epi versus nonAD_NoEpi, AD_Epi versus HC, nonAD_Epi versus HC, AD_NoEpi versus HC and nonAD_NoEpi versus HC. Analyses were adjusted for multiple comparisons. A total of 703 participants were included [391(55.62%) female, average age: 70.78 years]. These included 35 AD_Epi, 28 nonAD_Epi, 183 AD_NoEpi, 137 nonAD_NoEpi and 320 HC. For shape analyses, AD_Epi showed greater left-to-right asymmetry (Left smaller than right) in hippocampal tail compared with HC. Those with nonAD_Epi demonstrated greater left-to-right asymmetry in the hippocampal head compared with both nonAD_NoEpi and HC. AD_NoEpi had an asymmetrically smaller left hippocampal head and right amygdala than HC. We found no group differences in volume asymmetries. Our study found left smaller than right hippocampal head asymmetry in non-Alzheimer's dementia with epilepsy and left smaller than right hippocampal tail asymmetry in Alzheimer's disease with epilepsy. These findings suggest that hippocampal shape asymmetry may serve as a neuroimaging correlate of epilepsy in ADRD.},
}

@article {pmid42232612,
year = {2026},
author = {Lohi, K and Aaltonen, A and Herukka, SK and Kokkola, T and Kärkkäinen, S and Urjansson, M and , and Palotie, A and Runz, H and Kaprio, J and Julkunen, V and Saari, T and Vuoksimaa, E},
title = {Scalable biological-cognitive profiling for Alzheimer's disease in the population.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag168},
pmid = {42232612},
issn = {2632-1297},
abstract = {Plasma phosphorylated tau217 has been suggested as a core biomarker for establishing a biological Alzheimer's disease diagnosis. This blood biomarker has not been studied together with scalable cognitive assessment tools in population-based samples. We investigated the prevalence of cognitive and Alzheimer's disease biomarker abnormalities and associations between plasma phosphorylated tau217 and remotely measured cognitive function in individuals without dementia. We used a population-based cross-sectional sample of 65-85-year-olds (n = 691, 57% females), excluding those with previously diagnosed Alzheimer's disease or other dementia-causing neurodegenerative disease. Cognition was measured with a telephone-administered word list recall task (episodic memory) and animal naming (semantic fluency). Plasma phosphorylated tau217 was determined with the ALZpath assay. The prevalence of individuals with abnormalities in tests measuring episodic memory, semantic fluency, and plasma phosphorylated tau217 was 10-13%. Higher plasma phosphorylated tau217 levels were associated with lower scores on telephone-administered cognitive tests. We found a substantial minority of a population-based sample of individuals without a clinical diagnosis of Alzheimer's disease to have cognitive and plasma phosphorylated tau217 profiles suggesting underlying Alzheimer's disease. Combining plasma phosphorylated tau217 with remote cognitive assessment could be a scalable, accessible, and cost-effective protocol for screening individuals with undiagnosed or at risk for Alzheimer's disease.},
}

@article {pmid42232651,
year = {2026},
author = {Kawachi, Y and Kocak, G and Korolchuk, VI and Kataura, T and Sarkar, S},
title = {From autophagy-lysosomal deficits to neurodegeneration in Niemann-Pick type C1 disease: implications for age-related neurodegenerative disorders.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1857866},
pmid = {42232651},
issn = {1662-4548},
abstract = {Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by loss-of-function mutations in the NPC1 gene. NPC1 deficit primarily disrupts lipid homeostasis and subsequently drives cellular degeneration through mechanisms involving impaired autophagy and mitophagy, mitochondrial dysfunction, and, recently demonstrated NAD depletion that links autophagy impairment to neuronal death. Emerging evidence also highlights the activation of innate immune signaling leading to neuroinflammation. In this review, we synthesize current mechanistic insights and describe how these molecular deficits are interconnected to drive neuronal death in NPC1 disease. We also discuss how these pathological processes parallel those observed in major age-related neurodegenerative pathologies such as Alzheimer's and Parkinson's disease. Finally, we highlight emerging therapeutic strategies that can potentially ameliorate these cellular deficits, offering avenues for mitigating neurodegeneration in NPC1 disease and other related neurodegenerative disorders.},
}

@article {pmid42232655,
year = {2026},
author = {Yuan, Q and Xue, C and Qi, W and Liang, X and Tang, Y and Ruan, Y and Xiao, C},
title = {Amygdala subregional atrophy across ATN-defined Mild Cognitive Impairment subgroups.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1791269},
pmid = {42232655},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology begins years before clinical symptoms, with Mild Cognitive Impairment (MCI) as a prodromal stage. The ATN framework (Amyloid, Tau, Neurodegeneration) aids in stratifying MCI risk. While amygdala atrophy is a recognized biomarker, amygdala subregional changes across ATN-defined MCI subgroups remain underexplored.

METHODS: This study analyzed MRI data and cerebrospinal fluid biomarkers from 134 MCI participants classified into A-T-, A+T-, and A+T+ subgroups. The volumes of amygdala subregions were computed and compared among the different groups. Furthermore, we also investigated the relationship between the altered brain regions and cognitive function.

RESULTS: Significant atrophy was observed in the A+T+ group within bilateral basal, accessory basal, central nuclei, and right cortical-amygdaloid transition area compared to other groups. Volume reductions in the left central nucleus correlated positively with cognitive scores.

CONCLUSION: Amygdala subregional atrophy, particularly in the central, basal, accessory basal, and cortical-amygdaloid transition nuclei, is linked to AD pathology progression and cognitive decline. The findings suggest a potential vulnerability of the right amygdala and suggest these subregions may be associated with AD-related pathological progression.},
}

@article {pmid42232963,
year = {2026},
author = {Chan, JW and Wang, Z and Xu, E and Abboud, I and Alhasany, A and Xu, S and Wu, X and Astraea, N and Jiang, F and Hu, ZJ},
title = {Inner retinal layer thickness reflects plasma biomarkers in preclinical Alzheimer's disease.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1800287},
pmid = {42232963},
issn = {2296-858X},
abstract = {PURPOSE/BACKGROUND: Few studies have examined layer- and region-specific retinal thickness in relation to plasma Alzheimer's disease (AD) biomarkers in cognitively normal adults at increased risk for AD. We conducted an exploratory pilot study to examine whether thickness measurements of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL) were associated with plasma AD biomarkers.

METHODS: Spectral-domain optical coherence tomography was performed on 20 eyes from 11 cognitively normal participants enriched for AD risk using a low plasma Aβ42/40 ratio (<0.10). Retinal layers were segmented using a novel deep-learning algorithm, followed by manual review and refinement by trained graders when needed. Associations between retinal thickness and plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), Aβ42/40, p-tau217, and p-tau181 were evaluated using ridge regression with participant-level bootstrap resampling.

RESULTS: Exploratory relationships suggest that thinner INL and GCL measurements are associated with higher p-tau217 and GFAP levels.

CONCLUSION: Larger, longitudinal studies with confirmatory AD biomarker characterization are needed to validate these preliminary findings to determine how retinal OCT adds complementary value to plasma biomarkers for early AD risk assessment.},
}

@article {pmid42233248,
year = {2026},
author = {Senador, J and Montesinos, R and Custodio, B and Huilca, J and Agüero, K and Verastegui, G and Bartolo, P and Nuñez-Huanca, M and Pereira, MFA and Custodio, N},
title = {Validity of the two different scoring methods of the Clinical Dementia Rating scale in staging and detection of cognitive impairment in the Peruvian population.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71550},
doi = {10.1002/alz.71550},
pmid = {42233248},
issn = {1552-5279},
mesh = {Humans ; Peru ; Female ; Male ; *Cognitive Dysfunction/diagnosis ; Reproducibility of Results ; Aged ; *Alzheimer Disease/diagnosis ; *Neuropsychological Tests ; Psychometrics ; Sensitivity and Specificity ; Aged, 80 and over ; *Mental Status and Dementia Tests ; Severity of Illness Index ; Middle Aged ; },
abstract = {INTRODUCTION: In Peru, the Global Deterioration Scale is the only available tool for assessing dementia severity. The Spanish translation and cultural adaptation of the Clinical Dementia Rating (CDR) is used locally but requires formal psychometric validation in the Peruvian sociocultural context.

METHODS: A total of 1,600 older adults: 902 controls, 271 mild cognitive impairment (MCI), and 427 Alzheimer's disease patients (AD) were assessed to validate two CDR scoring methods: CDR Global Score (CDR-GS) and CDR Sum of Boxes Score (CDR-SB). Discriminative validity, inter-item reliability, and concurrent validity were evaluated using MMSE, RUDAS, PFAQ, and Uniform Data Set (UDS) v3 Neuropsychological Battery.

RESULTS: CDR demonstrated high reliability and validity among normal cognition, mild cognitive impairment, and AD. For AD screening, CDR-SB showed 98.2% sensitivity and 99.6% specificity, while CDR-GS demonstrated 99.8% sensitivity and 100% specificity.

DISCUSSION: The Peruvian CDR version exhibited good psychometric properties comparable to those reported in Latin American CDR validation studies.},
}

Humans
Peru
Female
Male
*Cognitive Dysfunction/diagnosis
Reproducibility of Results
Aged
*Alzheimer Disease/diagnosis
*Neuropsychological Tests
Psychometrics
Sensitivity and Specificity
Aged, 80 and over
*Mental Status and Dementia Tests
Severity of Illness Index
Middle Aged

@article {pmid42233253,
year = {2026},
author = {Eberly, SG and Phumsatitpong, C and Munro, CE and Neylan, TC and Kaufer, D and Ehrenberg, AJ},
title = {Stress, stress systems, and Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71542},
doi = {10.1002/alz.71542},
pmid = {42233253},
issn = {1552-5279},
support = {2146752//National Science Foundation Graduate Research Fellowship Program/ ; //Alzheimer's Association Research Fellowship/ ; //UC Berkeley Neuro-AI center/ ; //Kissick Family Foundation/ ; //Bluefield Project to Cure FTD/ ; //Shurl and Kay Curci Foundation/ ; T32GM139780/GM/NIGMS NIH HHS/United States ; },
abstract = {Stress is increasingly recognized as an important, modifiable factor for Alzheimer's disease (AD), yet its roles in initiation, progression, and outcomes remain incompletely elucidated. Epidemiologic studies link chronic stress, early-life adversity, and trauma to increased AD risk, while experimental models have uncovered mechanisms by which stress hormones directly drive core AD pathological processes, including amyloid beta and tau aggregation, neuroinflammation, and neurodegeneration. Complicating the relationship, brain structures that regulate the stress response are themselves selectively vulnerable to early degeneration in AD. As these circuits degenerate, interpreting changes in stress biomarkers becomes more challenging, with physiological measures potentially decoupling from perceived stress. Here, we review evidence connecting stress to AD pathophysiology as both a risk factor and a driver, examine how the degeneration of stress neuroendocrine systems accelerates disease progression, and discuss implications for intervention and clinical trial design.},
}

@article {pmid42233291,
year = {2026},
author = {Shihadeh, L and Rosselli, M and Conniff, J and Asken, B and Goytizolo, A and Barker, W and Matusz, EF and Collie, A and Coombes, SA and Armstrong, M and Velez-Uribe, I and Adjouadi, M and Smith, GE and Duara, R and DeKosky, SD and Loewenstein, DA},
title = {Associations among sleep quality, cognitive decline, and Alzheimer's disease pathology in older adults: A longitudinal study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71470},
doi = {10.1002/alz.71470},
pmid = {42233291},
issn = {1552-5279},
support = {R01AG080468 R01AG068128 P30AG066506//National Institutes of Health/National Institute on Aging/ ; 1920182//National Science Foundation's Division of Computer and Network Systems (NSF CNS)/ ; CNS1920182//Directorate for Computer and Information Science and Engineering/ ; P30AG066506/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging ; Male ; Aged ; Longitudinal Studies ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; tau Proteins/blood ; *Sleep Quality ; Cross-Sectional Studies ; Hippocampus/pathology/diagnostic imaging ; Sleep Duration ; Positron-Emission Tomography ; Middle Aged ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: This study aimed to investigate whether sleep quality predicts cognitive/functional decline, and whether Alzheimer's disease (AD) pathology modifies these relationships.

METHODS: The Pittsburgh Sleep Quality Index was administered to 326 older adults (113 cognitively normal, 192 mild cognitive impairment, 21 dementia; mean age = 66.4 ± 8.0 years) enrolled in the 1Florida Alzheimer's Disease Research Center. The Clinical Dementia Rating Sum of Boxes (CDR-SB) assessed cognitive/functional decline at baseline and over time. Moderators included hippocampal volume (HV), amyloid beta (Aβ) positron emission tomography, and plasma phosphorylated tau (p-tau)217.

RESULTS: Cross-sectionally, longer sleep duration and later wake time were associated with worse CDR-SB, with stronger associations observed among individuals with higher Aβ and p-tau217 levels, and smaller HV. Longitudinally, prolonged sleep duration was associated with faster cognitive decline, particularly in individuals with elevated Aβ or p-tau217 levels and smaller hippocampal volumes at baseline.

DISCUSSION: Prolonged sleep duration and later wake times predicted worsening cognitive performance, and these effects were strengthened by greater AD pathology.},
}

Humans
Female
*Alzheimer Disease/pathology/diagnostic imaging
Male
Aged
Longitudinal Studies
*Cognitive Dysfunction/pathology/diagnostic imaging
Amyloid beta-Peptides/metabolism
tau Proteins/blood
*Sleep Quality
Cross-Sectional Studies
Hippocampus/pathology/diagnostic imaging
Sleep Duration
Positron-Emission Tomography
Middle Aged
Neuropsychological Tests

@article {pmid42233314,
year = {2026},
author = {Tsuda, Y and Madokoro, Y and Suzuki, K and Ooba, T and Sato, T and Uchida, Y and Nagai-Arakawa, I and Saito, T and Hara, H and Hida, H and Matsukawa, N},
title = {Reduction in hippocampal cholinergic neurostimulating peptide enhances memory impairment in App[NL-G-F] KI mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71531},
doi = {10.1002/alz.71531},
pmid = {42233314},
issn = {1552-5279},
support = {JPMXS0441500024//Japan Society for the Promotion of Science/ ; Kakenhi//Japan Society for the Promotion of Science/ ; 23K14697//Japan Society for the Promotion of Science/ ; 23K14698//Japan Society for the Promotion of Science/ ; //Dainippon Sumitomo Pharma/ ; //Eisai/ ; //Daiichi-Sankyo/ ; //Otsuka Pharmaceutical/ ; },
mesh = {Animals ; *Amyloid beta-Protein Precursor/genetics ; *Hippocampus/metabolism/pathology ; Mice ; *Memory Disorders/metabolism/genetics/pathology ; Disease Models, Animal ; Mice, Knockout ; *Neuropeptides/metabolism/genetics ; Mice, Transgenic ; *Alzheimer Disease/metabolism/genetics ; Long-Term Potentiation/physiology ; Male ; },
abstract = {INTRODUCTION: Whether cholinergic activity in the septohippocampal network affects cognitive dysfunction via hippocampal cholinergic neurostimulating peptide (HCNP) in Alzheimer's pathogenesis remains unclear.

METHODS: An Alzheimer's pathogenesis by mutation in amyloid-beta precursor protein gene (App[NL-G-F]) knock-in (KI) and HCNP precursor protein conditional knockout (HCNP-pp cKO) mouse model was generated, exhibiting both cholinergic dysfunction and amyloid pathogenesis. Theta power-related cholinergic function and long-term potentiation (LTP) were evaluated in App[NL-G-F] KI/HCNP-pp cKO mice. Molecules associated with the cholinergic/glutamatergic neurons, amyloid beta (Aβ), and inflammation were examined.

RESULTS: Reduced HCNP levels enhanced cognitive impairment, inhibiting theta power and LTP, although without accompanying pathological changes or inflammation. Decreased N-methyl-D-aspartate receptor subunit 2A (NR2A), choline acetyltransferase (ChAT), and Vesicular acetylcholine transporter (VAChT) levels were observed in the hippocampus and ChAT in the medial septal nucleus (MSN) of App[NL-G-F] KI/HCNP-pp cKO mice.

DISCUSSION: Cholinergic dysfunction in HCNP-pp cKO mice exacerbates cognitive dysfunction in App[NL-G-F] KI mice. The obtained mouse models are expected to be used to investigate cholinergic dysfunction and amyloid pathogenesis in AD.},
}

Animals
*Amyloid beta-Protein Precursor/genetics
*Hippocampus/metabolism/pathology
Mice
*Memory Disorders/metabolism/genetics/pathology
Disease Models, Animal
Mice, Knockout
*Neuropeptides/metabolism/genetics
Mice, Transgenic
*Alzheimer Disease/metabolism/genetics
Long-Term Potentiation/physiology
Male

@article {pmid42233646,
year = {2026},
author = {Kessing, LV and Munkholm, K},
title = {Bipolar disorder and the risk of developing dementia - a systematic review and meta-analysis.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000001100},
pmid = {42233646},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: To present an up-to-date systematic review and meta-analysis on the risk of dementia in patients with bipolar disorder.

RECENT FINDINGS: We included 22 studies investigating the risk of developing dementia among patients with bipolar disorder of which 21 studies provided data for the meta-analysis, comprising a total of 185 306 patients with bipolar disorder and 10 702 744 participants without bipolar disorder. Random effects meta-analysis showed an increased risk of being diagnosed with dementia in patients diagnosed with bipolar disorder [odds ratio (OR): 3.13 (95% CI: 2.40-4.09), I2 = 99.8%, 21 studies]. In a secondary analysis excluding studies with overlapping populations, the pooled effect estimate was OR = 2.60 (95% CI 1.76-3.85, I2 = 99.9%, 11 studies). The evidence was uncertain due to substantial and unexplained between-study heterogeneity, methodological limitations, and risk of bias in the included studies.

SUMMARY: Patients with bipolar disorder have an increased risk of developing dementia, but the evidence is uncertain.},
}

@article {pmid42233874,
year = {2026},
author = {Souza, BA and Freitas, MID},
title = {Linguistic-cognitive intervention in a case of early-onset Alzheimer's disease.},
journal = {CoDAS},
volume = {38},
number = {3},
pages = {e20250126},
doi = {10.1590/2317-1782/e20250126pt},
pmid = {42233874},
issn = {2317-1782},
abstract = {Early-Onset Alzheimer's Disease (EOAD) is an atypical variant of dementia that usually presents with impairments in language, visuospatial abilities, executive functions, or complex motor skills, with an early onset before the age of 65. This case study investigates the effect of a weekly language-cognitive intervention program in a patient with EOAD, diagnosed at the age of 58. The following protocols were applied for assessment before, during, and after the intervention: the Addenbrooke's Cognitive Examination - Revised (ACE-R), the Arizona Battery for Communication Disorders of Dementia (ABCD), and the Boston Naming Test (BNT). This case study demonstrated that the language-cognitive intervention had a beneficial effect in maintaining linguistic expression abilities, despite the expected progression of a neurodegenerative disease.},
}

@article {pmid42234065,
year = {2026},
author = {Agheshteh Sabzevar, N and Musaie, F and Ostovar Ravari, A and Gharehdaghi, N and Kianfar, K and Ahmadi, S and Irannejadrankouhi, S and Fazel, T and Sadeghi, S and Yarahmadi, D and Malekpour, H and Deravi, N},
title = {The link between dental care use and incident diabetes, cancer, and Alzheimer disease among older Americans: the health and retirement study.},
journal = {The Saudi dental journal},
volume = {38},
number = {6},
pages = {},
pmid = {42234065},
issn = {1013-9052},
abstract = {Oral health is crucial for overall well-being, especially in older adults at higher risk for chronic diseases. This study examines the link between regular dental care and 10-year incidence of major conditions-Alzheimer's, dementia, stroke, diabetes, cancer-using data from the Health and Retirement Study (HRS), a representative survey of older Americans. Data from 15,320 dementia‑free participants aged 50 years and older interviewed in 2008 were analyzed. Regular dental visits in the previous 2 years were the primary exposure, and a composite dental condition measure (poor versus good, combining edentulism and self‑rated oral health) was examined in an oral‑health subsample. Incident Alzheimer's disease, all‑cause dementia, stroke, diabetes, and cancer over approximately 10 years of follow‑up were ascertained from physician diagnoses and cognitive assessments. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs), controlling for sociodemographic, behavioral, and clinical factors. Regular dental visiting was associated with a substantially lower 10‑year risk of cognitive diseases, stroke, cancer, and diabetes outcomes. In fully adjusted models, regular attenders had markedly reduced odds of incident Alzheimer's disease and all‑cause dementia compared with non‑attenders, and similar but weaker associations with stroke, diabetes, and cancer were observed. In the oral‑health subsample, poor dental condition was strongly related to higher odds of incident all‑cause dementia, with attenuated but persisting elevation after adjustment, while showing little evidence of association with incident Alzheimer's disease, stroke, diabetes, or cancer. In this large cohort of older Americans, regular dental care use and favourable baseline dental condition were both associated with a lower 10‑year incidence of dementia, particularly all‑cause dementia, whereas links with vascular and metabolic outcomes were limited. These findings support integrating oral health maintenance into strategies to preserve cognitive health in ageing populations.},
}

@article {pmid42234183,
year = {2026},
author = {Cunniff, L and Weickenmeier, J and , },
title = {Aging-related lateral ventricular shape changes and corresponding mechanical loading derived from longitudinal image registration.},
journal = {Biomechanics and modeling in mechanobiology},
volume = {25},
number = {3},
pages = {},
pmid = {42234183},
issn = {1617-7940},
support = {1953323//Directorate for Engineering/ ; U19NS120384/NH/NIH HHS/United States ; },
abstract = {Lateral ventricular enlargement is one of the most prominent features of the aging brain and is clearly visible on structural magnetic resonance imaging. Both longitudinal and cross-sectional imaging studies have shown that ventricular volume progressively increases with age and expands even faster in neurodegenerative diseases such as Alzheimer's disease and related dementias. Strikingly, however, we only have a limited understanding of ventricular shape changes and the corresponding mechanical loads that act on the ventricular wall as we age. Therefore, we propose a framework that uses nonlinear registration to quantify subject-specific brain deformations between two longitudinal scans, maps the resulting warp field onto a ventricular surface template mesh, and quantifies mechanical loading measures including displacement magnitude, curvature change, area stretch, and maximum principal wall strain. From the Alzheimer's Disease Neuroimaging Initiative, we selected a cohort of 50 cognitively normal subjects aged 70-75 years at baseline and with a follow-up scan 4-5 years later. In this group, we observed mostly uniform expansion of the lateral ventricles with an average displacement magnitude of 0.88 ± 0.3 mm across the whole ventricle. At the same time, there are distinct sections of the ventricular wall that experience high mechanical loads with respect to our mechanomarkers. Specifically, maximum mechanical loading consistently localizes along the ventricular edges and atrium while the ventricle's main body exhibits minimal loading. Based on the cohort included in this study, we did not observe sex-based differences with respect to any mechanomarker, noticed that on average 29.2 ± 9.3% of the ventricular wall experience wall area increase, and that on average only 4.4 ± 2.5% of the ventricular wall experience wall shrinking. Interestingly, regions of elevated mechanical loading showed reliable spatial correspondence with periventricular white matter hyperintensity locations in our subjects for whom FLAIR imaging was available (n = 39). Additionally, mechanomarkers showed increased magnitudes with periventricular white matter hyperintensity burden, with curvature change demonstrating the strongest group separation. These findings suggest that ventricular enlargement is associated with localized mechanical stresses that coincide with vulnerable white matter regions. Taken together, we present strong evidence in support of the hypothesis that the mechanical loading associated with age-related ventricular enlargement is intricately linked to periventricular white matter degeneration and corresponding cognitive decline.},
}

@article {pmid42234329,
year = {2026},
author = {Qi, JW and He, XY and Gu, YC and Luo, ZJ and Duan, R and Zhang, YD and Xie, Y and Jiang, T},
title = {Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42234329},
issn = {1559-1182},
abstract = {Aging is recognized as the most significant risk factor for neurodegenerative diseases. Emerging evidence indicates that inflammation contributes to the progression of aging-related neurodegeneration. As a transmembrane immune receptor, triggering receptor expressed on myeloid cells 1 (TREM1) plays a crucial role in the regulation of inflammatory responses. Previously, our research group and others showed that the levels of a soluble form of TREM1 (sTREM1) were increased in the plasma or cerebrospinal fluid (CSF) of patients with Alzheimer's disease, the most common type of neurodegenerative disease among the elderly. Moreover, the elevated levels of CSF sTREM1 were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults. However, the precise mechanisms by which sTREM1 contributes to aging-related neurodegeneration remain largely unclear. In this study, by utilizing senescence accelerated mouse prone 8 mice, an animal model of accelerated aging, we confirmed that serum sTREM1 levels were significantly increased during the aging process. Importantly, we demonstrated that roundabout guidance receptor 2 (ROBO2) functioned as a receptor for sTREM1 in hippocampal neurons, and its expression was also upregulated with aging. Additionally, we revealed for the first time that knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. Furthermore, we provided the first evidence that sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase pathway. These findings elucidated the mechanisms through which sTREM1 contributed to aging-related neurodegeneration and suggested that the inhibition of sTREM1-mediated signaling might represent a novel therapeutic strategy for the treatment of neurodegeneration and cognitive decline induced by aging.},
}

@article {pmid42234356,
year = {2024},
author = {Li, X and Qin, Y and Ye, S and Song, H and Zhou, P and Cai, B and Wang, Y},
title = {Retraction notice to "Protective effect of Huangpu Tongqiao capsule against Alzheimer's disease through inhibiting the apoptosis pathway mediated by endoplasmic reticulum stress in vitro and in vivo" [Saudi Pharm. J. 30(11) (2022) 1561-1571].},
journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society},
volume = {32},
number = {11},
pages = {},
doi = {10.1016/j.jsps.2024.102183},
pmid = {42234356},
issn = {1319-0164},
}

@article {pmid42234953,
year = {2026},
author = {Kim, D and McInerney, K and Dagli, C and Armstrong, ND and Cushman, M and Bennett, A and Blue, EE and Sofer, T and Sawyer, RP and Yuan, Y and Crowe, M and Judd, SE and Olson, NC and Irvin, MR and Raffield, LM},
title = {Influence of Cardiometabolic and Alzheimer Disease Genetics on Cognitive-Related Outcomes in a Diverse Population.},
journal = {Neurology},
volume = {107},
number = {1},
pages = {e218163},
doi = {10.1212/WNL.0000000000218163},
pmid = {42234953},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Late-life dementia has a strong heritable component. While the APOE ɛ4 allele is the strongest genetic risk factor of Alzheimer disease (AD), polygenic risk factors also play a significant role. Cardiometabolic diseases (CMDs) and their risk factors predict dementia in many cohorts, but how genetic predictors of CMD influence dementia-related outcomes remains unclear. In this study, we examined the associations of polygenic risk scores (PRSs) for major CMDs and the established APOE risk alleles with dementia-related outcomes in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is enriched for Black participants underrepresented in late-life dementia research.

METHODS: We constructed PRSs for AD and related dementias (ADRDs) and CMDs, including stroke, coronary artery disease, venous thromboembolism, type 2 diabetes, atrial fibrillation, blood pressure (systolic blood pressure, diastolic blood pressure, and pulse pressure), and circulating lipid levels (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), using lead genome-wide significant genetic variants from the latest genome-wide association studies. We evaluated the predictive performance of each PRS on their primary end point and tested their associations with incident cognitive impairment (ICI), assessed using the 6-item screener and enhanced cognitive battery, and dementia as a contributing cause of death (DCCD). In addition, we explored the impact of APOE variants and, based on previous reports, local genetic ancestry at the APOE locus on these dementia-related outcomes.

RESULTS: Up to 8,818 participants were analyzed (mean age 63.7 years; 58.9% female; 83.3% Black). For CMD PRS, we identified a significant association between PRS for pulse pressure and DCCD (hazard ratio [HR] 1.16, 95% CI 1.06-1.28, p < 1.76 × 10[-3]). We observed that the PRS for ADRD was associated nominally with DCCD (HR 1.12, 95% CI 1.00-1.25), but not with ICI among REGARDS participants, suggesting heterogeneity in associations across different cognitive-related end points. Furthermore, we identified a nominally significant (p < 0.1) attenuated effect of APOE risk alleles on ICI among those with African ancestry at the APOE locus, similar to previous reports.

DISCUSSION: Higher PRS for pulse pressure was associated with increased DCCD risk, supporting shared genetic underpinnings between CMD and dementia.},
}

@article {pmid42234962,
year = {2026},
author = {Ahsan, N and Khan, FB and Basu, J and Shariq, M and Zaidi, N and Khan, RH and Raj, R and Ayoub, MA and Surolia, A and Ashraf, GM},
title = {Harnessing Neuronal Autophagy: Bridging Mechanistic Breakthroughs to Therapeutic Interventions.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0804},
pmid = {42234962},
issn = {2152-5250},
abstract = {Autophagy, an essential cellular process that degrades and recycles misfolded proteins, damaged organelles, and intracellular pathogens, is vital for neurons due to their limited capacity for apoptosis. Dysregulation of autophagy and lysosomal pathways is closely linked to the onset and progression of major neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In this manuscript, we offer a thorough examination of the molecular mechanisms that regulate autophagy, emphasizing both bulk and selective autophagy pathways and their roles in maintaining neuronal homeostasis. Genetic mutations in autophagy-related genes and endolysosomal genes are identified as significant risk factors, and the pathological roles of protein aggregation and mitochondrial dysfunction are also discussed. The therapeutic restoration of autophagic function represents a promising strategy for alleviating neurodegeneration. This manuscript examines potential interventions, including small molecules, gene therapy, and natural compounds, that enhance autophagic flux and facilitate protein clearance. Furthermore, the translational potential was underscored by including ongoing clinical trials that target autophagy pathways. This review artcile emphasizes the essential role of autophagy in neuronal health and disease, providing a framework for utilizing autophagic mechanisms to develop targeted therapeutic strategies for NDDs.},
}

@article {pmid42234965,
year = {2026},
author = {Lu, Z and Meng, C and Ren, X and Zhang, S and Xu, X and Hao, S and Wang, Q and Zhou, D},
title = {Astrocytic Ferroptosis: An Integrative Hub Linking Metabolic Dyshomeostasis, Glial Crosstalk, and Neurodegeneration in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0328},
pmid = {42234965},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a widespread age-related neurodegenerative disorder. Current therapies targeting Aβ plaques and hyperphosphorylated Tau show limited efficacy. The core pathology of AD involves neuroglial metabolic network collapse, which is tightly associated with brain iron dyshomeostasis and abnormal ferroptosis. As the main iron storage and antioxidant cells in the CNS, astrocytes transform into disease-associated astrocytes under AD conditions. Metabolic reprogramming switches them from a neuroprotective to a pro-ferroptotic phenotype, contributing to thereby exacerbating systemic metabolic dyshomeostasis. This review systematically elaborates the regulatory mechanisms of astrocytic ferroptosis in AD: disordered iron metabolism (e.g., aberrant DMT1/FPN1 expression) induces iron accumulation as the initiation prerequisite; excessive oxidative stress (Ang II/HIF-1α-NOX4 axis-mediated ROS generation) and impaired antioxidant defense (Nrf2-SLC7A11/GPX4 inactivation, ApoE4 dysfunction) serve as core regulatory modules; FTH1 and SAT1 dysregulation elevates the labile iron pool, while AQP4 dysfunction impairs metabolite clearance, amplifying ferroptosis. Moreover, aberrant crosstalk among astrocytes, microglia and oligodendrocytes exacerbates AD-related neurodegeneration. Collectively, astrocytic ferroptosis acts as a key integrative mechanism linking iron dysmetabolism, oxidative stress, neuroinflammation and Aβ/Tau pathology, offering a potential new avenue for decoding AD pathogenesis. Targeting astrocytic ferroptosis is expected to overcome the long-standing therapeutic limitations of conventional AD treatments, providing theoretical support and new directions for developing disease-modifying AD therapies. While individual components including disease-associated astrocytes, brain iron dyshomeostasis, NOX4- and NRF2-related ferroptosis have been documented separately, this review represents the first comprehensive synthesis that identifies astrocytic ferroptosis as a central hub that unifies these fragmented mechanisms into a cohesive pathogenic cascade driving AD.},
}

@article {pmid42234969,
year = {2026},
author = {Feng, Y and Si, Y and Pang, X and Feng, S and Zhang, Y and Xue, S and Guo, T},
title = {Melatonin in Circadian Rhythm and Brain Health: Neuroprotective Effects and Therapeutic Potential.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0119},
pmid = {42234969},
issn = {2152-5250},
abstract = {Melatonin is an indole-like hormone secreted by the pineal gland. It regulates circadian rhythms and exerts antioxidants, anti-inflammatory, immunomodulatory, tumor-suppressing, and sleep-improving effects. With global population aging, neurodegenerative diseases have gained public attention. Melatonin has been increasingly studied for brain diseases. This review synthesizes evidence on melatonin in circadian rhythm regulation, Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia-reperfusion, depression, insomnia, brain aging and dietary applications. We critically evaluate study methodologies, sample sizes, and reproducibility. While melatonin shows promise, many findings derive from small clinical trials or animal models requiring validation. We conclude that melatonin may positively affect brain health through multiple pathways but emphasize that evidence strength varies across conditions. From a safety perspective, obtaining melatonin from food and dietary supplements is ideal for consumers.},
}

@article {pmid42234971,
year = {2026},
author = {Zhou, J and Zhu, X and Chen, W and Tan, J and Hong, L and Yang, L and Liu, Y and Zhai, T and Chen, K},
title = {The Dickkopf Protein Family in Non-Neoplastic Disorders: Emerging Roles and Therapeutic Targeting.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1506},
pmid = {42234971},
issn = {2152-5250},
abstract = {The Dickkopf (DKK) family of secreted glycoproteins, comprising DKK1-4, serves as a pivotal regulator of the Wnt signaling pathway. Acting as canonical antagonists of the Wnt/β-catenin cascade, these proteins are indispensable for essential biological processes such as cellular proliferation, differentiation, development, and tissue homeostasis. In recent years, aberrant expressions of DKK proteins has been extensively documented in multiple cancers. Simultaneously, their pathophysiological roles and clinical relevance in non-oncological diseases have garnered growing attention. Disorders such as osteoporosis and arthritis, chronic kidney disease (CKD), myocardial injury, as well as neurodegenerative and dermatological conditions, including Alzheimer's disease (AD) and alopecia, have all been linked to DKK family members. These broad associations emphasize their substantial potential as diagnostic biomarkers and as promising therapeutic targets. This review provides a systematic synthesis of recent research within the past three years on the roles of the DKK protein family in diverse non-oncological diseases, further examining their prospective applications as biomarkers and therapeutic targets while addressing related challenges, with the aim of offering novel insights into diagnosis and treatment.},
}

@article {pmid42235139,
year = {2026},
author = {Mangala, N and Amistapuram, K and Garapati, RS},
title = {Comment on "Explainable machine learning on clinical features to predict and differentiate Alzheimer's progression by sex: Toward a clinician-tailored web interface".},
journal = {Journal of the neurological sciences},
volume = {488},
number = {},
pages = {126006},
doi = {10.1016/j.jns.2026.126006},
pmid = {42235139},
issn = {1878-5883},
}

@article {pmid42235332,
year = {2026},
author = {Zhao, A and Liu, Q and Wang, X and Wang, Y and Wang, Z and Liu, Z},
title = {Platelet lipid rafts: Disease regulatory hubs and precision therapeutic targets in membrane microdomains.},
journal = {Biochemical and biophysical research communications},
volume = {827},
number = {},
pages = {154039},
doi = {10.1016/j.bbrc.2026.154039},
pmid = {42235332},
issn = {1090-2104},
abstract = {Lipid rafts are dynamic membrane microdomains enriched in cholesterol and sphingolipids. Platelets, with their unique anucleate nature and a high cholesterol-to-phospholipid ratio, serve as an optimal model for studying lipid raft functionality. These microdomains regulate key platelet processes-including adhesion, aggregation, phosphatidylserine exposure, and the release of inflammatory mediators-by recruiting receptors such as GPIb-IX-V and GPVI, and downstream signalling molecules like Syk and Src family kinases. Consequently, platelet lipid rafts modulate a spectrum of physiological and pathological events, from thrombosis and immune regulation to tumour metastasis. This review delineates the pathogenic roles of platelet lipid rafts in atherosclerosis, sepsis, antiphospholipid syndrome, Alzheimer's disease, and cancer, elucidating underlying mechanisms such as aberrant signal activation, procoagulant microvesicle release, and intercellular crosstalk. Furthermore, we explore emerging therapeutic strategies that target the cholesterol content, protein composition, or dynamic architecture of lipid rafts, offering novel perspectives for personalised antithrombotic regimens.},
}

@article {pmid42235492,
year = {2026},
author = {Morais, RF and Duro, D and Pires, R and Lemos, R and Lima, M and Oliveira, TG and Santana, I},
title = {Emotion Perception in Behavioral Variant Frontotemporal Dementia and Alzheimer Disease: The Parahippocampal Conundrum.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {39},
number = {2},
pages = {43-52},
pmid = {42235492},
issn = {1543-3641},
abstract = {BACKGROUND: Emotion perception is the capacity that enables humans to correctly identify the cues that guide interpersonal interactions, forming the basis for social behavior. The parahippocampal cortex may contribute to emotion perception by mediating the associations between context and emotion. Individuals with behavioral variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) appear to show deficits in this process. Investigating emotion perception impairment in these individuals could offer valuable insights into the underlying neurobiological mechanisms.

METHODS: Participants included a convenience sample of 29 individuals with bvFTD, 25 with AD, and a comparison group of 15 individuals without bvFTD or AD. We performed an extensive neuropsychological assessment and administered the Comprehensive Affect Testing System (CATS) to evaluate the emotion perception process. We then used multiple regression analysis to assess the relationship between CATS main quotient scores and parahippocampal thickness (P ≤ 0.001) obtained from MRI analysis.

RESULTS: Participants with bvFTD scored higher on cognitive tests than participants with AD but showed greater deficits in social behavior. On the CATS, participants with bvFTD had lower scores in all 3 emotional quotients (ie, face, prosody, and global), with a statistically significant correlation to parahippocampal thickness. Participants with AD showed milder deficits in all 3 emotion quotients, with no statistically significant correlation to parahippocampal thickness.

DISCUSSION: Our data suggest a significant emotion perception deficit in individuals with bvFTD and support the importance of the parahippocampal gyrus in context-emotion associations. Targeted rehabilitation with the objective of improving emotion perception deficits may be beneficial for individuals with bvFTD.},
}

@article {pmid42235661,
year = {2026},
author = {Wang, Z and Huang, L and Guan, Y and Pan, J and Yuan, C and Xie, F and Huang, CC and Guo, Q},
title = {Stage-specific hippocampal network degeneration links amyloid-cognition relationships: Right subiculum as structural substrate for memory maintenance and biomarker in amyloid-positive mild cognitive impairment.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122022},
doi = {10.1016/j.neuroimage.2026.122022},
pmid = {42235661},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD) represents a continuum progressing from preclinical stages through prodromal mild cognitive impairment (MCI) to dementia. The stage-specific relationships between amyloid-β (Aβ) pathology, hippocampal subfield atrophy, and cognitive decline remain poorly understood, particularly whether network-level hippocampal degeneration mediates Aβ-cognition relationships and whether preserved subfield volumes are associated with preserved cognitive function. We investigated 465 participants from the Chinese Preclinical Alzheimer's Disease Study, stratified into cognitively normal Aβ-negative (n=132), MCI Aβ-negative (MCI-, n=128), MCI Aβ-positive (MCI+, n=93), and AD dementia (n=112) groups. Participants underwent neuropsychological assessments, T1-weighted MRI, APOE genotyping, and amyloid imaging. We employed elastic net regression, mediation, moderation, and structural covariance network analyses to investigate stage-specific associations between hippocampal subfields and cognition. We further evaluated the clinical utility of subfield volumes for discriminating Aβ status in MCI patients. Progressive hippocampal atrophy emerged prominently at the MCI+ stage. Mediation analyses revealed that Aβ-associated subfield atrophy statistically mediated cognitive decline exclusively in MCI+, affecting global cognition, memory, and attention. These mediating subfields were organized into three domain-specific structural covariance networks with bootstrap-confirmed stable morphological covariances, showing coordinated degeneration patterns that statistically mediated Aβ-cognition associations. Preserved right subiculum volume was associated with better memory function in MCI+ (β=0.358, 95%CI: 0.205-0.511). Incorporating right subiculum volume improved discrimination of amyloid-positive status in MCI, with significant Net Reclassification Improvement and Integrated Discrimination Improvement (both P <0.01), providing incremental improvement beyond conventional demographic and cognitive measures. In conclusion, MCI+ represents a pivotal phase where Aβ is linked to the emergence of coordinated hippocampal network deterioration. The right subiculum demonstrates dual significance: as a critical structural substrate supporting memory maintenance in the presence of amyloid pathology and as a potential MRI-based marker for identifying amyloid-positive MCI patients.},
}

@article {pmid42235718,
year = {2026},
author = {Oh, JM and Jeong, WK and Son, HJ and Kwon, YJ and Kim, SY and Oh, TW and Ji, M and Baek, M and Shin, WH and Kim, HJ and Choi, B and Kim, SH and Paik, MJ and Kim, H},
title = {Broussochalcone A alleviates cognitive impairment in scopolamine-induced mice as a potent β-amyloid aggregation inhibitor and changes blood and brain metabolite profiles.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121958},
doi = {10.1016/j.jep.2026.121958},
pmid = {42235718},
issn = {1872-7573},
abstract = {Broussonetia papyrifera (BP) has been used for traditional medicine in amelioration of cognitive decline. Accumulation of β-amyloid (Aβ) plaques majorly contributed to the pathogenesis of Alzheimer's disease (AD).

AIM OF THE STUDY: This study aimed to investigate the role of broussochalcone A (BCA), a bioactive constituent of BP, in alleviation of cognitive impairment via Aβ aggregation inhibition in model mice.

METHODS: We screened a potent Aβ aggregation inhibitor from a herbal library and analyzed its effect on improving cognitive functions in model mice and principal protein expression. In addition, we compared the metabolite profiling of blood and tissues. We used the aggregation inhibition assay to screen 960 herbal compounds using Aβ42-, and a leading compound was selected based on drug-like properties. Animal behavioral tests including the Morris water maze were performed using scopolamine (SCO)-treated mice. Western blotting and histopathological analysis were performed. Key compounds in the blood, hippocampus, and cortex were analyzed to compare the metabolic profiles.

RESULTS: BCA was a potent Aβ aggregation inhibitor (IC50 = 1.75 ± 0.021 μM) with a predicted binding energy of -6.405 kcal/mol, and nontoxic to MDCK and SH-SY5Y cells. Molecular dynamics simulation revealed that the atomic contact numbers of BCA with Aβ were highly fluctuated during 100 ns; however, the transient contacts might prevent the aggregation. Cognitive function was significantly improved in BCA-treated mice in behavioral tests. Western blotting and histopathological analysis demonstrated that BCA treatment attenuated apoptosis, preserved hippocampal pyramidal neuron integrity, and alleviated SCO-induced spatial memory impairment. Metabolite profiling demonstrated that BCA modulated the metabolic pathways related to energy metabolism, redox homeostasis, amino acid turnover, and lipid metabolism in the serum and brain tissues, partially attenuating SCO-associated metabolic alterations.

CONCLUSIONS: BCA is a potent Aβ aggregation inhibitor and exhibits significant cognitive improvement, as well as neuroprotective effects, decreasing inflammation, and retaining neuron structures. In addition, BCA induced distinct metabolic alterations in the serum and brain tissues compared to SCO. These results strongly support the use of BCA as a promising candidate for the amelioration of cognitive impairment and application to AD therapeutics.},
}

@article {pmid41957153,
year = {2026},
author = {Yu, J and Rosbergen, MT and Wolters, FJ and Bron, EE and Vernooij, MW and Ikram, MA and Roshchupkin, GV},
title = {Imaging-genetics-based dementia risk prediction using deep survival neural networks in the Rotterdam Study.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41957153},
issn = {2045-2322},
support = {202006640010//China Scholarship Council/ ; 10510032120005//BIRD-NL dementia prevention initiative grant/ ; 1936320//ZonMw Veni grant/ ; },
abstract = {UNLABELLED: Accurate dementia risk prediction is challenging, and may be facilitated by better use of imaging and genetic data, including their complex interactions. We explored using deep survival neural networks to integrate these multi-modal, high-dimensional data. We included 3521 Rotterdam Study participants, 6340 magnetic resonance imaging (MRI) scans, with follow-up clinical diagnosis for dementia, and used 515 samples from Alzheimer’s Disease Neuroimaging Initiative (ADNI) as an external validation. Genetic data included APOE-ε4 status and 76 additional SNPs. We developed models combining Convolutional Neural Networks (CNN) and Cox Proportional Hazards (CPH) models and provided post-hoc explanations. Our models outperformed CPH models including age, sex, and genetic inputs in both Rotterdam Study and ADNI by C-index of 0.88/0.63 V.S. 0.85/0.58, p-value of 0.02/0.002. Although their performance did not surpass CPH models also included MRI markers (0.89/0.66), additional predictability was obtained in age-stratified prediction in ADNI. Incorporating CNN image features in CPH models further increased performance to highest C-index of 0.90/0.69. Age and image had the highest importance in prediction, with age, image and genetic features showing the strongest interactions. Our approach indicates that imaging and genetic data can be feasibly integrated for dementia risk prediction, with informative extraction, reliable explanations and potential predictive gains.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-47047-y.},
}

@article {pmid42223932,
year = {2026},
author = {Algeciras-Schimnich, A and Bornhorst, JA and Figdore, DJ and Rea Reyes, RE and Ashrafzadeh-Kian, S and Wilson, R and Burkett, BJ and Johnson, DR and Botha, H and McCarter, SJ and Day, GS and Graff-Radford, J and Ramanan, VK and Jack, CR and Johnson, SC and Zetterberg, H and Petersen, RC},
title = {Variability in Clinical Performance of the FDA-Cleared Lumipulse P-Tau217/β-Amyloid 1-42 Plasma Ratio.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.1565},
pmid = {42223932},
issn = {2168-6157},
}

@article {pmid42223952,
year = {2026},
author = {Poettcker, K and Peckham, A and Pituch, KA and Squires, A and Maxfield, M},
title = {Emotional reactions to vignettes depicting varying degrees of behavior modification to reduce risk for alzheimer's disease.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13607863.2026.2676644},
pmid = {42223952},
issn = {1364-6915},
abstract = {OBJECTIVES: Without cures for Alzheimer's disease and related dementias (ADRD), public health messaging emphasizes lifestyle modification to reduce risk (e.g. diet, physical activity). While this framing promotes a sense of personal control, it may also contribute to negative evaluations of individuals who do not modify their behavior.

METHODS: This vignette-based experiment examined how behavioral modification and personal exposure to ADRD influence emotional reactions toward a fictional individual experiencing cognitive decline. Participants (n = 239) were randomly assigned to read one of two vignette versions in which the individual either implemented recommended lifestyle changes and showed health improvements or did not implement recommended changes and continued to show elevated health risk indicators (modified vs. unmodified). Emotional responses were assessed to examine effects of behavioral framing and prior ADRD exposure.

RESULTS: Participants reported greater negative emotional reactions in response to the unmodified condition. Those with both genetic and social ADRD exposure reported greater anxiety and rejection relative to other exposure groups. ADRD exposure did not moderate the effects of behavior modification.

CONCLUSION: Findings highlight the need for careful risk-reduction messaging that balances empowerment with compassion to avoid reinforcing negative emotional reactions toward individuals with ADRD.},
}

@article {pmid42224107,
year = {2026},
author = {Su, Y and Ren, H and Huang, S and Hao, Y},
title = {Identification of Functional lncRNAs in Alzheimer Disease by Integrative Analysis of lncRNA-mRNA Network Based on Competing Endogenous RNA Mechanism.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000724},
pmid = {42224107},
issn = {1546-4156},
abstract = {BACKGROUND: Emerging evidence highlights the critical involvement of noncoding RNAs (ncRNAs) in the pathologic process of Alzheimer disease (AD). However, the precise functional contributions and regulatory landscapes of long noncoding RNAs (lncRNAs) in AD remain unclear.

OBJECTIVE: This study aims to delineate the regulatory roles of functional lncRNAs in AD by systematically analyzing lncRNA-mRNA interactions within an AD-associated network, leveraging the competing endogenous RNA (ceRNA) framework.

METHODS: We constructed an AD-specific lncRNA-mRNA network by integrating a probe reannotation pipeline with experimentally validated microRNA (miRNA)-lncRNA/mRNA interactions. Key lncRNAs were identified through topological analysis, while bidirectional hierarchical clustering was applied to define functional modules. Pearson correlation coefficients were computed to assess the association patterns of lncRNA-mRNA pairs.

RESULTS: Using a structured analytical approach, we identified 31 differentially expressed lncRNAs and 1045 mRNAs within the AD network. Topological analysis revealed SNHG12, MIR17HG, and GAS5 as central regulatory nodes, indicating their potential roles in network stability and transcriptional regulation. A functionally coherent module of lncRNA-mRNA interactions was identified through clustering, with enrichment in multiple AD-relevant signaling pathways, including neuroinflammation and synaptic dysfunction, suggesting a mechanistic role for lncRNAs in disease-associated processes. Furthermore, leveraging the ceRNA model, we mapped dysregulated ceRNA interactions, uncovering significant alterations in ceRNA crosstalk between AD and non-AD conditions, which may reflect broader disruptions in posttranscriptional gene regulation.

CONCLUSIONS: Our findings provide key insights into the functional architecture of lncRNA regulatory networks in AD, offering a refined perspective on their contributions to disease pathology and highlighting potential biomarkers and therapeutic targets.},
}

@article {pmid42224229,
year = {2026},
author = {Valdevila Figueira, JA and Monteros Andrade, MAEL and Yambay-Bautista, XR and Ramírez, A and Carvajal Parra, ID and Valdevila Santiesteban, R and Pico, MJ and Rodas, JA},
title = {Knowledge about Alzheimer's disease in medical, nursing, and psychology students in Ecuador: A problem that needs an urgent solution.},
journal = {PloS one},
volume = {21},
number = {6},
pages = {e0350624},
pmid = {42224229},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease ; Ecuador ; Female ; Male ; *Students, Nursing ; *Students, Medical/psychology ; Cross-Sectional Studies ; *Health Knowledge, Attitudes, Practice ; Adult ; Psychologists ; Young Adult ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: Alzheimer's disease represents one of the greatest healthcare challenges of the 21st century due to the aging population and its impact on the quality of life of patients and their families. Preparing future healthcare professionals to address this condition is crucial.

AIMS: This article analyzes the level of knowledge about Alzheimer's disease held by university students in medicine, nursing, and psychology, highlighting the differences and similarities between disciplines and proposing strategies to improve training in this field.

METHODS: A cross-sectional study was conducted with a convenience sample of 1,023 Ecuadorian students: nursing (n = 727, 71.1%), medicine (n = 170, 16.6%), and psychology (n = 126, 12.3%). Participants completed the Alzheimer's Disease Knowledge Scale (ADKS) and a demographic survey. The percentage of correct answers on the ADKS was used to assess knowledge levels.

RESULTS: The overall percentage of correct answers was 54.68%, indicating a limited level of knowledge. Medical students obtained the highest mean score (17.44 [SD: 2.864]), followed by psychology (16.28 [SD: 2.348]) and nursing (16.18 [SD: 2.649]). A weak but significant correlation was found between knowledge level and prior contact with people with dementia (P < 0.001).

CONCLUSIONS: Students across all disciplines demonstrated a broad knowledge gap regarding Alzheimer's disease, although medical students obtained slightly higher scores than psychology and nursing students. The findings highlight the need for improved educational training and curriculum development to enhance dementia knowledge, especially in psychology and nursing programs.},
}

Humans
*Alzheimer Disease
Ecuador
Female
Male
*Students, Nursing
*Students, Medical/psychology
Cross-Sectional Studies
*Health Knowledge, Attitudes, Practice
Adult
Psychologists
Young Adult
Surveys and Questionnaires

@article {pmid42224406,
year = {2026},
author = {Morris, C and Mok, PLH and Robinson, DL and Allan, L and Ashcroft, DM and Blakeman, T and Kontopantelis, E},
title = {Prescribing of anti-dementia medications in primary care: A retrospective cohort study in 1489 English General Practices.},
journal = {PloS one},
volume = {21},
number = {6},
pages = {e0347921},
doi = {10.1371/journal.pone.0347921},
pmid = {42224406},
issn = {1932-6203},
mesh = {Humans ; Retrospective Studies ; *Memantine/therapeutic use ; *Cholinesterase Inhibitors/therapeutic use ; *Dementia/drug therapy ; *Practice Patterns, Physicians'/statistics & numerical data ; England ; *Primary Health Care/statistics & numerical data ; Female ; Aged ; Male ; General Practice ; Aged, 80 and over ; Alzheimer Disease/drug therapy ; Mixed Dementias ; Lewy Body Disease/drug therapy ; Drug Prescriptions/statistics & numerical data ; },
abstract = {OBJECTIVE: Evidence suggests that patient-level characteristics such as socio-economic status or ethnicity affect the likelihood of receiving guideline recommended anti-dementia medications. Existing studies often included all-cause dementia, not just the specific subtypes in which medication is indicated. Patterns of prescribing of Acetyl Cholinesterase Inhibitors (AChEIs) and memantine require further exploration, with little evidence about rates of co-prescribing in English primary care. We examined variations in anti-dementia medication prescribing with patient-level characteristics, and over time.

DESIGN AND SETTING: Retrospective cohort study, using the Clinical Practice Research Datalink Aurum. Data from 1,489 practices, in England between 2006-2024, were included and linked to patient level Index of Multiple Deprivation data (2019). Cox-regression modelling, clustered at practice level, assessed association between patient-level characteristics and receiving AChEIs, and/or memantine. Time-series analyses examined co-prescribing of memantine and AChEIs.

PARTICIPANTS: 242,007 patients, aged >=18 years, with Alzheimer's or Lewy-Body Dementia, or mixed dementia including one of these subtypes, were included.

RESULTS: Among the 242,007 patients, 63.1% were prescribed an anti-dementia medication; co-prescribing of memantine and AChEIs peaked at 4.2%. Those in the most deprived quintile were less likely to be prescribed AChEIs (Hazard Ratio (HR) 0.82,0.78-0.86) compared to the most affluent quintile. People with Asian (HR 0.89,0.84-96), or Black (HR 0.79, 0.73-0.86) ethnicities were less likely to be prescribed memantine compared to white people. Those with learning disabilities were substantially less likely to be prescribed AChEIs (HR 0.46,0.42-0.50) or memantine (HR 0.58, 0.50-0.67) compared to those without.

CONCLUSION: Overall rates of prescribing of anti-dementia medications were lower than expected. Rates of co-prescription of AChEIs and memantine were low, despite guideline recommendations. We found inequity in anti-dementia medication prescribing, relating to multiple patient-level characteristics highlighting the need for more equitable access to evidence-based treatments.},
}

Humans
Retrospective Studies
*Memantine/therapeutic use
*Cholinesterase Inhibitors/therapeutic use
*Dementia/drug therapy
*Practice Patterns, Physicians'/statistics & numerical data
England
*Primary Health Care/statistics & numerical data
Female
Aged
Male
General Practice
Aged, 80 and over
Alzheimer Disease/drug therapy
Mixed Dementias
Lewy Body Disease/drug therapy
Drug Prescriptions/statistics & numerical data

@article {pmid42224636,
year = {2026},
author = {Trieu, C and Dicks, E and de Leeuw, D and de Wit, KDM and Van Leeuwenstijn, MSSA and Schlüter, LM and Boonkamp, L and Barkhof, F and Ten Kate, M and van de Giessen, E and Van Der Flier, WM and Van Harten, AC and Teunissen, CE},
title = {Longitudinal Change in Blood-Based Biomarkers and the Association With MRI-Measured Neurodegeneration in Cognitively Unimpaired Individuals.},
journal = {Neurology},
volume = {106},
number = {12},
pages = {e218119},
doi = {10.1212/WNL.0000000000218119},
pmid = {42224636},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Blood-based biomarkers are reliable indicators of Alzheimer disease (AD)-related pathology in cognitively normal individuals. However, it remains unclear how changes in these biomarkers relate to emerging brain atrophy. We aimed to investigate longitudinal associations between blood-based biomarkers and brain atrophy, and the temporal sequence of these processes.

METHODS: In the prospective observational Subjective Cognitive Impairment Cohort based in Amsterdam, individuals with subjective cognitive decline recruited from a memory clinic underwent repeated blood sampling (484 samples, follow-up 5 ± 3 years) and MRI scans (457 scans, follow-up 5 ± 3 years). We measured blood-based biomarkers (Aβ42/40 ratio [Aβ42/40], phosphorylated tau [pTau217], glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) using the SIMOA platform. AD-signature brain volumes (5 temporal, 4 parietal, and 2 frontal regions) were determined using the FreeSurfer pipeline. We used linear mixed models to examine associations between baseline or slope of biomarker and brain volume changes. In an exploratory analysis, extrapolated pTau217 trajectories were compared with hippocampal volume trajectories to estimate the temporal gap between these changes.

RESULTS: A total of 167 individuals were included (49 amyloid-positive and 118 amyloid-negative), with amyloid-positive individuals being older (age: 66 ± 8 years, 57.1% female) than amyloid-negative individuals (61 ± 8 years, 33.9% female). Baseline levels and longitudinal increases in GFAP showed associations with higher rates of atrophy across nearly all AD-signature regions (β range -0.02 to -0.00, 95% CI range -0.04 to -0.00, pFDR < 0.05). Baseline pTau217 was associated with atrophy across several medial temporal regions (β range -0.03 to -0.01, 95% CI range -0.04 to -0.00, pFDR < 0.05), whereas increases in pTau217 were only associated with atrophy primarily in temporal regions (β range -0.02 to -0.01, 95% CI range -0.02 to -0.00), although the latter associations were only trend-level after FDR correction (pFDR = 0.077). Baseline concentrations, but not increases in NfL, showed associations with temporal regions (β range -0.02 to -0.01, 95% CI range -0.04 to -0.00, pFDR < 0.05). By contrast, baseline Aβ42/40 showed only associations with hippocampal atrophy (0.01 [0.00-0.03]), but not after FDR correction. Using baseline and (extrapolated) trajectories over time, we estimated that changes in pTau217 preceded hippocampal atrophy by 19.8 (10.7-43.7) years.

DISCUSSION: Blood-based biomarkers capture distinct aspects of brain atrophy, with pTau217 primarily indicating atrophy in medial temporal regions and GFAP more widespread neurodegeneration. This supports the complementary use of both markers for early identification and monitoring in preventive trials and clinical care.},
}

@article {pmid42224827,
year = {2026},
author = {Lu, C and Wang, Y and Zhang, Z and Zhang, X},
title = {Integrated single-nucleus transcriptomics reveals stage-dependent neuronal and oligodendroglial remodeling in the Alzheimer's disease prefrontal cortex.},
journal = {Biochemical and biophysical research communications},
volume = {827},
number = {},
pages = {154047},
doi = {10.1016/j.bbrc.2026.154047},
pmid = {42224827},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD) progression is accompanied by cell-type-specific vulnerability in the human cortex, but how neuronal and glial subtypes are remodeled across pathological stages remains incompletely understood. Here, we integrated five publicly available single-nucleus RNA-seq datasets from the human prefrontal cortex, comprising 945,692 high-quality nuclei, to investigate transcriptional and compositional alterations associated with Braak pathological progression. Seven major cell types were identified across cohorts, including excitatory neurons, inhibitory neurons, astrocytes, oligodendrocytes, oligodendrocyte precursor cells, microglia, and vascular cells. Sample-level pseudobulk differential expression analysis revealed stage-dependent transcriptional remodeling, with prominent alterations in excitatory neurons, oligodendrocytes, and oligodendrocyte precursor cells at advanced pathological stages. Subtype-level compositional analysis further identified selective remodeling of excitatory neuronal and oligodendrocyte subtypes. Exc_0 showed a biphasic pattern across Braak stages, whereas Exc_1 decreased and Exc_4 increased at high pathological burden. In oligodendrocytes, Oligo_1 was enriched at high Braak stages. Functional enrichment analysis linked these key subtypes to synaptic organization, cell junction assembly, cytoplasmic translation, oxidative phosphorylation, and electron transport chain-related processes. These findings suggest that AD pathological progression in the prefrontal cortex involves coordinated neuronal and oligodendroglial remodeling associated with synaptic and metabolic dysfunction.},
}

@article {pmid42225170,
year = {2026},
author = {Kashtiban, BA and Rezazadeh, M and Gharesouran, J and Jafari, B and Ghafouri-Fard, S},
title = {Stress Granules and Tau Pathology in Alzheimer's Disease: A Scoping Review of Bidirectional Interactions, Liquid-Liquid Phase Separation, and Proteostatic Consequences.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111974},
doi = {10.1016/j.brainresbull.2026.111974},
pmid = {42225170},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Stress granules (SGs), dynamic ribonucleoprotein condensates formed under cellular stress have been implicated in several neurodegenerative disorders, but their role in AD pathogenesis remains incompletely understood.

METHODS: Following PRISMA-ScR guidelines, we systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library (through February 2026) for peer-reviewed studies investigating SGs in AD models or human tissue. Two reviewers independently screened records, extracted data, and performed narrative synthesis.

RESULTS: Thirty-five studies met inclusion criteria. TIA1 (51.4%) and G3BP1 (42.9%) were the most frequently used SG markers. Multi-model designs incorporating human tissue validation predominated (40.0%). Evidence suggests a bidirectional pathogenic interplay: tau pathology promotes SG assembly and persistence, while SG proteins, particularly TIA1 and USP10 can drive tau oligomerization and toxicity via liquid-liquid phase separation in experimental models. Additional SG network components, including HDAC6 and TRIM21, have been independently implicated in AD pathology, though they remain less explored in direct SG-tau interaction studies. Conversely, G3BP2 exerts protective effects by directly binding tau and inhibiting aggregation. SG dysregulation is associated with disrupted RNA metabolism, sequesteration of AD-associated transcripts, and impaired autophagy. Therapeutic strategies targeting SG modulation, including autophagy enhancers (mTOR inhibitors, myricetin), show promise in reducing tau pathology and SG burden in preclinical systems.

CONCLUSION: The reviewed evidence suggests that SGs are associated with AD pathogenic processes through bidirectional interactions with tau pathology, RNA dysregulation, and proteostatic collapse. These findings, derived largely from preclinical models, support further investigation into SG modulation as a potential therapeutic strategy for AD, while definitive causal roles in human disease remain to be established.},
}

@article {pmid42225501,
year = {2026},
author = {Rossi, M and Tartaglia, E and Askarinejad, A and Serio, L and Ferri, C and Bucci, T and Lip, GYH},
title = {Lipoprotein(a) and risk of dementia: A propensity score-matched real-world analysis from a global federated research network.},
journal = {European journal of internal medicine},
volume = {},
number = {},
pages = {106984},
doi = {10.1016/j.ejim.2026.106984},
pmid = {42225501},
issn = {1879-0828},
abstract = {BACKGROUND: The association between lipoprotein(a) [Lp(a)] and dementia remains controversial.

PURPOSE: To assess the relationship between Lp(a) and dementia in a global federated research network.

METHODS: A retrospective cohort study using data from the TriNetX network. Adults with at least one Lp(a) measurement from 2010 onward were categorized as having elevated (≥50 mg/dL) or normal (<50 mg/dL) Lp(a). Propensity score matching (1:1) balanced baseline characteristics. The primary outcome was incident all-cause dementia; secondary outcomes included Alzheimer's disease, vascular dementia, and frontotemporal dementia. Follow-up extended up to 10 years from the index Lp(a) measurement. Sensitivity analyses accounted for death as a competing event, a 30-day landmark analysis, and comparison across low, high, and very high Lp(a) levels. Subgroup analyses were performed by age, sex, and history of atherosclerotic cardiovascular disease or stroke.

RESULTS: Of 151,117 patients with available Lp(a) data, 54,929 had elevated Lp(a) (mean age 56.5 ± 15.9 years; 53.2% female), while 96,188 had normal Lp(a) (mean age 56.4 ± 16.5 years; 48.4% female). After matching, each cohort included 54,841 patients. Over a maximum follow-up of 10 years, elevated Lp(a) was not associated with an increased risk of all-cause dementia (HR 0.99, 95% CI 0.88-1.10), Alzheimer's disease (HR 1.04, 95% CI 0.85-1.27), vascular dementia (HR 1.05, 95% CI 0.86-1.27), or frontotemporal dementia (HR 0.94, 95% CI 0.48-1.83). Findings were consistent across sensitivity and subgroup analyses.

CONCLUSION: In this large real-world cohort, elevated Lp(a) levels were not significantly associated with an increased risk of incident dementia or its major subtypes.},
}

@article {pmid42225606,
year = {2026},
author = {Jang, H and Lee, S and Kim, Y and Lee, J and Kim, JC and Kim, JS and Park, JH and Kim, J and Son, Y and Moon, C},
title = {Behavioral characterization of olfactory, auditory, and motor deficits in 5×FAD mice.},
journal = {Journal of veterinary science},
volume = {27},
number = {3},
pages = {e35},
doi = {10.4142/jvs.26012},
pmid = {42225606},
issn = {1976-555X},
support = {RS-2022-NR069130/NRF/National Research Foundation of Korea/Korea ; RS-2022-NR070407/NRF/National Research Foundation of Korea/Korea ; RS-2023-00219517/NRF/National Research Foundation of Korea/Korea ; RS-2024-00398561/IPET/Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry/Korea ; },
abstract = {IMPORTANCE: The 5×FAD transgenic mouse model is widely used in Alzheimer's disease (AD) research, yet its non-cognitive phenotypes -- particularly motor coordination, olfactory sensitivity, and auditory reactivity -- remain poorly characterized across the full disease trajectory. Defining these sensory and sensorimotor deficits may enhance the translational relevance of this model and provide insight into non-cognitive features in preclinical AD studies.

OBJECTIVE: To characterize age-related motor, olfactory, and auditory changes in 5×FAD mice and assess associated AD pathologies and neuroinflammation in relevant brain regions.

METHODS: 5×FAD and control mice were tested at 3, 6, and 12 months. Locomotor activity and motor coordination were assessed using the open field and rotarod tests, respectively. Olfactory and auditory performance were evaluated using the buried food test and the acoustic startle response test, respectively. Amyloid-β pathology and glial activation were examined in relevant nervous system components using western blot and immunohistochemistry analyses.

RESULTS: 5×FAD mice showed no differences in open-field locomotion at any age, but exhibited a significantly greater passive clinging duration at 12 months compared to wild-type controls (p < 0.001). In the buried food test, olfactory latency was significantly prolonged in 5×FAD mice at 6 months (p = 0.035) and 12 months (p < 0.001). Acoustic startle amplitude was significantly reduced at 6 months (p = 0.030) and 12 months (p = 0.007). Amyloid-β and p-Tau accumulation and glial activation were elevated in the olfactory bulb and auditory cortex in an age-dependent manner.

CONCLUSIONS AND RELEVANCE: This study provides an age-related behavioral and pathological characterization of olfactory and auditory impairments in the 5×FAD mouse model, with motor measures included as complementary assessments. Our findings broaden the spectrum of functional deficits associated with the AD pathology in this model.},
}

@article {pmid42225719,
year = {2026},
author = {Llabrés-Mas, AM and López-Sánchez, N and Garrido-García, A and Cano-Daganzo, V and Camacho-Olmos, I and Frade, JM},
title = {Resistance of E2F4DN to p38[MAPK] phosphorylation reduces genotoxic cell death in N2a neuron-like cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54592-z},
pmid = {42225719},
issn = {2045-2322},
abstract = {E2F4 is a transcription factor involved in cellular homeostasis and a substrate of the stress-activated kinase p38[MAPK], which phosphorylates a conserved Thr248/Thr250 motif. A non-phosphorylatable mutant, E2F4DN (Thr248Ala/Thr250Ala), has demonstrated preclinical efficacy in a murine model of Alzheimer's disease (AD), but its mechanism of action remains unknown. We hypothesized that cell stress-induced phosphorylation disrupts E2F4's homeostatic function, whereas exogenous E2F4DN restores it. To begin testing this hypothesis, we treated differentiated N2a neuroblastoma cells (N2a neuron-like cells) with camptothecin (CPT) to induce genotoxic stress. CPT activated p38[MAPK] within 8 h, leading to phosphorylation of E2F4 at Thr248/Thr250. We then overexpressed E2F4DN or a phosphomimetic variant, E2F4CA (Thr248Glu/Thr250Glu), and assessed apoptosis via procaspase-3 cleavage. The pro-apoptotic factor E2F1 strongly induced caspase-3 activation in this model system. This effect was partially mimicked by E2F4CA, while E2F4DN markedly suppressed it. Notably, E2F4DN, but not E2F4CA, upregulated the antiapoptotic factor Cited2, and knockdown experiments suggest it may contribute to E2F4DN's protective effect. Overall, these findings indicate that E2F4DN counteracts p38[MAPK]-driven neuronal apoptosis and helps preserve neuronal homeostasis, at least in part, through Cited2 upregulation. This provides mechanistic insight into the neuroprotective role of E2F4DN as a potential therapy for AD.},
}

@article {pmid42225737,
year = {2026},
author = {Yadav, SK and Srivastava, R and Yadawa, AK and Gamiotea-Turro, D and Verma, R},
title = {Effect of acute ischemic stroke in 3xTg-AD mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54645-3},
pmid = {42225737},
issn = {2045-2322},
support = {1R01NS125405/NS/NINDS NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) and acute ischemic stroke (AIS) are major cerebral pathologies that impose significant social and economic burdens. The high prevalence of multimorbidity in older adults is often attributed to shared risk factors like hypertension, smoking, and diabetes. AIS, through vascular complications and acute inflammation, may accelerate AD pathology and cognitive decline. However, the extent to which AIS exacerbates AD-related neurodegeneration remains unclear. To investigate this interaction, we used the 3xTg-AD mouse model, which exhibits both amyloid-beta (Aβ) and Tau pathologies, to assess the impact of AIS on AD progression. Eight-month-old control B6129SF2/J and 3xTg-AD mice underwent a 45-min transient middle cerebral artery occlusion (MCAo) followed by reperfusion at different time points to induce ischemic stroke. Mice were sacrificed at 3- and 50-days post-stroke, and brain tissues were analyzed via western blot and immunohistochemistry to evaluate protein changes. Additionally, we assessed long-term functional impairments in these mice. Our findings show that 3xTg-AD mice had higher infarct volumes, Aβ accumulation, and amyloid-beta precursor protein (AβPP) levels while the total Tau levels were reduced as compared with wild-type (WT) control B6129SF2/J mice after AIS. Functionally, 3xTg-AD mice showed more severe impairments in spatial memory and locomotion tasks post-stroke. Overall, our study demonstrates that AIS worsens AD pathology in 3xTg-AD mice, leading to greater neurodegeneration, functional decline, and increased mortality. These findings highlight the detrimental impact of cerebrovascular events on AD progression, emphasizing the need for targeted interventions in stroke-affected AD patients.},
}

@article {pmid42225834,
year = {2026},
author = {Li, Q and Guo, Z and Li, Y and Zhang, M and Yao, Y and Wang, X and Zhao, L and Cai, Y},
title = {Ammonium sulfate provides an efficient method for isolating small extracellular vesicles from human biofluids.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55129-0},
pmid = {42225834},
issn = {2045-2322},
support = {2021YFC2501205//National Key Research and Development Program of China/ ; },
abstract = {Small extracellular vesicles (EVs) are nanosized vesicles (< 200 nm) secreted from various tissues, including the central nervous system (CNS), into diverse biofluids. Due to their ability to carry molecular cargo that reflects the physiological state of their parental cells, small EVs represent promising diagnostic carriers for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). While biofluid-derived small EVs offer a "liquid biopsy" solution, their clinical translation is severely hindered by the limitations of conventional isolation methods, which are often time-consuming, costly, or yield low purity. Building upon the "ExoPRISM" (Exosome Precipitation by Ionic Strength Modulation) framework, we developed and validated an optimized, cost-effective ammonium sulfate (AS)-based pipeline for small EVs isolation. We have refined and established the optimal AS ratio specifically for plasma and further demonstrated its feasibility for isolating small EVs from saliva. Subsequently, we introduced a targeted purification step using glutamate aspartate transporter (GLAST) antibodies to specifically isolate central nervous system (CNS)-derived EVs. This step robustly demonstrated that our AS-based approach preserves small EVs integrity and enables the effective isolation of Astrocyte-Derived Extracellular Vesicles (ADEVs) for downstream applications. Finally, the practical utility of this optimized protocol was validated in a clinical cohort. Our findings highlight the robustness, high efficiency, and significant translational potential of this AS-based method for the early and accurate diagnosis of neurodegenerative diseases. We optimized the AS concentration for small EVs precipitation, ultimately identifying 2.66 M as the optimal working concentration. This method demonstrated remarkable time efficiency, completing the entire isolation process in approximately 90 min. Furthermore, it only requires centrifugation at 12,000 xg, significantly enhancing its practicality in clinical diagnostic scenarios. To expand its potential application scope, we also tested the method's efficacy on other bodily fluids and found that the concentration of 2.66 M was equally effective in isolating small EVs from saliva. Comparative analyzes against the commercially available ExoQuick kit demonstrated that our AS-based precipitation method achieved comparable efficacy in isolating small EVs from the plasma of AD patients and in purifying ADEVs. Furthermore, comprehensive validation using nanoparticle tracking analysis (NTA), electron microscopy, and detection of canonical small EVs markers (CD63, CD9) confirmed the functional equivalence of the two isolation methods. The cumulative evidence from this study firmly establishes the AS-based small EVs isolation protocol as a viable and robust efficacy comparable to commercially available kits. This method confers three distinct advantages: enhanced temporal efficiency, reduced cost burden, and minimal interference with downstream assays, rendering it highly amenable to clinical implementation. Notably, it enables the effective isolation of small EVs from plasma, a conventional biofluid widely utilized in clinical diagnostics, as well as from saliva. These attributes underscore the method's potential in advancing the early detection of neurodegenerative disorders. Looking ahead, the versatility of this approach suggests its applicability across a diverse array of biological specimens, thereby facilitating the expansion of small EVs-based diagnostic research and clinical practice.},
}

@article {pmid42226198,
year = {2026},
author = {Lee, HJ and Hoe, HS},
title = {The CDK4/6 inhibitor abemaciclib attenuates cognitive impairment and neuroinflammation via DYRK1A in human tau transgenic mice.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01318-x},
pmid = {42226198},
issn = {1756-6606},
support = {RS-2024-00357857//National Research Foundation of Korea/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2024-00343370//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)/ ; H0501-25-1001//NIPA (National IT Industry Promotion Agency) to support digital medical devices for AI-based Neurodevelopmental disorders/ ; RS-2026-25492172//NRF/ ; },
abstract = {We recently demonstrated that abemaciclib treatment modulates cognitive function, Alzheimer's disease (AD) pathology, and neuroinflammatory responses in wild-type mice treated with lipopolysaccharide and in 5xFAD mice. In this study, we investigated the influence of abemaciclib treatment on neuroinflammation and cognitive function in 6- or 9-month-old PS19 mice, a P301S mutant tauopathy model. We found that abemaciclib administration suppressed microglial activation in 6-month-old PS19 mice, whereas astrocytic activation was partially attenuated in the entorhinal cortex but not in the hippocampus. In addition, abemaciclib treatment improved short-term and recognition memory and the dendritic spine formation in 6- and 9-month-old PS19 mice. More importantly, abemaciclib administration enhanced short-term and recognition memory in a DYRK1A-dependent manner in 6-month-old PS19 mice. Collectively, our results suggest that abemaciclib treatment alleviates neuroinflammatory responses and cognitive impairment through DYRK1A in 6- or 9-month-old human tau transgenic PS19 mice, highlighting how this multi-kinase-targeting drug could be leveraged for the treatment of neurodegenerative diseases.},
}

@article {pmid42226232,
year = {2026},
author = {Liu, Z and Tang, L and Sun, Z and Liu, Z and Lyu, Y and Ruan, W and Xu, Y and Shan, L and Shin, J and Chen, X and Zhu, D and Liu, T and Liu, R and Huang, C},
title = {AD-GPT: large language models in Alzheimer's disease.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03579-x},
pmid = {42226232},
issn = {1472-6947},
abstract = {BACKGROUND: Alzheimer's disease (AD) research produces extensive genomic and clinical data, yet general large language models (LLMs) often generate inaccurate or superficial outputs. We introduce AD-GPT, a domain-specific framework for reliable information retrieval and synthesis of AD-related knowledge.

METHODS: We integrated curated genomic resources, including cis-eQTL and sQTL data across 13 brain regions from GTEx, genomic location information from NCBI, and gene function annotations from OMIM, together with approximately 150,000 AD-related publications from NCBI's PubMed. AD-GPT adopts a retrieval-augmented generation (RAG) workflow with task-specific database partitioning, a BERT-based query router, and fine-tuned Llama models, augmented with router and context verifiers to validate task assignment and evidence relevance, supporting three tasks: genetic information retrieval, association study reasoning, and general AD-related knowledge synthesis.

RESULTS: AD-GPT consistently outperformed strong baseline LLMs in evidence-grounded evaluation metrics across all tasks, including factual consistency, citation validity, and instruction-level faithfulness. Task-specific retrieval and stacked routing improved evidence grounding and substantially reduced hallucination in complex AD-related queries.

CONCLUSION: AD-GPT harmonizes curated genomic databases with biomedical literature, offering a scalable and accurate informatics tool to advance AD research.},
}

@article {pmid42226490,
year = {2026},
author = {Lin, J and Yu, G},
title = {[Progress in prognostic assessment methods for mild cognitive impairment].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-16},
doi = {10.3724/zdxbyxb-2025-0669},
pmid = {42226490},
issn = {1008-9292},
abstract = {Mild cognitive impairment (MCI), a key prodromal stage of dementia, requires precise prognostic assessment to delay disease progression. Given the high heterogeneity of MCI, any single indicator has limited predictive efficacy. Different clinical subtypes of MCI, such as amnestic MCI, non-amnestic MCI, and subjective cognitive decline, exhibit fundamental differences in pathological mechanisms and outcomes, forming the basis for stratified prognostic assessment. Abnormal sleep duration, physical functional decline, and psychiatric symptoms (depression, anxiety, apathy) are indicative of cognitive decline risk to varying degrees and can serve as clinical observational indicators for evaluating MCI prognosis. Neuropsychological assessment scales and instrumental activities of daily living assessments can characterize the features of cognitive impairment, but their results are susceptible to educational and cultural influences. Core cerebrospinal fluid (CSF) biomarkers, including amyloid β-protein (Aβ) 42, phosphorylated Tau protein (P-tau)181, and total tau protein (T-tau), are highly correlated with the core pathology of Alzheimer's disease and can accurately predict MCI prognosis. Plasma biomarkers such as P-tau217, neurofilament light chain, glial fibrillary acidic protein (GFAP), and the Aβ42/Aβ40 ratio are suitable for screening and follow-up; combining CSF and plasma biomarkers enhances predictive performance. In contrast, Serum markers like Klotho and insulin-like growth factor-1 lack specificity, and their independent predictive value requires further validation. Multimodal neuroimaging, including structural magnetic resonance imaging (MRI), functional MRI (revealing neural network compensation and decompensation), and positron emission tomography (PET) showing molecular pathological changes (Aβ deposition, Tau aggregation), can form a complete chain of evidence linking molecular events to clinical phenotypes. Intelligent prediction models, ranging from basic risk stratification and static integrated models to longitudinal dynamic prediction, significantly improve the fusion predictive performance of multimodal data. Consequently, the prognostic assessment of MCI is moving away from a single modality toward a stepwise integrated approach: primary screening adopts the combination of "clinical information (including MCI subtype characteristics)+core neuropsychological assessment (focusing on delayed recall and executive function subtests of the Montreal Cognitive Assessment)+blood biomarkers (plasma P-tau217 and GFAP testing)"; the precise diagnostic phase adds structural MRI to assess hippocampal atrophy; for difficult cases and research settings, CSF testing, Aβ-PET, and Tau-PET are further introduced. Future research should focus on constructing dynamic monitoring frameworks and deepening mechanistic exploration of modifiable risk factors, thereby advancing individualized prognostic management and early intervention strategies for MCI.},
}

@article {pmid42226517,
year = {2026},
author = {Kim, JY and Kim, D and Kim, GH and Yoon, HJ},
title = {Effects of apolipoprotein E ε4 on amyloid deposition and relative cerebral perfusion in cognitively normal individuals: a dual-phase 18F-florbetaben PET study.},
journal = {Nuclear medicine communications},
volume = {},
number = {},
pages = {},
doi = {10.1097/MNM.0000000000002186},
pmid = {42226517},
issn = {1473-5628},
support = {RS-2025-02214254//Korea Health Technology/ ; },
abstract = {OBJECTIVES: Apolipoprotein E (APOE) genotypes, amyloid burden, and relative cerebral perfusion surrogate provide crucial insights into Alzheimer's disease pathophysiology. This study aimed to investigate the effects of APOE ε4 on relative perfusion and amyloid deposition in cognitively normal individuals using dual-phase 18F-florbetaben PET.

METHODS: Cognitively normal subjects who underwent dual-phase 18F-FBB PET and APOE genotyping were included. Participants carrying at least one ε4 allele were classified as carriers. Standardized uptake value ratios (SUVRs) were analyzed for relative perfusion and amyloid deposition using early phase 18F-florbetaben (eFBB) and delayed-phase FBB (dFBB), respectively, in the composite region, including the frontal, parietal, temporal, and occipital cortices, as well as the precuneus, cingulate, and striatum. Target subregions comprised the frontal, parietal, temporal, and occipital cortices along with the precuneus. Correlations between eFBB and dFBB SUVRs were also examined.

RESULTS: APOE ε4 carriers exhibited significantly higher relative perfusion in the composite region (P = 0.0042), frontal cortex (P = 0.0054), and parietal cortex (P = 0.0056). Increased amyloid burden was observed in the composite region (P = 0.0065), frontal cortex (P = 0.0028) and precuneus (P = 0.0071). Moreover, eFBB and dFBB SUVRs were significantly positively correlated in the temporal cortex (P = 0.0007) and precuneus (P = 0.0080).

CONCLUSION: APOE ε4 may be associated with distinct patterns of increased amyloid deposition and relative perfusion in specific brain regions in cognitively normal individuals. Dual-phase 18F-FBB PET may provide complementary information on Alzheimer's disease-related changes in APOE ε4 carriers during the preclinical stage.},
}

@article {pmid42226867,
year = {2026},
author = {Navarra, AN and Ikramuddin, S and Greenberg, SM and Doraiswamy, PM},
title = {Utility of the Medical Knowledge AI Copilot, OpenEvidence: A Patient With 100 Cerebral Microhemorrhages.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e108098},
pmid = {42226867},
issn = {2168-8184},
abstract = {Cerebral amyloid angiopathy (CAA) is a highly prevalent condition that often poses diagnostic and therapeutic challenges, especially in people with comorbid mild cognitive impairment (MCI). OpenEvidence (OE; Miami, Florida, US), a leading free medical knowledge copilot, reports it has supported over 100 million Artificial Intelligence (AI)-powered clinical consultations from U.S. doctors and other frontline clinicians. The objective of this study is to use a single case with two common comorbid neurological conditions to retrospectively appraise the ability of OE to serve as a clinically relevant knowledge aid. We input the de-identified summary of a case of probable CAA and MCI in OE. Overall, the AI recommendations very closely matched the diagnosis and care that was actually provided. We identified some areas (e.g., prognostication, geriatric risk-benefit trade-offs, diagnostic terminology) where it could be improved to match the logic and knowledge of a subspecialist. OE used as a knowledge copilot can help inform point-of-care physician decisions by giving them more information than they may have otherwise considered.},
}

@article {pmid42227044,
year = {2026},
author = {Singh, VK and Gupta, P and Jain, SK and Matreja, PS},
title = {The gut-brain axis in Alzheimer's and Parkinson's diseases: a systematic review of microbiota-derived biomarkers and novel therapeutic approaches.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/13803395.2026.2673084},
pmid = {42227044},
issn = {1744-411X},
abstract = {BACKGROUND: The altered gut microbiota substantially impacts the onset and progression of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most widely studied neurodegenerative conditions. Microbiome-derived metabolites have been increasingly associated with disease onset, progression, and therapeutic targets in neurodegenerative disorders. Exploring the diagnostic and therapeutic implications of gut microbiome-derived biomarkers is critical to advancing our understanding and management of neurodegeneration.

METHODOLOGY: We systematically reviewed both clinical and preclinical studies published from 2010 to 2025. Studies examining gut microbiota composition, microbial-derived metabolites, or therapeutic interventions targeting the gut microbiome were included. Identification of gut microbiome alterations, discovery of microbial or metabolite-based biomarkers, association with disease onset or progression, and/or therapeutic effects on cognitive, neurological, or inflammatory outcomes were evaluated.

RESULT: Short-chain fatty acids(SCFAs) such as butyrate and acetate were found to be noninvasive biomarkers in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD). Lower SCFA levels correlated with cognitive decline. Diagnostic accuracy improved when SCFA combinations were used, with AUCs ranging from 0.75 to 0.87. Trimethylamine N-oxide(TMAO) levels showed inconsistent associations, with both elevated and reduced levels linked to disease risk. Therapeutic approaches targeting gut microbiota, including probiotics, prebiotics, dietary changes, and fecal microbiota transplantation, demonstrated cognitive benefits and modulation of gut-brain signaling pathways.

CONCLUSION: Overall, gut-derived biomarkers offer a promising avenue for early diagnosis and novel therapeutic approaches in AD and PD, while acknowledging that evidence in other neurodegenerative diseases remains limited through modulation of the gut-brain axis.},
}

@article {pmid42227120,
year = {2026},
author = {Gillet, JN},
title = {Overinvestment in ultra‑rare APOE variants and highly speculative apoE-inhibitor docking risks undermining translational progress in sporadic Alzheimer's disease.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/07391102.2026.2671163},
pmid = {42227120},
issn = {1538-0254},
abstract = {Misclassification of ultra-rare and isoform-defining APOE variants, together with unsupported attempts to dock small-molecule 'inhibitors' to apolipoprotein E (apoE), continues to appear in the structural bioinformatics literature. Such inconsistencies stem from a broader misunderstanding of apoE as a highly flexible, two-domain protein with extensive intrinsically disordered regions (IDRs), a context essential for interpreting sequence variation. A recurring issue is the treatment of the pathogenic ε4 and protective ε2 substitutions as independent rare variants rather than as the canonical APOE isoform-defining polymorphism, a misinterpretation arising, for instance, from inconsistent minor-allele-frequency filtering and leading to overinterpretation of ultra-rare substitutions lacking established clinical relevance. Likewise, no experimental evidence supports stable interactions between apoE and small 'inhibitors' such as donepezil or other acetylcholinesterase drugs that provide only symptomatic benefit in Alzheimer's disease (AD). Docking such small ligands to apoE-frequently using incompatible homology models and outdated molecular-dynamics force fields ill-suited for proteins with large IDRs (e.g. AMBERff03)-tends to generate simulation-artifact cavities and non-biological ligand poses; compounding this, ligand protonation is frequently misassigned, such as the neutral state often attributed to donepezil, leading to meaningless structure-activity relationships. Collectively, these issues risk obscuring the well-established genetic architecture of APOE-associated AD and highlight the need for methodological rigor in in-silico structural modeling.},
}

@article {pmid42227129,
year = {2026},
author = {Andreev, AI and Neganova, ME and Aleksandrova, YR and Salikhova, DI and Belousova, EV and Shedenkova, MO and Sudina, AK and Maksimov, YM and Orlova, EA and Lapshina, MA and Popov, VS and Ahremenko, EA and Goldshtein, DV and Ustyugov, AA and Nebogatikov, VO},
title = {[Glial Progenitor Cell Therapy Improves Mitochondrial Function in the Hippocampus of 5xFAD Mice, but Does Not Restore the Multiscale Structure of Behavioral Stress Response].},
journal = {Molekuliarnaia biologiia},
volume = {60},
number = {2},
pages = {328-344},
doi = {10.7868/S3034555326020096},
pmid = {42227129},
issn = {0026-8984},
abstract = {Cell therapy is increasingly used to treat a variety of medical conditions, including cancer, immune system disorders, and neurodegeneration. Stem cells secrete growth factors, signaling molecules, and extracellular vesicles, that can be used to treat neurological diseases and promote neuronal regeneration. Transgenic 5xFAD mice, which are a model for Alzheimer's disease (AD), were used in this study. The mice were 7 months old and received retro-orbital injections of glial progenitor cells (GPCs) once a week for 4 months. At 11 months, their behavior was analyzed using a multichannel actigraphy system. Brain tissues from the cortex, hippocampus, and midbrain were collected for postmortem analysis of mitochondrial respiratory chain enzyme activity. The results showed that the GPCs injection significantly improved the response of the hippocampal p2 mitochondrial fraction in 5xFAD mice to succinate, reaching a level observed in control animals. A similar trend was also observed for the cytochrome c oxidase complex. The oxygen consumption rate of mitochondria did not differ from that of clinically healthy mice after ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride administration. A similar decrease in the efficiency of the electron transport chain was detected in the midbrain of 5xFAD mice, but no recovery was observed after GPCs treatment. Behavioral differences between non-transgenic and transgenic groups were observed in a multiparameter analysis using the actigraphy system. The behavior of transgenic mice in the treated and untreated groups was similar, while the behavior of non-transgenic mice varied. Additional analysis of locomotor activity and transient events in particular revealed that the activity of the GPCs-treated 5xFAD mice was differed fundamentally compared to other groups. Specifically, GPCs-treated mice exhibited greater number of transitions between intermediate activity states. In contrast, untreated mice showed transitions between extreme activity states, such as from low to high activity or vice versa. These findings suggest that changes in behavior and activity of the AD mice may be associated not only with hippocampal dysfunction, but also with disruptions in midbrain structures.},
}

@article {pmid42227145,
year = {2026},
author = {Kumar, V and Kashif, M and Singh, V and Rawat, RS and Khan, A and Sarkar, GC and Majood, M},
title = {Therapeutic targeting of DNA repair pathway dysregulation in aging, cancer, and neurodegeneration.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2683686},
pmid = {42227145},
issn = {1744-7631},
abstract = {INTRODUCTION: Genome maintenance is increasingly recognized as a shared vulnerability across aging, cancer, and neurodegeneration, yet the therapeutic implications of pathway-specific dysregulation of DNA repair remain incompletely defined.

AREAS COVERED: This review integrates recent mechanistic and translational literature on how base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, canonical non-homologous end joining, and alternative end joining are remodeled across these conditions. We discuss how oxidative stress, replication stress, telomere dysfunction, mitochondrial injury, and persistent DNA damage response signaling drive senescence and inflammation; how tumor cells exploit repair rewiring to survive genotoxic stress and acquire resistance; and how post-mitotic neurons are limited by restricted repair redundancy. We also summarize biomarkers for repair-state stratification and emerging strategies targeting PARP, ATR, ATM, DNA-PK, POLQ, and cGAS-STING.

EXPERT OPINION: Clinical translation will depend less on single-gene alterations than on defining context-specific repair states and pathway dependencies. Such stratification should enable rational combinations that either restore repair fidelity in aging and neurodegeneration or exploit repair addiction in cancer.},
}

@article {pmid42227173,
year = {2026},
author = {Zhao, Y and Liu, C and Yv, K and Wang, N and Li, Z},
title = {Integrative genomic and transcriptomic analysis identifies microglia-expressed genes with causal links to Alzheimer's disease risk.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452242},
doi = {10.1177/13872877261452242},
pmid = {42227173},
issn = {1875-8908},
abstract = {BackgroundMicroglia play a central role in Alzheimer's disease (AD) pathogenesis, yet it remains unclear whether microglia-related gene expression changes contribute causally to disease risk or reflect downstream responses to neurodegeneration.ObjectiveThis study aimed to systematically identify microglia-expressed genes with genetically regulated expression associated with AD risk and to characterize their functional relevance through integrative genomic analyses.MethodsWe compiled 2454 microglia-associated genes from four transcriptomic studies and five expression databases. Using brain cis-eQTL data from PsychENCODE (n = 1387), we performed summary-data-based Mendelian randomization (SMR) and HEIDI tests with AD GWAS data (111,326 cases, 677,663 controls). Significant SMR signals (FDR < 0.05) were evaluated using Bayesian colocalization. Regulatory context was assessed via overlap with PU.1-associated chromatin features, and differential expression was examined using single-nucleus RNA-seq from AD brains.ResultsSMR identified 16 genes whose genetically predicted expression was associated with AD risk (FDR < 0.05), including TSPAN14 (OR = 1.10, 95% CI: 1.07-1.13) and GRN (OR = 0.90, 0.86-0.95). Colocalization supported shared causal variants at eight loci (PPH4 > 0.8; e.g., BLNK, SIGLEC11, CASS4). Most prioritized genes overlapped with PU.1-associated regulatory regions. Single-nucleus RNA-seq confirmed dysregulation of several candidates (e.g., USP6NL, MS4A4A) in AD microglia.ConclusionsWe identify microglia-expressed genes with genetic evidence consistent with a potential causal role in AD. These genes are enriched in microglia-specific regulatory elements and exhibit transcriptional alterations in AD, highlighting microglial pathways as potential therapeutic targets.},
}

@article {pmid42227174,
year = {2026},
author = {Sainz-Pardo, M and Hernández, M and Suades, A and Juncadella, M and Ortiz-Gil, J and Ugas, L and Sala, I and Lleó, A and Calabria, M},
title = {Naming performance in bilinguals with Alzheimer's disease and mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452694},
doi = {10.1177/13872877261452694},
pmid = {42227174},
issn = {1875-8908},
abstract = {BackgroundThere is consistent evidence of a disadvantage in bilinguals' speech production compared to monolinguals in healthy individuals, but studies investigating this phenomenon in clinical populations such as mild cognitive impairment (MCI) and Alzheimer's disease (AD) are scarce. Given that both clinical groups are characterized by word-finding difficulties, understanding how bilingualism influences speech production in these populations is essential.ObjectiveTo investigate the effect of bilingualism on dominant-language speech production in individuals with MCI and AD relative to cognitively unimpaired (CU) older adults.MethodsEarly and highly proficient Catalan-Spanish bilinguals (active bilinguals) were compared to Spanish-dominant speakers with low proficiency in Catalan (passive bilinguals) using a picture-naming task. The study included 58 CU older adults, 66 patients with AD, and 124 individuals with MCI. Reaction times, accuracy, and error types were collected in the naming task in each individual's dominant language.ResultsFirst, we observed an advantage for active bilinguals compared to passive bilinguals, as indexed by faster responses, particularly for cognate words. Second, active bilinguals with MCI exhibited a disadvantage, making more naming errors than passive bilinguals with MCI, especially for non-cognates, including a higher incidence of cross-language intrusions and anomia. Third, passive bilinguals with MCI and AD showed more semantic errors than active bilinguals.ConclusionsDisadvantages in naming are discussed in terms of predictions from cognitive and linguistic theories, whereas potential advantages of speaking a second language are considered as a protective factor, consistent with frameworks such as cognitive reserve.},
}

@article {pmid42227185,
year = {2026},
author = {Li, J and Lian, T and Guo, P and Li, J and Qi, J and Luo, D and Meng, Y and He, M and Zheng, Z and Yue, H and Liu, Z and Zhang, F and Wang, R and Zhang, W and Zhang, W},
title = {Gut-brain axis crosstalk in patients with Alzheimer's disease and high body mass index: Gut dysbiosis, blood-brain barrier disruption, and neuroinflammation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441465},
doi = {10.1177/13872877261441465},
pmid = {42227185},
issn = {1875-8908},
abstract = {BackgroundAccumulating evidence indicates that body mass index (BMI) is related to Alzheimer's disease (AD).ObjectiveThis study aimed to investigate the impact of high BMI on cognitive function in AD patients and potential mechanisms involving gut dysbiosis, blood-brain barrier (BBB) disruption, and neuroinflammation in brain.MethodsA total of 50 AD patients were recruited and divided into AD with normal BMI (AD-nBMI) and AD with high BMI (AD-hBMI) groups. Cognitive function was assessed, the levels of BBB variables, neuroinflammatory factors, and AD biomarkers in cerebrospinal fluid (CSF) were measured, gut microbiota and metabolites were analyzed using 16S ribosomal ribonucleic acid gene sequencing and gas chromatography-mass spectrometry analysis, and the correlations among gut microbiota and metabolites, BBB variables, and neuroinflammatory factors in CSF were analyzed.ResultsAD-hBMI group exhibited impaired overall cognition, elevated CSF levels of zonula occludens-1 (ZO-1) and occludin (OCLN) (BBB disruption), and increased CSF levels of nitric oxide (NO) and hydroxyl radical (·OH) (neuroinflammation) compared with AD-nBMI group. Correlation analyses revealed that BMI was positively associated with impaired cognition, CSF levels of OCLN and NO in AD patients. AD-hBMI group displayed a unique gut dysbiosis pattern characterized by the alterations in specific metabolite levels. In AD-hBMI group, elevated thioridazine, 4-hydroxybenzaldehyde, and N-acetylleucine were positively correlated with ZO-1 level in CSF, reduced acesulfame and undecanoic acid were negatively correlated with OCLN level in CSF, and elevated (S)-S-methylcysteine sulfoxide was positiveiy correlated with both ZO-1 and OCLN levels in CSF. Elevated thioridazine and medroxyprogesterone were positively correlated with NO level in CSF, and decreased butyric acid was negatively correlated with ·OH level in CSF.ConclusionsHigh BMI may accelerate gut dysbiosis, leading to disrupted BBB, enhanced neuroinflammation, and ultimately accelerated cognitive impairment in AD patients.},
}

@article {pmid42227192,
year = {2026},
author = {Diane Zheng, D and Curiel Cid, RE and Ortega, A and Crenshaw, KH and Crocco, EA and Vaillancourt, D and Armstrong, MJ and Wang, WE and Asken, B and Adjouadi, M and Marsiske, M and Rosselli, M and Barker, WW and Smith, G and Dekosky, ST and Duara, R and Loewenstein, DA},
title = {Combining plasma biomarkers and cognitive challenge tests enhances prediction of functional trajectories of decline among older adults with cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453396},
doi = {10.1177/13872877261453396},
pmid = {42227192},
issn = {1875-8908},
abstract = {BackgroundPlasma biomarkers have emerged as promising, less invasive indicators of Alzheimer's disease (AD) pathology. However, biomarkers alone cannot indicate whether actual clinical symptoms are present or progressing. Plasma biomarkers when paired with specific cognitive deficits on brief novel Cognitive Challenge Tests (CCTs), provide excellent sensitivities to underlying AD pathology in preclinical and prodromal stage. There is a lack of data on the extent to which plasma biomarkers and CCTs independently and jointly, predict longitudinal functional decline in the earliest stages of cognitive impairment.ObjectiveTo evaluate whether plasma biomarkers and CCTs independently and in combination predict baseline and longitudinal changes on the Clinical Dementia Rating scale Sum of Boxes (CDR-SOB) among older adults with cognitive impairment without dementia.MethodsOlder adults aged 54 to 98 years diagnosed with cognitive impairment without dementia (n = 159) at baseline were followed annually for a minimum of 3 visits, mean follow-up was 41.5 months (SD 11.9). CDR-SOB trajectory was estimated using latent growth curve modeling. The associations between plasma biomarkers (p-tau217, GFAP, and NfL) and CCTs with baseline levels and longitudinal change in CDR-SOB were evaluated.ResultsAfter adjusting for age, sex, education, Hispanic ethnicity, APOE ɛ4, and amyloid positivity, p-tau217 (β=0.70, SE = 0.23, p < 0.01), and NfL (β=0.03, SE = 0.008, p < 0.001) predicted baseline and longitudinal changes in CDR-SOB, respectively. Deficits in CCTs (β=-0.11, SE = 0.03, p < 0.001) contributed independently to predicting the rate of change on CDR-SOB.ConclusionsIntegrating plasma biomarkers with sensitive CCTs enhances diagnostic accuracy, monitoring, and prognosis during pre-dementia stages.},
}

@article {pmid42227197,
year = {2026},
author = {Chen, Y and Huang, H and He, Y and Chen, S and Tan, Y and Song, J and Chen, L and Wang, X and Lü, Y and Yu, W},
title = {Speech-based machine learning for detecting neuropsychiatric symptoms in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456293},
doi = {10.1177/13872877261456293},
pmid = {42227197},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD) and mild cognitive impairment (MCI), yet their detection relies on subjective assessments. Speech features offer a promising objective biomarker for NPS, reflecting emotional and cognitive states. However, existing studies are limited in terms of scale and duration.ObjectiveThis study aims to characterize acoustic features associated with NPS in early cognitive decline using Automated Assessment Model-Mini-Mental State Examination framework, and to evaluate machine learning classifiers for identifying indicators of NPS.MethodsSpeech data from 647 clinically diagnosed AD or MCI patients were collected and split into training and test sets in a 6:4 ratio. The training set was used for feature selection and model development, while test set was used for performance evaluation. The Synthetic Minority Over-Sampling Technique was applied to address class imbalance. Twelve machine learning models were trained to classify NPS categories. The best-performing models were evaluated, and SHapley Additive exPlanations (SHAP) were used to analyze feature importance.ResultsThe ExtraTrees model outperformed the others in identifying patterns associated with NPS categories, with cross-validated AUCs ranging from 0.869 to 0.901. SHAP revealed spectral_entropy_std and kurtosis_energy as key features across multiple NPS categories.ConclusionsThis study demonstrates that short speech samples obtained during the MMSE can identify acoustic patterns associated with NPS in clinically diagnosed AD and MCI using machine learning. Given the single-center design and absence of external validation, model outputs should be interpreted as directional signals to raise clinical awareness rather than as definitive diagnostic determinations.},
}

@article {pmid42227394,
year = {2026},
author = {Grasso, M and Fidilio, A and Varrasi, S and Chiechio, S},
title = {GLP-1 Receptor Agonists in Neuropathic Pain and Neurodegenerative Diseases: Mechanisms, Therapeutic Potentials, and Future Perspectives.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X450007260305034049},
pmid = {42227394},
issn = {1875-6190},
abstract = {Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), originally developed for type 2 diabetes mellitus, have demonstrated significant neuroprotective and analgesic properties in preclinical and early clinical studies. This review examines the role of GLP-1RAs and their therapeutic potential in neuropathic pain and neurodegenerative diseases, which share several overlapping pathophysiological mechanisms. These include chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired insulin signaling, and altered synaptic plasticity. In neuropathic pain, GLP-1RAs attenuate neuroinflammation and reduce central sensitization. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, they promote neuronal survival, restore metabolic homeostasis, and counteract protein aggregation and autophagic dysfunction. The convergence of these mechanisms supports the exploration of GLP-1RAs as a unified therapeutic approach across neuroinflammatory and neurodegenerative fields. GLP-1RAs exert multifaceted neuroprotective, anti-inflammatory, and autophagy-enhancing effects, highlighting their potential as disease-modifying agents in neuropathic pain and neurodegenerative disorders. Further studies are needed to optimize CNS delivery, refine patient selection, and evaluate long-term safety.},
}

@article {pmid42227397,
year = {2026},
author = {Xie, JX and Feng, XS and He, Y and Xiong, XY and Tang, Y},
title = {The Translational Potential of Oligodendrogenesis-Based Therapies for the Recovery of Neurological Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X460377260506205325},
pmid = {42227397},
issn = {1875-6190},
abstract = {Oligodendrogenesis, the process by which oligodendrocyte precursor cells (OPCs) proliferate, migrate, and terminally differentiate into mature oligodendrocytes (OLs) to myelinate axons, has been found to contribute to both brain development and functional recovery in brain diseases. Increasing evidence indicates that oligodendrocyte precursor cells and oligodendrocytes are not limited to functioning as myelinating cells, which may influence the efficacy of oligoden-drogenesis in improving functional recovery in neurological diseases. In this review, we first summarize the diverse biological roles of oligodendrocytes and oligodendrocyte precursor cells in normal and diseased brains, and the molecular mechanisms underlying oligodendrogenesis. Then, we discuss changes in the oligodendrocyte lineage in some representative neurological disorders, such as white matter injury, multiple sclerosis, aging, intracerebral hemorrhage, and Alzheimer's disease. Finally, we propose the potential therapeutic application of promoting oligodendrogenesis to improve functional recovery in neurological diseases. Although these approaches have shown encouraging efficacy in preclinical animal models, substantial translational barriers-including model limitations, patient heterogeneity, and safety concerns-remain unresolved. Addressing these challenges will be essential to determine whether pro-oligodendrogenic therapies can ultimately contribute to functional recovery in human neurological diseases.},
}

@article {pmid42227398,
year = {2026},
author = {Wu, X and Zhang, K and Kan, C and Sheng, S and Jing, D and Han, F and Sun, X},
title = {Transmembrane Proteins in Neurodegeneration: Pathophysiology from Alzheimer's to Parkinson's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X451846260403084025},
pmid = {42227398},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), represent a growing global health burden due to aging populations. These disorders are characterized by progressive neuronal dysfunction, protein aggregation, synaptic impairment, and neuronal loss. Transmembrane proteins, which regulate signal transduction, material transport, and cell communication, have emerged as key contributors to disease pathogenesis. In AD, amyloid precursor protein processing, N-methyl-D-aspartate receptor overactivation, and microglial receptor signaling drive β-amyloid accumulation, excitotoxicity, and neuroinflammation. In PD, α-synuclein aggregation, dopamine receptor dysregulation, mitochondrial dysfunction, and impaired iron homeostasis disrupt neuronal and synaptic integrity. Despite differences in clinical manifestations, both AD and PD share common mechanisms involving abnormal protein folding, altered calcium signaling, and oxidative and endoplasmic reticulum stress, largely mediated by transmembrane proteins. These shared pathways highlight the interconnected nature of these devastating conditions. These proteins also provide opportunities for therapeutic targeting and biomarker development. Current strategies include secretase inhibitors, N-methyl-D-aspartate receptor modulators, dopamine agonists, and emerging approaches targeting α-synuclein and other misfolded proteins. While challenges remain in achieving selectivity, delivery, and clinical efficacy, advances in molecular biology underscore the potential of transmembrane proteins as critical targets for diagnosis and treatment. Ongoing research continues to unravel their complex roles, and future studies will further elucidate their precise involvement in disease progression, offering hope for new interventions. This comprehensive review summarizes current knowledge on the structural and functional roles of transmembrane proteins in AD and PD, their contributions to shared pathological mechanisms, and their potential as biomarkers and therapeutic targets.},
}

@article {pmid42227403,
year = {2026},
author = {Yang, Z and Hou, X and Tan, Y and Tang, L and Ke, Z and Hu, Z and Ye, Q and Meng, H and Xu, Y and Chen, H},
title = {Neuro-navigated rTMS Targeting Left Angular Gyrus Promotes White-Gray Matter Remodelling to Improve Cognitive Function in Amnestic Mild Cognitive Impairment Patients: Evidence for Early Alzheimer.s Intervention.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438627260121063828},
pmid = {42227403},
issn = {1875-6190},
abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neuromodulation technique, has been increasingly applied in early intervention for amnestic Mild Cognitive Impairment (aMCI). However, the mechanism of changes in brain structure after rTMS treatment remains unclear.

METHODS: A total of 54 aMCI patients received neuro-navigation rTMS targeting the left angular gyrus for 4 weeks (rTMS group: n=28; sham group: n=26). All participants received multimodal MRI and cognitive assessments before and after rTMS. A white matter network was constructed, and Local Diffusion Homogeneity (LDH) was calculated to analyse white matter differences. Surface-based morphometry was used to detect cortical changes. In addition, the correlation between these structural alterations and improved cognitive function was analysed.

RESULTS: After rTMS, general cognitive function and episodic memory of aMCI patients significantly improved. Assortativity improved (P=0.039) while hierarchy decreased (P=0.036). Lower LDH was detected in the right hippocampus cingulum fasciculus, left inferior longitudinal fasciculus, right inferior/superior cerebellar peduncle, and right cingulum gyrus. The sulcus depth of the left medial orbitofrontal cortex, left superior frontal/parietal cortex, left middle/inferior temporal cortex, and right lateral occipital cortex was decreased. Improved general cognition was negatively correlated with decreased sulcus depth in left inferior temporal cortex (R=-0.585, P=0.001) and left superior parietal cortex (R=-0.447, P=0.017). Improved memory was negatively correlated with altered LDH in the right inferior cerebellar peduncle (R=-0.427, P=0.037).

DISCUSSION: Our study shows that neuro-navigated rTMS targeting the left angular gyrus can improve cognitive function and mood symptoms in aMCI patients by impacting brain structures, offering new biological evidence for its potential as an early AD intervention.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus improves aMCI cognition, linked to specific brain structural changes, supporting its early intervention value.},
}

@article {pmid42227404,
year = {2026},
author = {Sun, N and Liu, Q and Wu, P and Qing, L and Zeng, L and Tang, J},
title = {Immunotherapeutic Innovations in Alzheimer's Disease: A Bibliometric Landscape of Global Research Trends and Evolution.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X407781251023061519},
pmid = {42227404},
issn = {1875-6190},
abstract = {BACKGROUND: Immunotherapy has emerged as a promising strategy for Alzheimer's disease by targeting pathological proteins like amyloid-β. Despite increasing research, systematic assessments of this field remain scarce. Bibliometric analysis offers a quantitative approach to map trends, identify collaborations, and reveal hotspots such as antibody therapies and immune modulation mechanisms in neurodegenerative studies.

OBJECTIVE: This study aimed to perform a bibliometric analysis assessing the therapeutic efficacy and recent advancements in immunotherapy for Alzheimer's disease (AD), with an emphasis on emerging trends and key challenges.

METHODS: This study systematically retrieved 5,585 articles from the Science Citation Index Expanded (SCIE) within the Web of Science Core Collection (WoSCC) from 2005 to March 2025. Multi-dimensional analyses were performed on countries, institutions, authors, and keyword cooccurrence patterns using advanced visualization tools such as VOSviewer, CiteSpace, and R software.

RESULTS AND DISCUSSION: The United States and China constitute the predominant proportion of research output, with amyloid-beta (Aβ)-targeted therapies (like aducanumab, lecanemab, donanemab) and tau immunomodulation serving as the principal research foci. Emerging research frontiers encompass neuroinflammatory regulation mechanisms (like NOD-like receptor protein 3 (NLRP3) inflammasome) alongside innovative approaches, including gut-microbiota axis modulation and extracellular vesicle-based strategies. Although these therapeutic interventions have exhibited potential in amyloid burden reduction and cognitive decline mitigation, Amyloid-Related Imaging Abnormalities (ARIA) persist as critical safety challenges demanding rigorous investigation.

CONCLUSION: Immunotherapy demonstrates disease-modifying potential in early-stage AD; however, it requires carefully optimized dosing regimens, precise biomarker-guided patient stratification, and integrated combinatorial strategies targeting Aβ, tau, and neuroinflammation. Future research should prioritize establishing robust translational models and promoting interdisciplinary collaboration to address preclinical-clinical translation gaps effectively.},
}

@article {pmid42227470,
year = {2026},
author = {Chellammal, HSJ and Janakiraman, AK and Ramachandran, D and Chellappan, RD and Sheikuduman, MST and Janakiram, MKS and Boyina, HK and Abdul Kader, MSM and Kannan, SK and Sugavasi, R},
title = {Immunotherapeutic Advances in Alzheimer's Disease: The Convergence of Vaccinology and Nanoscience.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050415433251106050120},
pmid = {42227470},
issn = {1875-5828},
abstract = {Amyloid-beta plaques and neurofibrillary tangles promote neuronal dysfunction and cognitive loss, the hallmarks of Alzheimer's disease (AD), a serious global health concern. Current medications offer only symptomatic alleviation, emphasizing the critical need for disease-- modifying therapy. This study was performed using MeSH term search by using keywords, like "Alzheimer's Disease", "AD", "Vaccines", "Nanoformulations", "Amyloid-Beta (Aβ) Vaccines", "lecanemab", "Tau protein Vaccines", "AADvac1", "Clinical trials". The development of vaccines and methods based on nanotechnology is the primary focal point of this review, which explores immunotherapeutic approaches. Active and passive immunization are used in the development of AD vaccines to target tau and amyloid-beta pathology. While passive immunization involves the direct delivery of pre-formed antibodies, active immunization aims to stimulate the patient's own immune system to produce antibodies in response to the antigen. The necessity for effective drug delivery across the blood-brain barrier (BBB), safety issues, and inconsistent efficacy are some of the difficulties facing vaccine delivery strategies. Nanotechnology can overcome the drawbacks of traditional treatments by providing novel approaches for gene therapy, RNA-based interventions, and targeted medication administration. Immunization approaches offer multiple benefits, including regulated and targeted antigen release, as well as stabilizing the vaccine antigens. Therapeutic drugs can be delivered across the BBB, and genes linked to AD can be modulated by nanoparticles and liposomes that resemble exosomes. Current developments, including the incorporation of short Aβ epitopes, liposomal formulations, conformational mimotopes, and virus-- like particles (VLPs), have markedly enhanced vaccine tolerability. Effective AD treatments depend on combination medications, individualized approaches, and ongoing research into crossing the BBB and improving the safety and effectiveness of vaccines.},
}

@article {pmid42227471,
year = {2026},
author = {Sridhar, SK and Goudanavar, P and Naveen, NR},
title = {Mitochondrial Dysfunction in Alzheimer's Disease: Beyond Energy Failure Toward a Pathogenic Nexus.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050433653251208201102},
pmid = {42227471},
issn = {1875-5828},
abstract = {BACKGROUND: Mitochondrial dysfunction has gained recognition as a central and early event in the pathophysiology of Alzheimer's disease (AD), extending beyond classical energy failure to encompass complex and dynamic perturbations in organelle homeostasis. Despite extensive focus on amyloid-beta (Aβ) and tau, accumulating evidence implicates mitochondria as both targets and amplifiers of neurodegenerative cascades. This review provides a comprehensive synthesis of the mechanistic roles and therapeutic implications of mitochondrial dysfunction in AD, highlighting recent advances and emerging paradigms that underscore mitochondria as integrative nodes in disease onset, progression, and biomarker discovery.

MATERIALS AND METHODS: We critically evaluate literature from molecular, cellular, and systemslevel studies-including postmortem brain tissue, transgenic models, and patient-derived cellsfocusing on key domains such as bioenergetic collapse, redox imbalance, mitochondrial dynamics and quality control, Aβ and tau interactions, calcium dysregulation, and apoptosis. Novel mitochondrial mechanisms such as mitochondria-associated membranes (MAMs), mitochondrial unfolded protein response (UPRmt), and mitonuclear communication are discussed alongside recent translational efforts.

RESULTS: Alzheimer's disease is characterized by widespread mitochondrial abnormalities, including impaired oxidative phosphorylation, increased reactive oxygen species (ROS), disrupted mitochondrial fission/fusion equilibrium, defective mitophagy, and abnormal calcium buffering. Moreover, direct mitochondrial accumulation of Aβ and tau disrupts protein import, respiratory chain integrity, and transport dynamics.

DISCUSSION: These dysfunctions synergistically activate caspase-mediated apoptotic pathways, exacerbating synaptic loss and neuronal death. Promising therapeutic avenues involve antioxidants, NAD+ precursors, mitophagy modulators, and MAM-targeted strategies. Concurrently, mitochondrial biomarkers such as circulating mtDNA, cytochrome c, and neuroimaging via 31P-MRS or PET are emerging as tools for early diagnosis and disease monitoring.

CONCLUSION: Mitochondria constitute a mechanistic nexus in AD, bridging upstream pathological triggers with downstream neurodegeneration. Advancing the field will require patient-specific models (e.g., iPSC-derived neurons, brain organoids), a deeper understanding of mitochondrial heterogeneity, and integration of mitochondrial targets into multi-modal therapeutic strategies. Precision mitochondrial medicine holds promise to transform AD management through mechanismbased diagnosis, stratification, and intervention.},
}

@article {pmid42227472,
year = {2026},
author = {Amin, MA and Zehravi, M and Sweilam, SH and Darwin, R and Gupta, JK and Bhargav, E and Dharmamoorthy, G and Kumar, VV and Rao, AA and Suliman, M and Periyasamy, T and Emran, TB},
title = {Fisetin and Neurodegeneration: From Preclinical Studies to Potential Clinical Applications.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273427644251204045253},
pmid = {42227472},
issn = {1996-3181},
abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, pose significant challenges due to their gradual deterioration and limited available treatments. Fisetin, a naturally occurring flavonoid, has gained attention for its neuroprotective properties. This review explores the therapeutic potential of fisetin in NDs, focusing on its molecular processes and signaling pathways. Additionally, fisetin exhibits significant protective properties, particularly in reducing oxidative stress, neuroinflammation, and apoptosis. It enhances neuronal survival and reduces neuroinflammation by regulating key pathways, such as Nrf2/ARE, PI3K/Akt, and NF-κB. It also has anti-inflammatory, anti-apoptotic, and antioxidant actions. It stimulates autophagic processes, aiding in the removal of harmful protein aggregates, like tau tangles and amyloid plaques, which are hallmarks of NDs. Fisetin, as demonstrated through behavioral evaluations in animal models, has been found to improve motor coordination, synaptic plasticity, and cognitive function. Furthermore, fisetin's potential as a neuroprotective drug is emphasized by its role in enhancing autophagy and reducing tau and amyloid pathology. Research has shown its efficacy in enhancing neural resilience, synaptic plasticity, and cognitive function in both preclinical and in vitro settings. However, clinical translation remains limited due to challenges in pharmacokinetics and bioavailability, despite robust experimental evidence. Further clinical trials are needed to evaluate the safety and efficacy of fisetin, especially in early-stage NDs, explore potential synergistic effects, and understand the molecular interactions. The review demonstrates fisetin's therapeutic potential, recent research, and future strategies for NDs, highlighting bioavailability limitations and the need for new formulations or delivery systems.},
}

@article {pmid42227483,
year = {2026},
author = {Shankar, M and Tiwari, P and Dubey, S},
title = {Phosphodiesterase-5 Inhibitors in Neurodegenerative Diseases: A Path to Cognitive Rescue.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037397181251204145349},
pmid = {42227483},
issn = {1875-5550},
abstract = {Phosphodiesterase type 5 inhibitors (PDE5-Is) have emerged as potential therapeutic agents for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Originally developed for cardiovascular disorders, PDE5-Is have gained significant attention for their neuroprotective effects due to their ability to modulate intracellular signaling pathways. These inhibitors exert their effects by increasing nitric oxide synthase expression, elevating cyclic guanosine monophosphate (cGMP) levels, and activating protein kinase G (PKG), leading to improved synaptic plasticity, neuronal survival, and cognitive enhancement. By targeting these molecular pathways, PDE5-Is help regulate neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis, which are key pathological features of neurodegenerative disorders. Several preclinical studies have demonstrated that PDE5-Is can reduce neuroinflammation, enhance neurogenesis, and improve mental performance in animal models of AD, PD, and MS. Additionally, these agents have shown promise in mitigating β-amyloid and tau pathology in AD, improving dopamine signalling in PD, and exerting immunomodulatory effects in MS. Furthermore, emerging research suggests that PDE5-Is may protect against neuronal cell death and improve cognitive function following cerebral ischemia by enhancing cerebral blood flow, reducing excitotoxicity, and promoting neurovascular coupling. Despite these promising findings, the clinical translation of PDE5-Is for neurodegenerative diseases remains in its early stages. Challenges, such as blood-brain barrier permeability, optimal dosing strategies, and long-term safety, must be addressed through further research. Nevertheless, given their multifaceted mechanisms of action, PDE5-Is represent a novel and exciting therapeutic approach that warrants deeper investigation in both preclinical and clinical settings for the treatment of neurodegenerative diseases.},
}

@article {pmid42227493,
year = {2026},
author = {Yang, H and Li, Y},
title = {Identification and Regulation of Common Key Genes in COPD and AD.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073456087260329192856},
pmid = {42227493},
issn = {1875-5402},
abstract = {INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a prevalent comorbidity in Alzheimer's disease (AD) patients. Despite their potential links, the shared pathology of AD and COPD is unclear. This study used bioinformatics to identify key genes involved in both diseases.

METHODS: Transcriptome data of AD and COPD were obtained from the Gene Expression Omnibus (GEO) database, and common differentially expressed genes (DEGs) of the two diseases were screened by differential expression analysis. Hub genes were identified using topological analysis algorithms in the protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curve analysis, gene set enrichment analysis (GSEA), as well as the prediction of regulatory transcription factors (TFs) and microRNAs (miRNAs) were performed for these hub genes.

RESULTS: Thirty common DEGs were identified, with enrichment analysis linking them to neurodegeneration pathways. From the PPI network, five key genes (PDP1, SERPINI1, PPP3CA, ATP2B1, and VSNL1) were found to have significant diagnostic value (area under the curve > 0.6). GSEA revealed their functional roles, and a regulatory network suggested that TFs (e.g., ZNF76, KLF8) regulate these genes. Finally, a disease-miRNA-mRNA network was constructed, linking AD/COPD, four mRNAs, and seven miRNAs (e.g., hsa-miR-206).

DISCUSSION: This study preliminarily elucidated the cross-regulatory relationship between COPD and AD via bioinformatics, laying a theoretical foundation for investigating their comorbidity mechanism. However, all findings are based on bioinformatics analyses and require further experimental validation.

CONCLUSION: This study identified five key genes linking AD and COPD, providing insights into their shared pathogenesis and potential diagnostic biomarkers for this comorbidity.},
}

@article {pmid42227498,
year = {2026},
author = {Li, J and Rong, C and Wei, Z and Wang, X and Zhao, D},
title = {The Relationship between Antibody-mediated Immune Responses and Four Types of Neurodegenerative Diseases: A Mendelian Randomization Analysis.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073448107260325213324},
pmid = {42227498},
issn = {1875-5402},
abstract = {INTRODUCTION: Recognizing the risk factors associated with neurodegenerative diseases is essential for their prevention. Currently, no studies are exploring the causal link between antibody-mediated immune responses and neurodegenerative diseases. This Mendelian randomization (MR) study further examines whether a causal relationship exists between antibodymediated immune responses and neurodegenerative diseases, and offers evidence supporting causality.

METHOD: Data on antibody-mediated immune responses came from this study, which selected 9,724 subjects as the subgroup research participants and collected their serum samples for microbiological serological analysis. The large artery atherosclerotic stroke data includes 4,373 patients. The multiple sclerosis consists of 1,683 cases. Parkinson's disease comprises 37,688 cases. Alzheimer's disease includes 17,008 cases. MR analysis was conducted to estimate the associations between antibody-mediated immune responses(exposure) and neurodegenerative diseases(outcome) risk.

RESULT: The IVW analysis revealed that 9 antibody-mediated immune responses were associated with 4 neurodegenerative diseases, including anti-varicella-zoster virus and Epstein-Barr virus antibodies, and others.

DISCUSSION: This study systematically investigates, for the first time through Mendelian randomization analysis, the potential relationships between antibody-mediated immune responses and various neurodegenerative diseases. The results indicate that a total of 9 antibody-mediated immune responses are significantly associated with the risk of four neurodegenerative diseases: Conclusion: These antibody-mediated immune responses serve as potential markers for predicting the occurrence and development of neurodegenerative diseases. Our genetic analysis suggests that antibodies against antigens may be involved in the pathological process of neurodegenerative diseases, which provides a new direction for future exploration of their specific mechanisms.},
}

@article {pmid42227512,
year = {2026},
author = {Salem, GEM and El-Sakhawy, MA and Darwish, A and Negm, RM and Ashfaq, M and Alhoot, MA and Mohammad, ZZAE and Tongdeesoontorn, W},
title = {Microbial Proteases: Pioneering Tools for Modern Therapeutic Innovations.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501460061260513102822},
pmid = {42227512},
issn = {1873-5592},
abstract = {INTRODUCTION: Proteases are enzymes that play important physiological roles in both production and breakdown. They also play a variety of roles in physiology, biochemistry, and cell regulation. Furthermore, proteases have various uses in the chemical and pharmaceutical industries. Microbial proteases offer many advantages over animal and plant sources, including their wide substrate specificity, fast growth, and ease of genetic manipulation.

METHODS: This review explores the benefits of using microbial proteases. The literature search was conducted across electronic bibliographic databases, including PubMed, MEDLINE, Scopus, and Google Scholar, to find pertinent scientific publications on the therapeutic uses of microbial proteases.

RESULTS: Microbial proteases are the largest group of industrial enzymes. This review examines their wide range and organizes them according to their catalytic mechanisms and active sites. It highlights their physiological uses in dietary protein digestion, blood coagulation, and cell division. The study also highlights potential therapeutic uses, including biofilm degradation, anti-inflammatory effects, digestive assistance, wound healing, and fibrinolytic proteases. It also discusses its use in treating medical disorders like liver fibrosis and Alzheimer's disease.

DISCUSSION: The investigation of microbial proteases as promising new-generation therapeutic agents highlights their exceptional potential for tackling medical issues. Their adaptable catalytic capabilities and environmental friendliness make them attractive as therapeutic agents.

CONCLUSION: Microbial proteases are incredibly versatile, exhibiting unique features and functioning in harsh conditions, which creates opportunities for novel uses in treatments and improve biomarkers detection. This review highlights their growing importance in the creation of innovative therapeutic approaches and improve biomarkers detection.},
}

@article {pmid42227563,
year = {2026},
author = {Pakpahan, E and Guan, Z and Siervo, M and Muniz-Terrera, G and Mohan, D and Acosta, D and Sosa, AL and Acosta, I and Llibre-Rodriguez, JJ and Llibre-Guerra, JJ and Prince, M and Worrall, A and Naheed, A and Vella, AS and Jiang, J and Lipnicki, DM and Sachdev, PS and Robinson, L and Prina, M and Stephan, BCM},
title = {Development and validation of a dementia risk prediction model for low- and middle-income countries: the 10/66 study.},
journal = {American journal of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/aje/kwag116},
pmid = {42227563},
issn = {1476-6256},
abstract = {BACKGROUND: Most people with dementia live in LMICs, underscoring the need for LMIC-specific identification of high-risk individuals. This study aimed to develop and validate a simple dementia risk prediction model for these settings.

METHODS: Data from seven 10/66 Study sites were analyzed. Over 100 candidate predictors were screened based on existing models and the 2024 Lancet Commission, including LMIC-specific variables (eg, food insecurity and household assets). Predictors were selected using LASSO and modelled with the Fine-Gray method to generate a risk score. Predictive accuracy was pooled via meta-analysis.

RESULTS: 11143 participants were included, among whom 1069 (9.6%) developed dementia during follow-up. A five-factor risk score comprising age, social engagement, physical activity, hypertension, and difficulty in handling money was developed. The pooled c-statistic was 0.75 (95% CI: 0.72-0.78), with good calibration across sites. Decision curve analysis showed a modest net benefit, with variation across countries.

CONCLUSION: It is possible to predict incident dementia with reasonable accuracy using a simple model across different LMICs. Our findings support the use of context-specific risk assessment tools to identify individuals at elevated dementia risk in LMIC settings, which may inform resource allocation for dementia care services and public health planning.},
}

@article {pmid42227644,
year = {2026},
author = {Baek, G and Salat, DH and Jang, I and , },
title = {Improved Multiscale Structural Mapping with Supervertex Vision Transformer for the Detection of Alzheimer's Disease Neurodegeneration.},
journal = {Human brain mapping},
volume = {47},
number = {8},
pages = {e70548},
doi = {10.1002/hbm.70548},
pmid = {42227644},
issn = {1097-0193},
support = {R21AG072431/NH/NIH HHS/United States ; RS-2024-00455720//National Research Foundation of Korea/ ; 2024-ER0407-00//Korea National Institute of Health/ ; 2025-ER0403-00//Korea National Institute of Health/ ; 2026-ER0904-00//Korea National Institute of Health/ ; KSC-2024-CRE-0021//Korea Institute of Science and Technology Information/ ; KSC-2025-CRE-0065//Korea Institute of Science and Technology Information/ ; 2025//Hankuk University of Foreign Studies/ ; },
abstract = {Alzheimer's disease (AD) confirmation often relies on positron emission tomography (PET) or cerebrospinal fluid (CSF) analysis, which are costly and invasive. Consequently, structural MRI biomarkers such as cortical thickness (CT) are widely used for noninvasive AD screening. Multiscale structural mapping (MSSM) was recently proposed to integrate gray-white matter contrasts (GWCs) with CT from a single T1-weighted MRI (T1w) scan. Building on this framework, we propose MSSM+, together with surface supervertex mapping (SSVM) and a Supervertex Vision Transformer (SV-ViT). 3D T1w images from individuals with AD and cognitively normal (CN) controls were analyzed. MSSM+ extends MSSM by incorporating sulcal depth and cortical curvature at the vertex level. SSVM partitions the cortical surface into supervertices (surface patches) that effectively represent inter- and intra-regional spatial relationships. SV-ViT is a Vision Transformer architecture operating on these supervertices, enabling anatomically informed learning from surface mesh representations. Compared with MSSM, MSSM+ identified more spatially extensive and statistically significant group differences between AD and CN. In AD versus CN classification, MSSM+ achieved a 3%p higher area under the precision-recall curve than MSSM. Vendor-specific analyses further demonstrated reduced signal variability and consistently improved classification performance across MR manufacturers relative to CT, GWCs, and MSSM. These findings suggest that MSSM+ combined with SV-ViT is a promising MRI-based imaging marker for AD detection prior to CSF/PET confirmation.},
}

@article {pmid42227745,
year = {2026},
author = {Zhang, J and Teng, Y and Li, Y and Zhang, M},
title = {Global research landscape of oligodendrocytes in Alzheimer's disease: A bibliometric and knowledge-mapping analysis from 1990 to 2025.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456313},
doi = {10.1177/13872877261456313},
pmid = {42227745},
issn = {1875-8908},
abstract = {BackgroundOligodendrocyte (OL) lineage biology is increasingly recognized as a contributor to Alzheimer's disease (AD) pathophysiology, but its global knowledge structure and emerging frontiers remain unclear.ObjectiveTo map the development, major contributors, intellectual bases, and research frontiers of OL-related AD research using bibliometric and visualization approaches.MethodsEnglish-language articles and reviews published from 1990 to 2025 were retrieved from the Web of Science Core Collection on January 2, 2026. After deduplication, 1746 records were analyzed. VOSviewer 1.6.20 assessed publication output, contributors, collaborations, and citation networks. CiteSpace 6.1.6 performed keyword co-occurrence, clustering, and burst detection.ResultsAnnual publications increased from 5 in 1990 to 149 in 2025, peaking at 154 in 2024, with acceleration after 2020. The United States led in productivity and impact (684 publications; 54,075 citations). Harvard University was the most productive institution (46 publications), whereas the University of California, Los Angeles had the highest average citation impact among leading institutions (147.20 citations per publication). Acta Neuropathologica was the most productive journal (66 publications; 6548 citations). Mathys et al. was the most influential cornerstone reference. Keyword clustering was robust (Q = 0.701, S = 0.958), identifying "white matter" as the central thematic cluster.ConclusionsOL-related AD research is expanding rapidly and shifting toward white matter-centered, cell state-resolved, and multi-omics paradigms. Future priorities include defining OL and oligodendrocyte precursor cell transcriptional states, clarifying myelin vulnerability and repair mechanisms, and linking OL pathology to amyloid-related processes.},
}

@article {pmid42227779,
year = {2026},
author = {Sharma, DK and Prasad, CS},
title = {Chitosan-based nanocarriers in Alzheimer's disease therapy: Recent developments and future perspectives.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-32},
doi = {10.1080/1061186X.2026.2683967},
pmid = {42227779},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a neurological condition that worsens with time and causes behavioral problems, memory loss, and cognitive decline. It is a major global health concern. Alzheimer's complexity and the blood-brain barrier (BBB) limit effective disease-modifying treatments despite extensive research. The primary goal of conventional pharmacotherapies is to relieve symptoms; however, they frequently have low absorption, a short half-life, and peripheral adverse effects. The use of anti-Alzheimer medications in nanoparticles (NPs) is a potential remedy for these issues. Although many NPs are biocompatible and nontoxic, many are not biodegradable, making them unsuitable for CNS targeting. Chitosan (CS)-based NPs stand out among polymeric nanocarriers as stable, biodegradable delivery systems for central nervous system drugs. In this review, we examine the design, mechanisms of BBB penetration, drug-loading capacity, controlled-release behaviour, and therapeutic efficacy of CS-based delivery platforms, including nanoparticles, nanogels, lipid nanoparticles, polymeric micelles, nanoemulsions, and acetylcholinesterase inhibitor-loaded systems. Furthermore, the benefits of CS-based systems, including improved brain bioavailability, reduced toxicity, intranasal delivery, and support for multifunctional and stimuli-responsive therapeutics, are highlighted. All things considered, chitosan-based drug delivery systems offer a flexible and promising strategy for enhancing AD treatment results.},
}

@article {pmid42227878,
year = {2026},
author = {Liu, G and Hong, C and Huang, Y and Liu, Y and Guan, B and Jin, X and Dai, W and Luo, Y},
title = {Mediating effect of Life's Essential 8 score in the associations of SES mobility with cognitive function, dementia incidence and neuroimaging markers.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2679698},
pmid = {42227878},
issn = {1364-6915},
abstract = {OBJECTIVES: To explore the links between SES mobility and dementia incidence, cognitive function, and neuroimaging markers, and to assess whether cardiovascular health mediates these associations.

METHODS: Data were from UK Biobank, involving 130,036 participants aged 40-70 in main analysis. SES mobility was rated via childhood and adulthood SES, and categorized into stable low, upward mobility, downward mobility, stable medium and stable high. Cox and linear regression models were conducted to examine associations of SES mobility with dementia risk, cognitive function, and neuroimaging markers.

RESULTS: Individuals with disadvantaged SES mobility were more likely to experience all-cause dementia (HR = 1.90, 95% CI: 1.55, 2.32), Alzheimer's disease (HR = 2.07, 95% CI: 1.51, 2.83), and vascular dementia (HR = 5.19, 95% CI: 2.65, 10.15) compared to stable high SES. Participants with stable low SES scored lowest in fluid intelligence (β = -1.21, 95% CI: -1.26, -1.15) and numeric memory (β = -0.59, 95% CI: -0.66, -0.53) and had smallest hippocamps volume (β = -163.97, 95% CI: -221.36, -106.57) compared to stable high SES. The above associations were mediated by Life's Essential 8 score, which was measured simultaneously with SES mobility.

CONCLUSION: Disadvantaged SES mobility in transition between childhood and adulthood SES was related to adverse brain health and cardiovascular health mediated these relationships.},
}

@article {pmid42227964,
year = {2026},
author = {Huang, X and Miao, Q and Li, Y and Cong, P and Feng, B and Li, C and Dan, T and Li, X and Wu, Q and Han, S and Chen, Q and Zhang, H and Zhang, L and Zheng, Y and Feng, E and Xiong, L},
title = {Machine-Learning-Assisted Triple-Gated Raman Enhancement Platform for Selectively Quantifying Lysophosphatidylcholine (16:0) as a Potential Biomarker for Cognitive Impairments.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.6c07748},
pmid = {42227964},
issn = {1936-086X},
abstract = {Accurate quantification of structurally similar metabolites as biomarkers in biofluids has remained a longstanding challenge. Here, we report a semiconductor-organic hybrid interface (ZrS2@ZrOx-C16) with a triple-gated molecular recognition environment for high-specificity detection of lysophosphatidylcholine (16:0) (LysoPC (16:0)), which is identified as a potential biomarker associated with aging and cognitive decline. Through integrating phosphocholine-selective Zr-O-P coordination, chain-length-matched hydrophobic free-energy minimization, and a dual-resonant charge-transfer pathway, ZrS2@ZrOx-C16 affords molecular-level discrimination among lysophospholipids with nearly identical chemical structures, enabling amplified and selective quantitative Raman signals. Coupled with machine-learning extraction of Raman fingerprints, ZrS2@ZrOx-C16 achieves rapid, label-free quantification with an accuracy of R[2] = 0.999 across human and mouse serum samples, allowing precise mapping of LysoPC (16:0) deficits as a biomarker and therapeutic target across aging, Alzheimer's disease, and perioperative neurocognitive impairment. This work establishes a framework for precision lipid analytics and high-selectivity metabolic sensing, enabling mechanistic insights in neurometabolic biology.},
}

@article {pmid42228053,
year = {2026},
author = {Niknam, N and Songhori, N and Nekahi, N and Kavian, M and Khosravi, F and Fard, AM and Moshiri, Y and Haghshenas, N and Sadegh, MH and Torabi, P},
title = {Ultrasound-induced blood-brain barrier opening in Alzheimer's disease: a systematic review of clinical studies.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-026-03408-1},
pmid = {42228053},
issn = {1720-8319},
abstract = {BACKGROUND: Focused ultrasound (FUS) has emerged as a non-invasive approach to transiently open the blood-brain barrier (BBB) and facilitate therapeutic delivery in Alzheimer's disease (AD). This systematic review evaluates current clinical evidence regarding the feasibility, safety, and reported biological and clinical outcomes of FUS-mediated BBB opening.

METHOD: A systematic search of PubMed, Scopus, and Web of Science was conducted in accordance with PRISMA 2020 guidelines and supplemented by Google Scholar. Human clinical studies employing FUS-induced BBB opening in AD were included. Risk of bias was assessed using the ROBINS-I tool for non-randomized studies.

RESULTS: From an initial screening of 587 records, 27 studies met the inclusion criteria. Across these studies, FUS-mediated BBB opening was generally feasible and well tolerated, with no reports of irreversible procedure-related adverse events. Reported adverse effects were typically mild and transient, including localized headache, fatigue, or imaging-detected edema. Exploratory findings included heterogeneous changes in cognitive measures and regional amyloid-β biomarkers assessed by neuroimaging or cerebrospinal fluid analysis. Substantial variability in study design, target regions, sonication parameters, and outcome measures limited quantitative synthesis and definitive interpretation.

CONCLUSION: Current clinical evidence supports the short-term feasibility and safety of FUS-mediated BBB opening in AD. However, the available data remain preliminary, and well-designed randomized controlled trials with larger cohorts, standardized imaging and cognitive endpoints, and longer follow-up are required to determine therapeutic efficacy and sustained clinical benefit.},
}

@article {pmid42228145,
year = {2026},
author = {Zhang, S and Zhuang, X and Jiang, Y and Wang, H and He, X and Zhang, Q and Ji, X and Lu, Y and Li, F},
title = {Association of combined ultra-processed food intake (ultra-processed dietary pattern) with cognitive function impairment: a meta-analysis of prospective cohort studies.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42228145},
issn = {1432-1459},
mesh = {Humans ; Food, Processed ; *Cognitive Dysfunction/epidemiology/etiology ; Prospective Studies ; *Fast Foods/adverse effects ; *Diet/adverse effects ; Cohort Studies ; },
abstract = {BACKGROUND: Previous studies on ultra-processed foods (UPF) and cognitive impairment often isolated UPF from overall dietary patterns, limiting real-world interpretation.

METHODS: We systematically searched PubMed, Embase, Web of Science, and Cochrane Library up to April 2026 for prospective cohort studies assessing total UPF intake (defined by NOVA) and risk of cognitive impairment (including cognitive dysfunction, dementia, and Alzheimer's disease). A random-effects model was used to pool adjusted hazard ratios (HRs) comparing highest versus lowest UPF consumption.

RESULTS: Eight cohort studies (total > 250,000 participants) were included. High combined UPF intake was associated with a 14% higher risk of cognitive impairment (pooled HR = 1.14, 95%CI 1.04-1.25, I[2] = 64.6%). The association was more pronounced in participants aged < 60 years (HR = 1.19, 95%CI 1.06-1.33) but not statistically significant in those > 60 years. Large studies (> 10,000) and longer follow-up (> 15 years) showed stable estimates with lower heterogeneity.

CONCLUSION: Higher consumption of UPF within a ultra-processed dietary context is positively associated with cognitive impairment risk, particularly among middle-aged adults. These findings support dietary guidelines that recommend limiting UPF intake.},
}

Humans
Food, Processed
*Cognitive Dysfunction/epidemiology/etiology
Prospective Studies
*Fast Foods/adverse effects
*Diet/adverse effects
Cohort Studies

@article {pmid42228248,
year = {2026},
author = {Pal, A and Yadav, H and Yadav, D and Goel, F and Rajput, MS},
title = {A Biomarker Out of Context: Understanding High p-tau217 in the Developing Brain.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42228248},
issn = {1559-1182},
abstract = {Phosphorylated tau at threonine 217 (p-tau217) is generally considered a very specific biomarker of Alzheimer's disease and tau-mediated neurodegeneration in adult patients, where its increase is strongly associated with amyloid, pathology, synaptic dysfunction, and progressive cognitive decline. However, surprisingly, some data report extremely elevated levels of p-tau217 in plasma and cerebrospinal fluid of healthy neonates and infants, i.e., without the presence of neurodegeneration, cognitive impairment, or structural brain damage. The latter paradoxical situation raises a fundamental question that might literally rewrite the interpretations about the tau phosphorylation being a strictly pathological process. This overview aims to bring together the latest clinical, biochemical, and developmental neuroscience literature to unveil the physiological function of p-tau217 during early brain development. We argue that high p-tau217 in infancy may be indicative of ongoing neurodevelopmental processes, such as axonal growth, synaptogenesis, neuronal plasticity, and cytoskeletal remodeling, rather than tau toxicity. Further, we analyze the contribution of the differential expression of tau isoforms, phosphorylation rates, clearance pathways, and BBB permeability in development that could explain the age-dependent biomarker profiles. In addition, this review compares the biology of tau in neonates and adults in a detailed manner, explaining how the context-dependent regulation of tau phosphorylation distinguishes p-tau217 as a developmental marker or a pathological marker. Grasping this difference is essential for the correct reading of tau biomarkers throughout the life span and for preventing the neurodegenerative risk in children from being wrongly diagnosed. In the end, this paradox highlights the need for biomarker frameworks that are specific to different ages and offers new understandings of tau physiology that might lead to novel therapies for tauopathies in the future.},
}

@article {pmid42228255,
year = {2026},
author = {Isıyel, M and Ceylan, H and Demir, Y},
title = {Integrative Transcriptomic, Network, and Machine Learning Analyses Identify Genistein and Resveratrol-Associated Therapeutic Targets in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42228255},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by complex molecular alterations across multiple brain regions. In this study, we applied an integrative systems-level framework combining multi-region transcriptomic analysis, protein-protein interaction (PPI) network topology, machine learning-based validation, and in silico approaches to identify robust and pharmacologically relevant molecular targets in AD. Gene expression data from four AD-related brain regions (entorhinal cortex, frontal cortex, hippocampus, and temporal cortex) were obtained from the GSE5281 dataset, yielding 467 genes consistently dysregulated across all regions. Network analysis identified a subset of downregulated hub genes predominantly associated with mitochondrial bioenergetics and proteostasis pathways. Intersection with experimentally curated targets of genistein and resveratrol prioritized four elite genes, COX5B, ENO1, HSP90AB1, and SDHB as shared and biologically central nodes. To assess the collective discriminative capacity of the identified gene set, a random forest classifier was trained using shared differentially expressed genes. The model demonstrated strong classification performance with a low out-of-bag error rate, while feature importance analysis identified SDHB as the most influential contributor, followed by COX5B and ENO1, indicating synergistic multigene effects rather than isolated biomarker behavior. Machine learning was applied as an integrative validation layer to reinforce biological relevance, rather than as a standalone diagnostic tool. Finally, molecular docking analyses revealed favorable binding affinities of genistein and resveratrol toward all four elite targets. Overall, these findings highlight a convergent mitochondrial-proteostasis dysfunction axis in AD and suggest COX5B, ENO1, HSP90AB1, and SDHB as promising multi-target nodes for polyphenol-based therapeutic strategies.},
}