@article {pmid42761825,
year = {2026},
author = {Dunton, KL and Monchal, H and Achorn, BE and Mandé-Niedergang, B and Roucard, C and Roche, Y and Evrard, A and Menniti, FS},
title = {Human P301L tau expression in mice alters neuronal excitability independent of neurodegeneration.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1814637},
pmid = {42761825},
issn = {1662-4548},
abstract = {Variation in the microtubule-binding protein tau is causally implicated in numerous neurodegenerative diseases, including Alzheimer's disease. However, the mechanisms by which such variation results in disease are not well understood. The JNPL3(P301L) mouse model mimics the effects of the P301L mutation on human tau associated with frontotemporal dementia. As previously reported, phospho-tau aggregates immunolabeled with AT8 increase with age in a rostral progression from the brainstem; however, there is relatively limited forebrain pathology by the time these animals die prematurely at approximately 1 year of age. In this study, we investigated the functional effects of P301L tau expression on electrophysiological signatures as a function of age in mice expressing P301L tau from 3 to 10 months. The P301L mice had a distinct electrophysiological phenotype of increased power in higher EEG frequency bands detected with a depth electrode in the hippocampus and, to a lesser extent, with dural surface electrodes over the frontal and parietal cortices. Significantly, this electrophysiological phenotype was present at the first recording at 3 months of age and did not differ over monthly recordings up to 9 months of age, after which point animals became moribund and were euthanized. P301L mice at 10 months of age also showed electrical synchronization to a 40 Hz tone (ASSR) that was not observed in WT mice and an increase in inter-trial coherence compared with WT mice. We confirmed that AT8, as well as markers of neuroinflammation, increased progressively with age from the hindbrain to the forebrain, as previously reported. Together, these data suggest an increase in neuronal excitability in P301L mice compared with WT, but that this phenotype is not correlated with the age-dependent accumulation of AT8-labeled tau aggregates and the accompanying neuroinflammation. We hypothesize that the expression of P301L mutant tau disrupted the physiological functions of tau, resulting in the functional electrophysiological phenotype. Whether this functional effect drives neurodegeneration or is a separable phenomenon has implications for understanding the mechanisms underlying the role of tau variation in neurodegenerative conditions.},
}

@article {pmid42761867,
year = {2026},
author = {El Sayed, T and Patel, A and Xu, K and Salaiza, JA and Azhakath Valappil, H and Majumdar, S and Sutton, BP and Mirica, LM},
title = {Design of bifunctional pyridinophane ligands as Mn[2+] MRI agents for diagnostic imaging of Alzheimer's disease.},
journal = {Inorganic chemistry frontiers},
volume = {},
number = {},
pages = {},
pmid = {42761867},
issn = {2052-1553},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose prevalence is rising with the aging of the global population. Among the proposed pathological hallmarks, the beta-amyloid (Aβ) peptide aggregates and soluble Aβ oligomers are established biomarkers and remain valuable diagnostic targets. While positron emission tomography (PET) imaging agents dominate AD diagnostic imaging, there are no FDA-approved MRI agents for AD. Herein, we report five bifunctional chelators built on the 2,11-diaza[3.3](2,6)pyridinophane framework, and which were evaluated as chelators for Mn[2+]-based MRI contrast agents. Based on in vitro studies, including thermodynamic stability and kinetic inertness measurements, T 1 relaxivity and [17]O transverse relaxivity measurements to extract hydration numbers and water-exchange parameters, we obtained a clear structure-activity correlation for the corresponding bifunctional chelators: anionic picolinate and acetate arms increase thermodynamic stability and kinetic inertness, while the benzothiazolyl-phenol arm accelerates water exchange. Importantly, a high hydration number alone is insufficient, as a rapid water exchange is also needed for an appreciable contrast. Moreover, we show both the bifunctional chelators and their Mn[2+] complexes exhibit appreciable affinity for Aβ aggregates, both in vitro and in 5xFAD mouse brain sections. [Mn(TE-8)], the most kinetically inert complex with favorable relaxivity, log D, and Aβ affinity, was advanced to in vivo MRI studies. Unlike MnCl2, which accumulates non-specifically, [Mn(TE-8)] cleared through renal and hepatobiliary routes and produced measurable brain contrast enhancement. Together, these results establish the diazapyridinophane scaffold as a viable first-generation platform for blood-brain barrier (BBB)-permeable Mn[2+] MRI contrast agents.},
}

@article {pmid42762164,
year = {2026},
author = {Thorpe, RJ and Esiaka, D and Surawkar, S and Nwakasi, C and Kim, B},
title = {Correlates of Subjective Cognitive Impairment Among Community Dwelling Older Non-Hispanic Black and Non-Hispanic White Men.},
journal = {Journal of aging and health},
volume = {},
number = {},
pages = {8982643261490956},
doi = {10.1177/08982643261490956},
pmid = {42762164},
issn = {1552-6887},
abstract = {BackgroundSubjective cognitive impairment (SCI) predicts Alzheimer's disease and related dementias (ADRD). Identifying SCI correlates may identify cognitive risk earlier in the ADRD continuum. We examined SCI correlates among older non-Hispanic Black (NHB) and non-Hispanic White (NHW) men.MethodCross-sectional data were from 669 men in the 2012 National Health and Aging Trends Study. Logistic regression was used to identify SCI correlates, accounting for complex sampling and attrition.ResultHigher education (OR = 0.33, 95% CI: 0.13-0.87) and former smoking (OR = 0.38, 95% CI: 0.16-0.91) were associated with lower SCI odds. Sleep difficulties (OR = 2.81, 95% CI: 1.22-6.47), multimorbidity (OR = 2.16, 95% CI: 1.09-4.29), and ADL disability (OR = 4.19, 95% CI: 2.03-8.61) were associated with higher odds.DiscussionEducation, smoking status, sleep, multimorbidity, and functional status may be important SCI correlates among older NHB and NHW men. Addressing modifiable correlates may support cognitive health earlier in the ADRD continuum.},
}

@article {pmid42762305,
year = {2026},
author = {Onwu, DO and Oria, RS and Adekunle, YA and Adams, MD and Ani, ON and Adele, H and Tyohemba, TS and Osioma, E and Popoola, BM and Bakare, OS and Okon, VE and Maxwell, CC},
title = {Integration of network pharmacology, structure-based pharmacophore modeling, DFT, molecular docking, and molecular dynamics simulations to identify multi-target small molecule inhibitors against Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42762305},
issn = {1432-1912},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive impairment, synaptic malfunction, oxidative stress, cholinergic deficits, and a lack of effective disease-modifying therapeutics. In this study, we integrated in silico approaches with network pharmacology to identify novel multi-target ligands against three key AD-associated proteins: acetylcholinesterase (AChE), protein kinase B (AKT1), and monoamine oxidase B (MAO-B). Structure-based e-pharmacophore modeling and virtual screening were conducted using Pharmit, a large compound library from the ZINC and COCONUT databases, followed by stringent ADMET filtering to obtain drug-like candidates. Network pharmacology analysis identified AKT1 as the best hub gene between predicted hit compounds and AD-associated gene-enriched pathways, such as PI3K-Akt, FoxO, calcium, and cAMP signaling pathways. Four hits (1-4) were screened for binding affinity evaluation using molecular docking, followed by MM-GBSA, and molecular dynamics (MD) simulations. Hit1 (N-(2-(1H-indol-3-yl)ethyl)-7-hydroxy-5,6-dimethoxy-[1,2,4]triazolo[4,3-a]quinazoline-3-carboxamide) (ZINC000033435965) demonstrated the strongest binding affinities across all complexes, with docking scores of - 11.4, - 11.8, and - 12.1 kcal/mol for hAChE, AKT1, and MAO-B, respectively. MD simulations over 100 ns for Hit1 revealed stable interaction as described by RMSD, RMSF, Rg, SASA, and HB profiles. E-pharmacophore and validation demonstrated strong predictive performance across the complexes, especially for AKT1 and MAO-B with high enrichment factors and ROC-AUC values (0.95 and 0.94). Additionally, DFT analysis of Hit1 revealed a favorable electronic stability energy (- 1479.283992 Eh). ADMET profiling predicted favorable oral bioavailability, BBB permeability, drug-likeness, and low predicted toxicity. The findings of this study suggest that Hit1 could be a promising multi-target molecule capable of modulating cholinergic transmission, neuronal survival pathways, and oxidative stress in AD. Experimental validation, including in vitro enzymatic assays and in vivo evaluations, is essential to further establish the therapeutic potential of Hit1.},
}

@article {pmid42762360,
year = {2026},
author = {Carroll, JA and Soukup, J and Groveman, BR and Orrú, CD and Race, B and Haigh, CL},
title = {Life at the interface: Byron Caughey's search for prion disease inhibitors through chemistry, structure, and cell physiology.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42762360},
issn = {1432-0533},
mesh = {Humans ; *Prion Diseases/drug therapy/history ; Animals ; *Prions/metabolism ; History, 20th Century ; *Drug Discovery/history ; History, 21st Century ; },
abstract = {The search for effective therapeutics that can bring hope to patients and families affected by rare prion diseases is ongoing. Self-propagating, misfolded proteins underlie a broad range of neurodegenerative disorders that include prion diseases as well as more common conditions such as Parkinson's and Alzheimer's disease. Byron Caughey was a pioneer in the field of prion therapeutic discovery. His seminal contributions in drug development included elucidating disease biochemistry, understanding the need to target conformational changes, and developing cell-free conversion assays to monitor protein misfolding in real time. These advances laid the foundation for therapeutic strategies aimed at preventing, slowing or reversing the conversion of native protein into a pathogenic, seed-competent conformer and/or its assembly into amyloid fibrils. Within the Caughey laboratory, small molecule inhibitors targeting the misfolded prion, the process of conversion and aggregation, or stimulating disassembly were studied intensively. More recent approaches targeted the relocation, removal or downregulation of the normal protein substrate. These efforts in combination with high-resolution structural characterization of the infectious prions now offer new opportunities for intelligent drug design. Equally important to drug discovery have been advances in the development of sensitive and reliable methods to detect the agent and its clearance, which is necessary to validate that putative treatments are efficacious. Herein, we highlight 4 decades of Byron Caughey's contributions and dedication to the search for anti-prion therapeutics.},
}

Humans
*Prion Diseases/drug therapy/history
Animals
*Prions/metabolism
History, 20th Century
*Drug Discovery/history
History, 21st Century

@article {pmid42762395,
year = {2026},
author = {Katsumata, Y and Morganti, JM and Liao, A and Zhou, W and Zhong, Y and Fister, S and Saito, K and Qiao, Q and Artiushin, S and Wei, A and Jian, G and Nichols, CG and Lee, TL and Niedowicz, DM and Shahidehpour, RK and Norris, CM and Rogers, CB and Fardo, DW and Cao, J and Nelson, PT},
title = {ABCC9/SUR2 has a Complex Expression Pattern in Human Brain Gliovascular Unit Cells, Including Astrocytes.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42762395},
issn = {1559-1166},
support = {grants P30 AG072946, R01 NS118584, RF1 AG082339, P01 AG078116, and R01 AG076932//NIH/ ; },
mesh = {Humans ; *Astrocytes/metabolism ; Animals ; *Sulfonylurea Receptors/genetics/metabolism ; *Brain/metabolism/cytology/blood supply ; Mice ; Pericytes/metabolism ; },
abstract = {The ABCC9 gene and its cognate protein SUR2 play important roles in neurovascular coupling and are implicated in hippocampal sclerosis of aging (HS-Aging). However, prior studies have not focused on human brain SUR2 expression or SUR2 in glial cells. Here we analyzed cell type-specific ABCC9/SUR2 expression patterns, and correlation with known genetic risk variants, using multiple data sets and a novel antiserum. Existing single-nucleus RNA sequencing data sets and new spatial transcriptomics data indicated that SUR2 transcripts were expressed primarily in human brain pericytes, astrocytes, smooth muscle cells, and endothelial cells. Evaluation of Sur2 expression in a sample of mice brains showed similar results except Sur2 was not detected in the mice astrocytes. In a SUR2-enriched subcluster of human astrocytes, the pattern of transcript expression suggested responsiveness to thyroid hormone signaling: SUR2-correlated gene products were enriched for thyroid hormone-sensitive transcripts and SLCO1C1, the astrocyte thyroid hormone importer, was the transcript with the strongest correlation with SUR2 expression. Cells in the SUR2 + astrocyte cluster tended to have been derived from individuals lacking severe Alzheimer's disease pathology. An ABCC9 single nucleotide variant (rs1914361, also a HS-Aging risk allele) was associated with increased SUR2 expression in astrocytes, but not other cell types. SUR2 mRNA splicing differed between cell types; astrocytes preferentially expressed the SUR2B variant. A novel SUR2 antiserum immunolabeled blood vessel walls and some astrocyte-morphology cells in human brain. Overall, human brain SUR2 expression was enriched among different cell types of the gliovascular unit. A SUR2-enriched, possibly-homeostatic astrocyte subcluster suggested connections to thyroid hormone signaling.},
}

Humans
*Astrocytes/metabolism
Animals
*Sulfonylurea Receptors/genetics/metabolism
*Brain/metabolism/cytology/blood supply
Mice
Pericytes/metabolism

@article {pmid42762549,
year = {2026},
author = {Zhijian, C and Haizhi, Z and Yihong, H and Weiyang, X and Jingjing, Z and Qiuyan, C and Tianxiu, Z},
title = {Diagnostic value of intravoxel incoherent motion imaging of deep gray matter nuclei in Alzheimer's disease.},
journal = {European journal of radiology},
volume = {205},
number = {},
pages = {113244},
doi = {10.1016/j.ejrad.2026.113244},
pmid = {42762549},
issn = {1872-7727},
abstract = {OBJECTIVE: To evaluate clinical diagnostic value of intravoxel incoherent motion (IVIM) imaging in Alzheimer's disease (AD).

METHODS: Sixty-six subjects from Ningde City Hospital were classified into AD (n = 23), mild cognitive impairment (MCI) (n = 28), and normal control (NC) (n = 15) groups. Standardized apparent diffusion coefficient (ADCst) and IVIM parameters, including true diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*), were measured in the caudate nucleus, thalamus, putamen, globus pallidus, and amygdala using 3.0 T magnetic resonance imaging. Mini-mental state examination (MMSE) scores were recorded, and Pearson correlation and receiver operating characteristic analyses were performed.

RESULTS: IVIM-f in the right thalamus was significantly reduced in the AD group compared with the NC and MCI groups (p < 0.05), and IVIM-f in the bilateral amygdala was lower in AD than in NC (p < 0.01). IVIM-D* in the right caudate nucleus was significantly decreased in AD relative to both NC and MCI groups (p < 0.001), whereas IVIM-D in the left putamen was increased in AD compared with NC (p < 0.001). No significant intergroup difference was observed for ADCst (p > 0.05). Correlation analysis showed that MMSE scores were positively associated with IVIM-f in the right thalamus (r = 0.5471, p < 0.001), IVIM-D* in the right caudate nucleus (r = 0.6587, p < 0.001), and IVIM-f in the right amygdala (r = 0.6129, p < 0.0001), and negatively associated with IVIM-D in the left putamen (r =  - 0.5078, p < 0.001). ROC analysis showed that IVIM-f yielded higher AUC values than ADCst for distinguishing AD from non-AD participants (AUC = 0.7644 vs. 0.6643), NC from MCI participants (AUC = 0.8548 vs. 0.6571), and MCI from AD participants (AUC = 0.7205 vs. 0.6211); however, this comparison should be interpreted cautiously because ADCst did not show significant intergroup differences.

CONCLUSION: IVIM-derived parameters are closely associated with cognitive impairment severity and provide improved differentiation among AD, MCI, and normal controls, supporting their potential clinical utility for early diagnosis and disease assessment.},
}

@article {pmid42763018,
year = {2026},
author = {Patergnani, S and Trentini, A and Rosta, V and Guindani, P and Greatti, A and Pedrini, D and Meneguzzo, G and Rigon, L and Filippini, N and Giusto, E and Zuliani, G and Pinton, P and Cervellati, C},
title = {Dysfunctional mitophagy in Alzheimer's disease: evidence from peripheral Optineurin.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.09.013},
pmid = {42763018},
issn = {1873-4596},
abstract = {Mitophagy and mitochondrial quality-control pathways are impaired in Alzheimer's disease (AD), but the relevance of peripheral mitophagy markers and their regulation during sustained amyloid-β (Aβ) stress remain unclear. We investigated whether serum optineurin, a mitophagy receptor, is altered in mild cognitive impairment (MCI) and AD, and explored mitophagy dynamics in an in vitro model of Aβ1-42-induced mitochondrial stress. To achieve this aim, serum optineurin was measured in 458 older individuals, including controls and patients with AD, mild cognitive impairment (MCI), and mixed Alzheimer's disease/ vascular dementia (MIXED). Complementary in vitro experiments were performed in SH-SY5Y neuroblastoma cells exposed to Aβ1-42 over time, to evaluate mitochondrial function, oxidative stress, lipid peroxidation, lactate release, Parkin/optineurin recruitment, mitophagy, mitochondrial quality-control markers, apoptosis, and cell viability. Serum optineurin was markedly lower in MCI and AD groups than in controls (p < 0.001 for both) and was also reduced in MIXED (p < 0.001). Serum 4-HNE was increased in MCI and AD, consistent with systemic oxidative stress. In vitro, Aβ1-42 induced an early increase in mitophagy and optineurin expression, followed by a later decline associated with impaired mitochondrial quality-control markers, apoptotic activation, and reduced cell viability. In conclusion, optineurin emerges as a candidate peripheral biomarker associated with AD and MCI. In vitro, Aβ1-42 exposure was associated with an early increase in mitophagy-related responses followed by progressive mitochondrial dysfunction, oxidative stress, apoptotic activation, and reduced cell viability. These findings support the relevance of optineurin within mitochondrial quality-control pathways under AD-related stress.},
}

@article {pmid42763022,
year = {2026},
author = {Zhang, B and Wang, Z and Zhao, X and Zhu, J and Zhang, Y and Wang, Y and Yang, J and Cheng, J and Yang, X and Zhu, F and Shen, W and Lu, W},
title = {D-Cycloserine ameliorates innate fear deficits in young adult male APP/PS1 mice: Involvement of GluN2B-containing NMDA receptor.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {174272},
doi = {10.1016/j.pbb.2026.174272},
pmid = {42763022},
issn = {1873-5177},
abstract = {Neuropsychiatric symptoms can emerge early in Alzheimer's disease (AD), but whether innate fear is altered prior to amyloid plaque deposition remains unclear. This study aimed to examine innate fear responses in young adult male APP/PS1 mice and to evaluate whether D-cycloserine (DCS) rescues such deficits via GluN2B-containing NMDA receptors. Male APP/PS1 mice (2-3 months old) exhibited impaired innate fear responses in the looming disk test, while their motor function and contextual fear memory remained intact. Hippocampal Grin2b expression was reduced in the APP/PS1 mice. DCS restored normal fear responses, an effect blocked by GluN2B antagonists but unaffected by GluN2A inhibition. Our results demonstrate that innate fear deficits emerge early in male APP/PS1 mice and are rescued by DCS through activation of hippocampal GluN2B-containing NMDA receptor, highlighting a potential target for early AD-related neuropsychiatric symptoms.},
}

@article {pmid42763072,
year = {2026},
author = {Shehu, K and Onimisi, OB and Bunza, HA and Umar, SM and Oyem, JC and Adewumi, TA},
title = {Prenatal origins of neurodegeneration: The role of maternal immune activation in Alzheimer's and Parkinson's pathobiology.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116029},
doi = {10.1016/j.expneurol.2026.116029},
pmid = {42763072},
issn = {1090-2430},
abstract = {Recent evidence suggests that prenatal environmental factors, particularly maternal infection or maternal immune activation (MIA), may influence the progression of brain aging and lifetime risk for neurodegenerative disorders. The hypothesis is that even a short-lived inflammatory event during pregnancy may leave a lasting imprint on the developing brain and immune system of the fetus, such that aging or subsequent insults may later unmask neurodegenerative disorders. Support for this hypothesis comes largely from animal studies, where gestational inflammation has been shown to potentiate the onset of Alzheimer's and Parkinson's diseases (AD/PD), by increasing amyloid/tau pathology, reducing synaptic connections, and damaging nigrostriatal dopaminergic neurons. We review convergent mechanisms, including microglial priming, chronic cytokine excess, oxidative stress, epigenetic marks and proteostatic deficits, through which maternal immune activation may embed a latent "hit" that synergizes with aging to precipitate AD or PD. Furthermore, we appraise experimental models and available human data linking MIA to AD versus PD, noting shared and distinct pathways. Despite growing preclinical evidence, translation to human cohorts remains limited by heterogeneity in MIA exposure timing and outcome measures. An understanding of MIA's impact on neurodegeneration could suggest preventive strategies and interventions for early diagnosis and treatment.},
}

@article {pmid42763160,
year = {2026},
author = {Chen, CH and She, BC and Chen, YL and Wang, CC and Wu, SM},
title = {Magnetic-assisted catalytic hairpin assembly fluorescent aptasensor for highly sensitive detection of amyloid-beta oligomers as Alzheimer's disease biomarker.},
journal = {Analytica chimica acta},
volume = {1422},
number = {},
pages = {346100},
doi = {10.1016/j.aca.2026.346100},
pmid = {42763160},
issn = {1873-4324},
mesh = {*Amyloid beta-Peptides/analysis/blood ; *Aptamers, Nucleotide/chemistry ; *Alzheimer Disease/diagnosis/blood ; Humans ; *Biosensing Techniques/methods ; Biomarkers/blood/analysis ; Limit of Detection ; *Fluorescent Dyes/chemistry ; Catalysis ; Spectrometry, Fluorescence ; Magnetic Phenomena ; },
abstract = {BACKGROUND: The abnormal accumulation of amyloid-beta peptides is a key contributor to Alzheimer's disease. Of these peptides, soluble amyloid-beta oligomers (AβOs) have emerged as potent neurotoxins and early pathological biomarkers. Although AβOs are highly specific biomarkers, their low physiological abundance, structural heterogeneity and matrix interference associated present considerable challenges for conventional diagnostic approaches. Herein, we report a novel fluorescent aptasensor platform for the ultrasensitive detection of AβOs. The platform integrates magnetic preconcentration with a signal amplification strategy based on catalytic hairpin assembly (CHA).

RESULTS: To achieve simultaneous selective recognition of AβOs and efficient CHA initiation, magnetic beads were functionalized with rationally designed double-stranded DNA complexes, which were formed through the hybridization of an AβO-specific aptamer and a CHA-initiator fragment. Upon the specific binding of AβOs, the AβO-specific aptamer competitively dissociates from the magnetic beads, thereby unmasking the surface-tethered initiator to trigger the CHA circuit. The circularly generated CHA products serve as a self-amplifying signal indicator, whereas the magnetic beads enhance target-capturing capacity and facilitate the removal of complex matrix interferences prior to amplification. Experimental results revealed that the proposed system exhibited a broad linear detection range from 10 pg mL[-1] to 10 ng mL[-1] with a detection limit of 4.1 pg mL[-1] (r = 0.9821). Furthermore, to demonstrate its applicability, plasma samples from healthy individuals were analyzed. The results indicated that the AβO level ranged from 87 to 290 pg mL[-1].

SIGNIFICANCE AND NOVELTY: These findings demonstrate the potential of integrating aptamer-mediated magnetic capture with CHA-driven signal amplification for ultrasensitive AβO detection. The spatial separation of AβO-aptamer binding and CHA amplification through magnetic beads effectively minimizes matrix interference while permitting large sample volumes. This strategy has the potential to serve as sensitive tool for early Alzheimer's disease diagnosis.},
}

*Amyloid beta-Peptides/analysis/blood
*Aptamers, Nucleotide/chemistry
*Alzheimer Disease/diagnosis/blood
Humans
*Biosensing Techniques/methods
Biomarkers/blood/analysis
Limit of Detection
*Fluorescent Dyes/chemistry
Catalysis
Spectrometry, Fluorescence
Magnetic Phenomena

@article {pmid42763350,
year = {2026},
author = {Duan, X and Chen, Z and Tong, X and Li, X and Liu, Z and Yang, Y and Liu, X and Liu, W},
title = {Irisin-BDNF axis mediates muscle-brain communication: a complete molecular cascade and potential bidirectional feedback from peripheral activation to central protection.},
journal = {Biogerontology},
volume = {27},
number = {5},
pages = {},
pmid = {42763350},
issn = {1573-6768},
support = {Grant No. 2026JJ90271//Natural Science Foundation of Hunan Province/ ; },
mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; *Fibronectins/metabolism ; Animals ; *Brain/metabolism ; *Muscle, Skeletal/metabolism ; *Alzheimer Disease/metabolism ; Myokines ; Signal Transduction ; Feedback, Physiological ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, with core pathological mechanisms including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and impaired synaptic plasticity. Although exercise has neuroprotective effects, the molecular mechanisms by which it mediates peripheral-central communication remain unclear. The concept of the 'muscle-brain dialogue' offers a new perspective on this process. irisin, secreted by skeletal muscle in response to exercise, forms a molecular link between peripheral exercise and central neuroprotection by specifically regulating brain-derived neurotrophic factor (BDNF). This review summarizes the molecular cascade mechanisms of the irisin-BDNF axis in mediating the muscle-brain dialogue: Irisin is synthesized via the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)/fibronectin domain-containing protein 5 (FNDC5) pathway. Current evidence suggests that peripheral irisin may communicate with the central nervous system through mechanisms related to the blood-brain barrier, including potential αVβ5 integrin-mediated interactions, thereby participating in the regulation of BDNF. As a core effector molecule, BDNF improves cognitive decline in AD by enhancing neuroplasticity, reducing Aβ deposition, inhibiting tau hyperphosphorylation, and alleviating neuroinflammation. However, oxidative stress and mitochondrial dysfunction associated with AD pathology negatively regulate this axis, creating a vicious cycle. Therefore, this paper explores potential intervention strategies and the prospects for future translational research, including upstream exercise interventions, midstream barrier-crossing enhancing peptides, and downstream small-molecule TrkB agonists. Targeting this axis provides a new theoretical foundation and translational direction for the early prevention and treatment of AD, as well as for drug development.},
}

Humans
*Brain-Derived Neurotrophic Factor/metabolism
*Fibronectins/metabolism
Animals
*Brain/metabolism
*Muscle, Skeletal/metabolism
*Alzheimer Disease/metabolism
Myokines
Signal Transduction
Feedback, Physiological

@article {pmid42763575,
year = {2026},
author = {Jahanbin, K and , },
title = {Glial and Vascular Plasma Biomarkers Across the Alzheimer's Disease Continuum: An ADNI-Based Longitudinal Study.},
journal = {FASEB bioAdvances},
volume = {8},
number = {9},
pages = {e70155},
pmid = {42763575},
issn = {2573-9832},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multicellular disorder involving neurovascular unit dysfunction. Investigating glial and vascular biomarkers together may provide a more integrated view of AD biology. This study characterized baseline distributions, interrelationships, and longitudinal trajectories of plasma glial (GFAP, sTREM2) and vascular/endothelial (VEGF, sICAM-1, sVCAM-1) biomarkers across the AD continuum. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) data, this retrospective longitudinal cohort study included a covariate-complete clinical cohort of 2650 participants classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD dementia. Biomarker-specific analytic samples were determined by assay availability and complete-case requirements. Associations were evaluated using covariate-adjusted linear regression and linear mixed-effects models with participant random intercepts, adjusted for baseline age, sex, education, and APOE ε4 status. Vascular models were additionally refitted with body mass index, systolic blood pressure, antihypertensive and antidiabetic medication use, smoking history, and estimated glomerular filtration rate. Baseline GFAP showed a robust stepwise elevation from CU to MCI to AD (56.3% higher in AD than CU, q = 1.7 × 10[-14]; area under the curve 0.82), whereas sTREM2 distributions overlapped across groups. VEGF and sVCAM-1 were higher in AD than CU (14.1%, q = 0.014; 14.7%, q = 0.002), with areas under the curve of 0.61 and 0.63 and more than 80% distribution overlap. GFAP increased by 4.50% per year in CU participants and sTREM2 by 2.99% per year, with no significant diagnosis-by-time interactions for either. Over a 12-month interval, sICAM-1 declined in CU participants, and this decline was attenuated in MCI and AD, while sVCAM-1 increased in CU participants and showed negative diagnosis-by-time interactions. The vascular longitudinal findings were unchanged by adjustment for cardiometabolic and renal covariates, by time-varying diagnosis, and by separating stable MCI from MCI-to-AD converters. Correlations among vascular markers were consistent and well estimated, whereas glial-vascular correlations were based on 64 to 94 overlapping participants and were not significant. Glial and vascular plasma biomarkers did not progress synchronously across the AD continuum. GFAP showed the strongest and most discriminating diagnosis-associated elevation. Vascular markers showed statistically robust but small group-level differences with no individual-level discriminative utility, and their divergent 12-month trajectories require replication over longer follow-up before they can be interpreted as stage-dependent regulation.},
}

@article {pmid42763636,
year = {2026},
author = {Sarangal, M and Sarangal, C and Vora, J and Soni, K},
title = {Auvelity (Dextromethorphan-Bupropion) for Agitation and Aggression in Alzheimer's Disease Dementia: Mechanism, Efficacy, Safety, and Clinical Considerations.},
journal = {Psychopharmacology bulletin},
volume = {56},
number = {4 Suppl 1},
pages = {82-87},
pmid = {42763636},
issn = {2472-2448},
mesh = {Humans ; *Dextromethorphan/therapeutic use/adverse effects/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/psychology/complications ; Drug Combinations ; *Psychomotor Agitation/drug therapy/etiology ; *Aggression/drug effects ; *Bupropion/therapeutic use/adverse effects/pharmacology/administration & dosage ; Cytochrome P-450 CYP2D6 Inhibitors/therapeutic use/adverse effects/pharmacology ; },
abstract = {BACKGROUND: Agitation and aggression in Alzheimer's disease (AD) are highly distressing behavioral symptoms traditionally managed with off-label atypical antipsychotics, despite boxed warnings for increased mortality in elderly patients. The emergence of Auvelity (dextromethorphan-bupropion) provides a critical, non-antipsychotic therapeutic alternative.

MECHANISM: This combination utilizes bupropion as a CYP2D6 inhibitor to achieve therapeutic central nervous system concentrations of dextromethorphan. Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, bypassing dopaminergic blockade to promote synaptic plasticity via glutamatergic and monoaminergic modulation.

EFFICACY: Key clinical trials (ADVANCE-1 and ACCORD) demonstrate that dextromethorphan-bupropion produces rapid, statistically significant reductions in Cohen-Mansfield Agitation Inventory (CMAI) scores. Furthermore, it offers robust long-term maintenance, demonstrating a 3.6-fold lower risk of agitation relapse compared to placebo.

SAFETY: The combination therapy was generally well-tolerated in trials, successfully avoiding the sedation, cognitive blunting, and heightened fall risks characteristic of antipsychotics. Clinicians must, however, monitor for blood pressure changes and potential CYP2D6 drug-drug interactions.

CONCLUSION: Dextromethorphan-bupropion represents a highly efficacious, safer paradigm shift in the pharmacological management of AD-associated agitation, offering targeted symptom relief while minimizing the severe risks associated with standard antipsychotic use.},
}

Humans
*Dextromethorphan/therapeutic use/adverse effects/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/psychology/complications
Drug Combinations
*Psychomotor Agitation/drug therapy/etiology
*Aggression/drug effects
*Bupropion/therapeutic use/adverse effects/pharmacology/administration & dosage
Cytochrome P-450 CYP2D6 Inhibitors/therapeutic use/adverse effects/pharmacology

@article {pmid42763949,
year = {2026},
author = {Higashi, K and Sasaki, T and Takahashi, H and Kawai, Y and Hennig, S and Shimizu, K and Nakai, M and Takahashi, K and Nakamura, Y},
title = {Population pharmacokinetic analysis and exposure-response analysis of brexpiprazole in Japanese patients with agitation in Alzheimer's dementia.},
journal = {Drug metabolism and pharmacokinetics},
volume = {71},
number = {},
pages = {101549},
doi = {10.1016/j.dmpk.2026.101549},
pmid = {42763949},
issn = {1880-0920},
abstract = {The efficacy and safety of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD) were demonstrated in Japanese study with 1 and 2 mg/day doses. The purpose of this study was to investigate need for dose adjustment in Japanese patients with AAD using population pharmacokinetics (PopPK) and exposure-response (ER) analysis, given that this population was older and renally impaired. First, using PopPK analysis, applicability of the previous PopPK model for Japanese healthy volunteers and patients with schizophrenia, established in a previous study, was confirmed to predict brexpiprazole concentrations in Japanese patients with AAD. Then, using exposure data from the PopPK model, ER analysis demonstrated that ER relationship was adequately described by sigmoid Emax model, although some parameters (EC50 and Hill) had RSEs >60%. Covariate analysis using PopPK model indicated that older age and/or reduced renal function were associated with increased exposure. However, these changes were considered to remain within the plateau region of ER relationship, suggesting limited clinical impact on efficacy. Therefore, brexpiprazole dose adjustment according to patient characteristics was not considered necessary in Japanese patients with AAD. Given the limited data and residual model instability in ER analysis, further investigation may be warranted to confirm the findings.},
}

@article {pmid42763962,
year = {2026},
author = {Ye, J and Yin, S and Lin, Y and Yang, S and Ma, L and Wang, Y and Gao, K and Wang, Y and Yang, X and Yang, Z and Wang, N and Liu, H and Xu, S and Cui, W and Zhang, B},
title = {Substituted methyl acridone-carboxylate derivatives as CD1/CD2 dual-targeting HDAC6 inhibitors to ameliorate the pathological phenotype of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119350},
doi = {10.1016/j.ejmech.2026.119350},
pmid = {42763962},
issn = {1768-3254},
abstract = {Histone deacetylase 6 (HDAC6) has emerged as a promising target for Alzheimer' disease (AD). Although most reported HDAC6 inhibitors were designed to target CD2 catalytic domain, recent studies highlighted the functional importance of CD1 domain for the regulation of AD-related substrates. In this study, a series of substituted methyl acridone-carboxylate derivatives bearing a methyl ester moiety were discovered as CD1/CD2 dual-targeting HDAC6 inhibitors. The leading compound 6c could direct bind to HDAC6, and selectively inhibits HDAC6 with a high affinity in vitro. Molecular docking analysis revealed that 6c forms non-chelating coordination interactions with the zinc ions in both CD1 and CD2 domains of HDAC6. 6c inhibited Aβ oligomer-induced microtubule depolymerization and microglial phagocytic impairments in vitro. Furthermore, 6c effectively prevented HDAC6-driven α-tubulin and Hsp90 deacylation, as well as cognitive impairments in Aβ1-42 oligomer-treated mice. Combined with the acceptable physicochemical properties and promising biosafety of 6c, this study suggested that substituted methyl acridone-carboxylate derivatives, as CD1/CD2 dual-targeting HDAC6 inhibitors, might be developed as a novel lead drug for the treatment of AD.},
}

@article {pmid42763975,
year = {2026},
author = {Thattil, HJ and M N, A},
title = {Global transfer learning pipeline for protein disease association in Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109408},
doi = {10.1016/j.compbiolchem.2026.109408},
pmid = {42763975},
issn = {1476-928X},
abstract = {Researchers have prioritized the study of protein-disease associations to decode triggers of clinical pathology and isolate high-value targets for drug development. Comprehensive modeling of genetic network dynamics is equally vital for advancing our functional understanding of these disorders. In this study, we applied a hierarchical, transfer-learning framework to address the challenge of protein-disease association prediction, specifically targeting scenarios with limited labeled data for specific diseases. We used Alzheimer's disease as a case study to demonstrate the efficacy of our proposed Global Transfer Learning Pipeline model. We combined the embeddings generated from protein-protein interactions along with protein-cluster association and protein sequences to train the proposed model. We addressed the scarcity of reliable negatives by employing PU learning strategies with deep fusion architecture to ensure robustness of the model. The ordinal regression was integrated to the learning pipeline to learn granular confidence levels for protein-disease associations which was later fed into the stacked meta model. The model also uses techniques of hyperparameter optimization to enhance the prediction performance. Our model achieved a weighted F1 score of 96% with average AUC 0.852 and AUPRC 0.967 which outperforms the individual gradient boosting, tree models and deep neural network models. These results demonstrate the effectiveness of the proposed model in predicting protein-disease associations for Alzheimer's disease.},
}

@article {pmid42763978,
year = {2026},
author = {Lisazo, C and Casamitjana, A and Oliver, A and Lladó, X and , and , },
title = {Learning age-conditioned brain atlases via free-prototype modeling for brain age prediction.},
journal = {Artificial intelligence in medicine},
volume = {182},
number = {},
pages = {103534},
doi = {10.1016/j.artmed.2026.103534},
pmid = {42763978},
issn = {1873-2860},
abstract = {Brain age (BA) estimation from structural MRI is a promising biomarker for the early detection, monitoring, and risk stratification of neurodegenerative disorders, yet most existing approaches rely on black-box deep learning models that limit clinical interpretability. Prototype-based learning offers a promising alternative by grounding predictions in reference representations, but current methods depend on selecting prototypes from real training samples, introducing subject-specific variability and requiring curated datasets. In this work, we propose a free-prototype framework that directly learns age-conditioned prototypes in latent space instead of anchoring them to individual training samples. These prototypes are decoded into age-conditioned brain atlases that provide clinically interpretable visual references of anatomical aging. Extensive experiments across multiple large-scale neuroimaging cohorts demonstrate that the proposed approach achieves BA predictive performance comparable to state-of-the-art convolutional models in-domain while improving robustness under distribution shift in external datasets. Moreover, our results show that deviations from age-matched prototypes capture clinically relevant information beyond the conventional BA gap, enabling improved discrimination between healthy controls and Alzheimer's disease patients. Hence, beyond the limited notion of accelerated aging as a biomarker of disease, our findings support the use of residual information as complementary evidence to improve diagnostic frameworks in clinical settings. Finally, structural analyses confirm that the learned atlases follow smoother and more biologically consistent aging trajectories than prototype representations based on real-image selection. These findings demonstrate that structuring the latent space around learned prototypes enables accurate and robust BA estimation while providing clinically interpretable normative references for understanding deviations from healthy brain aging.},
}

@article {pmid42764010,
year = {2026},
author = {Shao, F and Hu, J and Traylor, A and Lei, H and Zhang, P and Akarapipad, P and Park, JS and Hsieh, K and Wang, TH},
title = {CRISPR-AMPED: A CRISPR/Cas-based immunoassay with attomolar sensitivity enabled by magnetic proximity extension and detection.},
journal = {Biosensors & bioelectronics},
volume = {315},
number = {},
pages = {119227},
doi = {10.1016/j.bios.2026.119227},
pmid = {42764010},
issn = {1873-4235},
abstract = {Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-associated systems have emerged as powerful tools for next-generation molecular diagnostics, particularly for nucleic acid detection. However, ultrasensitive protein detection is equally critical across diverse applications in biology and medicine, especially for diagnosing and prognosing diseases such as cancer, traumatic brain injury (TBI), Alzheimer's disease, and cardiovascular diseases. Despite recent efforts to adapt CRISPR/Cas systems for protein detection, these methods have typically achieved sensitivity in the femtomolar to picomolar range, underscoring the need for enhanced detection capabilities. Here, we developed CRISPR-AMPED, a CRISPR/Cas-based immunoassay enhanced by magnetic proximity extension and detection. This approach combines proximity extension assay (PEA) with magnetic beads to convert protein targets into DNA barcodes while enabling effective washing to reduce background noise. The resulting DNA barcodes are detected through recombinase polymerase amplification (RPA) coupled with CRISPR/Cas12a, eliminating thermocycling and providing simultaneous target and signal amplification. CRISPR-AMPED achieves attomolar-level sensitivity, surpassing ELISA by over three orders of magnitude and outperforming existing immunoassays and CRISPR/Cas-based protein detection systems. As an initial demonstration of clinical utility, we applied CRISPR-AMPED to detect the inflammatory biomarker interleukin-8 (IL-8) in serum samples from patients with TBI and healthy controls. Further integration with a smartphone-based detection device demonstrates its potential for portable testing, while the digital format extends the dynamic range and enhances quantitation precision. Together, these results establish CRISPR-AMPED as a sensitive protein detection approach using IL-8 as an initial model target and provide a framework for future adaptation to additional protein biomarkers.},
}

@article {pmid42764037,
year = {2026},
author = {Pereira, CS and Abid, H and Adair, C and Domalewski, RJ and Jabr, L and Nichols, MR},
title = {Aggregated amyloid-β(1-42) is internalized more efficiently than monomers by HEK293T cells.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {},
number = {},
pages = {141178},
doi = {10.1016/j.bbapap.2026.141178},
pmid = {42764037},
issn = {1878-1454},
abstract = {An early and continual event in Alzheimer's disease (AD) is upregulation of the immune response concomitant with accumulation of aggregated amyloid-β peptide (Aβ). The mechanisms by which Aβ can trigger an immune response involve stimulation of cell surface receptors and intracellular pathways, as well as internalization of Aβ into the cell cytosol. The HEK293T cell line has been a valuable model system for exploring a variety of biological processes, including internalization of protein aggregates such as Aβ. There have been some questions regarding the role of Aβ conformation in the HEK293T internalization process. The current study investigated the influence of Aβ42 conformation on HEK293T internalization using ELISA, confocal microscopy and flow cytometry. Analysis of HEK293T cell lysates by ELISA after exposure to Aβ42 conformational species indicated that protofibrillar and fibrillar Aβ42 were internalized to a much greater extent compared to purified Aβ42 monomers. The same trend was observed in HEK293T whole cells by confocal fluorescence imaging. HEK293T cell internalization occurred by 4 h for aggregated Aβ42 at concentrations in the low micromolar range. Fluorescent labeling of Aβ42 did not impact cell internalization and facilitated the use of flow cytometry as a third strategy to show significantly greater internalization of Aβ42 protofibrils compared to monomers, further confirming the Aβ42 conformational influence on HEK293T cell internalization. HEK293T cell models are valuable tools for mechanistic investigations of human disease and characteristically generate detailed information about cellular processes or pathways. These include Aβ cellular internalization and intracellular Aβ, which are key aspects of AD pathogenesis.},
}

@article {pmid42764107,
year = {2026},
author = {Desale, SH and Doshi, PP and Khutale, AA and Suresh, S},
title = {Unlocking the Blood-Brain Barrier: Can Low-Intensity Focused Ultrasound Enable Effective Delivery of Anti-Amyloid and Anti-Tau Antibodies in Alzheimer's Disease?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103379},
doi = {10.1016/j.arr.2026.103379},
pmid = {42764107},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) remains a major unmet medical challenge despite decades of progress in medicines that target tau and amyloid-β (Aβ) pathology. The clinical benefit of monoclonal antibodies (mAbs) against Aβ is limited, with current data showing only slight slowing of cognitive decline despite encouraging biomarker responses and recent regulatory approval of these drugs. Moreover, their wider clinical use is restricted by dose-dependent toxicities such as amyloid-related imaging abnormalities (ARIA), and by the need for continuous long-term assessment of efficacy and safety in AD patients. The poor penetration of the blood-brain barrier (BBB) by large biologics is a significant but often overlooked factor contributing to this discrepancy. Low-intensity focused ultrasound (LIFU) has emerged as a non-invasive technique for transient localized modification of BBB permeability when paired with intravenously administered microbubbles. This evaluation examines LIFU as a means of delivering anti-tau and anti-amyloid antibodies to AD patients. By integrating data from early-phase clinical research with biological insights, we investigate whether altering the BBB can overcome the pharmacokinetic (PK) limitations of existing immunotherapies. LIFU has biological effects that are critical to the pathophysiology of AD in addition to aiding the mobility of macromolecules, such as enhanced lymphatic clearance and focused neuroimmune activation, which could help treatments based on antibodies. Clinical research to date shows that, in properly chosen AD cohorts, LIFU-mediated BBB opening is practical, reversible, and generally safe; however, there is still a lack of conclusive evidence connecting BBB modulation to elevated intraparenchymal antibody levels or long-term cognitive enhancement. We propose that LIFU should currently be regarded as a promising investigational adjunct to immunotherapy rather than an established therapeutic modality for AD. Biomarker-driven evidence of enhanced cerebral medication distribution and therapeutic effects determines its translational significance; BBB alteration could become a standard Alzheimer's therapeutic strategy if LIFU is successful.},
}

@article {pmid42764149,
year = {2026},
author = {Omori, W and Kajitani, N and Okada-Tsuchioka, M and Takebayashi, M},
title = {Cerebrospinal Fluid p75 Neurotrophin Receptor Ectodomain Levels Across Clinically Diagnosed Alzheimer's Disease, Late-Life Depression, and Healthy Aging: A Preliminary Cross-Sectional Study.},
journal = {Neuropsychopharmacology reports},
volume = {46},
number = {3},
pages = {e70171},
pmid = {42764149},
issn = {2574-173X},
support = {23K14818//JSPS KAKENHI/ ; 18H02756//JSPS KAKENHI/ ; 18K07620//JSPS KAKENHI/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Female ; Male ; Cross-Sectional Studies ; Aged ; *Healthy Aging/cerebrospinal fluid ; *Receptors, Nerve Growth Factor ; *Depression/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; *Nerve Tissue Proteins/cerebrospinal fluid ; Receptor, Nerve Growth Factor ; },
abstract = {OBJECTIVE: The p75 neurotrophin receptor ectodomain (p75NTR-ECD) has been implicated in amyloid-β-related neurotoxicity, but cerebrospinal fluid (CSF) levels in late-life depression (LLD) remain uncertain. We compared clinically diagnosed Alzheimer's disease (AD), LLD, and healthy controls (HC) and reassessed exploratory symptom and cognitive associations.

METHODS: CSF p75NTR-ECD was measured in 50 participants (HC, n = 19; LLD, n = 19; AD, n = 12). The primary linear model adjusted for age, sex, and body mass index. Exploratory symptom and cognitive models additionally adjusted for diagnostic group; six p values underwent Benjamini-Hochberg false discovery rate (FDR) correction. Plate and below-calibrator sensitivity analyses were performed.

RESULTS: CSF p75NTR-ECD was higher in HC than in AD (B = 131.2 pg/mL, 95% CI 42.8-219.6, p = 0.005) and higher in LLD than in AD (B = 154.6 pg/mL, 95% CI 68.9-240.3, p < 0.001); HC and LLD did not differ. No symptom or cognitive association remained significant after diagnostic-group adjustment and FDR correction (all q ≥ 0.117). Plate adjustment did not materially change the primary contrasts. Excluding three concentrations below the lowest calibrator preserved the LLD-AD contrast but attenuated the HC-AD contrast.

CONCLUSIONS: CSF p75NTR-ECD showed preliminary differences across clinically defined groups. Because the sample was small, the recruitment site was perfectly confounded with AD versus non-AD status, and diagnoses were not uniformly biomarker-confirmed, the findings do not establish causality, clinical diagnostic utility, or added value beyond established AD biomarkers and require independent multisite replication.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Female
Male
Cross-Sectional Studies
Aged
*Healthy Aging/cerebrospinal fluid
*Receptors, Nerve Growth Factor
*Depression/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Aged, 80 and over
*Nerve Tissue Proteins/cerebrospinal fluid
Receptor, Nerve Growth Factor

@article {pmid42764315,
year = {2026},
author = {Shao, Y and Zhang, RF and Wang, Z and Gan, J and Jiang, XJ and Yang, L},
title = {From Dysbiosis to Blood-Brain Barrier Disruption: The Metabolite-Mediated Gut-Brain Axis in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42764315},
issn = {1559-1182},
mesh = {Humans ; *Blood-Brain Barrier/metabolism/pathology ; Animals ; *Alzheimer Disease/metabolism/pathology/microbiology ; *Dysbiosis/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is not merely a central nervous system disorder; rather, it is a systemic condition profoundly influenced by the peripheral internal environment. Recent research has revealed that imbalances in the gut microbiota (GM) and metabolite disturbances contribute to AD onset and progression. Clinical and animal studies have indicated that AD patients commonly exhibit reduced GM diversity, decreased populations of short-chain fatty acid (SCFA)-producing and indole-producing bacteria, disrupted bile acid (BA) profiles, and elevated levels of trimethylamine N-oxide (TMAO) and kynurenine pathway (KP) activity. These alterations not only reflect gut dysbiosis, but also impair blood-brain barrier (BBB) integrity and amplify neuroinflammation by modulating tight junction proteins and inflammatory signaling through their effects on receptors and transporters such as G protein-coupled receptors(GPR41/43), aryl hydrocarbon receptor(AhR), Farnesoid X receptor(FXR)/ Takeda G protein-coupled receptor 5(TGR5), L-type amino acid transporter 1(LAT1), and Major Facilitator Superfamily Domain containing 2A(MFSD2A). From an integrative perspective, these changes -including short-Chain Fatty Acids (SCFAs) deficiency, elevated TMAO and toxic BA levels, overactivation of the KP, and Lipopolysaccharides (LPS) leakage-often act synergistically, collectively forming key pathological nodes in the "metabolic network-BBB-AD" axis. GM-targeted strategies such as dietary interventions, probiotics and fecal microbiota transplantation (FMT) have demonstrated potential in improving metabolite profiles and BBB homeostasis. Future research should utilize induced pluripotent stem cell-derived organoids and multi-omics integration approaches to elucidate the spatiotemporal dynamics of metabolites within the gut-brain axis (GBA), thereby laying the foundation for precise microbiome-based interventions in AD.},
}

Humans
*Blood-Brain Barrier/metabolism/pathology
Animals
*Alzheimer Disease/metabolism/pathology/microbiology
*Dysbiosis/metabolism
*Gastrointestinal Microbiome/physiology
*Brain-Gut Axis/physiology
*Brain/metabolism

@article {pmid42764330,
year = {2026},
author = {Marimuthu, A and Singh, MT and Balasubramanian, S and Krishnamurthy, PT},
title = {Targeting the BACE1-GSK-3β Signaling Axis in Alzheimer's Disease: From Molecular Crosstalk to Nanotechnology-Based Translational Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42764330},
issn = {1559-1182},
mesh = {Humans ; *Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; Animals ; *Signal Transduction/physiology/drug effects ; *Nanotechnology/methods ; *Translational Research, Biomedical/methods ; *Glycogen Synthase Kinase 3/metabolism ; },
abstract = {Recent evidence demonstrates that the interplay of amyloidogenesis and tauopathy plays a significant role in exacerbating neurodegeneration in Alzheimer's disease. This interplay of molecular pathways aids in the formation and accumulation of amyloid beta and neurofibrillary tangles extracellularly and intracellularly, respectively. These interconnected pathways highlight the need for the simultaneous inhibition of BACE1 and GSK-3β for the mitigation of disease progression. There are several drugs developed against BACE1 and GSK-3β separately, but they have limited therapeutic efficacy and failed in clinical trials. The failure is due to systemic toxicity and off-target side effects, limited blood-brain barrier permeation, and lower therapeutic benefits. Advances in brain-targeted drug delivery approaches aim to provide site-specific drug delivery, co-delivery of dual drugs, and enhanced stability. Nanoformulations such as lipid-based nanoparticles, polymeric nanoparticles, and hybrid nanoformulations with surface functionalization demonstrate better results in pre-clinical studies. Various research studies have established that targeting amyloidogenesis and tau hyperphosphorylation pathways is a promising therapeutic approach for attenuating neurodegeneration, with the integration of nanotechnology. This review article provides insights into the interplay of BACE1 and GSK-3β molecular signaling pathways, examines the limitations of conventional therapies, and highlights the potential of dual-targeting nanoformulations, while emphasizing the challenges of clinical translation and effective therapeutic strategies to overcome these and treat AD.},
}

Humans
*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Alzheimer Disease/metabolism/drug therapy
*Glycogen Synthase Kinase 3 beta/metabolism
*Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors
Animals
*Signal Transduction/physiology/drug effects
*Nanotechnology/methods
*Translational Research, Biomedical/methods
*Glycogen Synthase Kinase 3/metabolism

@article {pmid42764440,
year = {2026},
author = {Ye, Z and Zhang, Q and Zhang, B and Teng, B and Wang, S and Chen, J and Li, B and Jin, H and Zheng, Z and Yang, Z and Hu, X and Zhao, X and Huang, S and Weng, Y and Yang, D},
title = {Baseline cerebrospinal fluid complement balance is associated with longitudinal memory decline in relation to plasma p‑tau181 levels in mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71836},
doi = {10.1002/alz.71836},
pmid = {42764440},
issn = {1552-5279},
support = {82302081//National Natural Science Foundation of China/ ; LQ24H090003//Zhejiang Provincial Natural Science Foundation of China/ ; },
mesh = {Humans ; *Cognitive Dysfunction/cerebrospinal fluid/blood ; *tau Proteins/blood/cerebrospinal fluid ; Female ; Male ; Aged ; *Memory Disorders/cerebrospinal fluid/blood ; Longitudinal Studies ; Biomarkers/cerebrospinal fluid/blood ; Phosphorylation ; Neuropsychological Tests ; Cross-Sectional Studies ; *Complement C3/cerebrospinal fluid ; Alzheimer Disease/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: The role of complement in Alzheimer's disease (AD) remains unclear, particularly regarding tau pathology and memory decline.

METHODS: In 123 mild cognitive impairment (MCI) participants from Alzheimer's Disease Neuroimaging Initiative (ADNI), linear mixed‑effects models and Johnson-Neyman analysis examined associations of baseline cerebrospinal fluid (CSF) C3/FH ratio with longitudinal memory decline moderated by time‑varying plasma phosphorylated tau181 (p‑tau181).

RESULTS: The three‑way interaction was significant (p = 0.023). A region of statistical significance was identified: the conditional association of C3/FH with memory decline became significant when p‑tau181 exceeded 0.76 SD, with higher C3/FH associated with slower decline at elevated p‑tau181 levels. Cross-sectionally, no significant C3/FH-memory associations were observed in any diagnostic group (all p > 0.05).

DISCUSSION: These findings indicate that complement balance is associated with memory decline in MCI in a manner dependent on plasma p‑tau181 levels, suggesting that complement may interact with AD‑related pathophysiology during the prodromal phase. The identified statistical region provides a hypothesis‑generating benchmark for future studies.},
}

Humans
*Cognitive Dysfunction/cerebrospinal fluid/blood
*tau Proteins/blood/cerebrospinal fluid
Female
Male
Aged
*Memory Disorders/cerebrospinal fluid/blood
Longitudinal Studies
Biomarkers/cerebrospinal fluid/blood
Phosphorylation
Neuropsychological Tests
Cross-Sectional Studies
*Complement C3/cerebrospinal fluid
Alzheimer Disease/cerebrospinal fluid
Aged, 80 and over

@article {pmid42764448,
year = {2026},
author = {},
title = {Correction to "Human iPSC-derived GABAergic interneuron transplantation restores circuit balance and cognitive function in an Alzheimer's disease model".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71875},
doi = {10.1002/alz.71875},
pmid = {42764448},
issn = {1552-5279},
}

@article {pmid42764449,
year = {2026},
author = {Peng, S and Butler-Laporte, G and Johnson, SC and Engelman, CD and Lu, T},
title = {Genetic evidence suggests a protective role of immunoglobulin M in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71865},
doi = {10.1002/alz.71865},
pmid = {42764449},
issn = {1552-5279},
support = {R35GM162188/NH/NIH HHS/United States ; RF1AG054047/NH/NIH HHS/United States ; //of the National Institutes of Health/ ; P2CHD047873//the Center for Demography and Ecology/ ; P30AG017266//the Center for Demography of Health and Aging/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/immunology/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; *Immunoglobulin M/genetics/blood ; Biomarkers/blood ; Immunoglobulin G/blood ; Glial Fibrillary Acidic Protein/blood ; Female ; Male ; Mendelian Randomization Analysis ; Genetic Risk Score ; Aged ; Neurofilament Proteins/blood ; Peptide Fragments/blood ; },
abstract = {INTRODUCTION: Immune dysfunction has been implicated in Alzheimer's disease (AD), but the roles of specific immunoglobulin classes remain unclear.

METHODS: We integrated human genetics and plasma biomarker analyses to evaluate immunoglobulin G (IgG), IgA, and IgM in relation to AD. Two-sample Mendelian randomization analyses were conducted with multiple sensitivity analyses. Polygenic risk scores for immunoglobulin classes were developed in the All of Us Research Program and tested in the UK Biobank for associations with AD and dementia, and in two Wisconsin-based cohorts for associations with plasma amyloid beta (Aβ)42/40, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

RESULTS: Higher genetically proxied IgM was consistently associated with lower AD risk, higher Aβ42/40, and lower p-tau217, but not with NfL or GFAP. No consistent associations were observed for IgG or IgA.

DISCUSSION: IgM-related humoral immunity may play a protective role in AD and warrants exploration for early intervention and prevention.},
}

Humans
*Alzheimer Disease/genetics/immunology/blood
Amyloid beta-Peptides/blood
tau Proteins/blood
*Immunoglobulin M/genetics/blood
Biomarkers/blood
Immunoglobulin G/blood
Glial Fibrillary Acidic Protein/blood
Female
Male
Mendelian Randomization Analysis
Genetic Risk Score
Aged
Neurofilament Proteins/blood
Peptide Fragments/blood

@article {pmid42764492,
year = {2026},
author = {},
title = {Correction to 'Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling'.},
journal = {Journal of neurochemistry},
volume = {170},
number = {9},
pages = {e70560},
doi = {10.1111/jnc.70560},
pmid = {42764492},
issn = {1471-4159},
}

@article {pmid42764574,
year = {2026},
author = {Bhise, MR and Thejomoorthy, K and Kumar, M and Patel, PKN and Mahajan, V and Naquvi, KJ and Ansari, I and Kumar, A},
title = {Advances in Novel Drug Delivery Systems for Targeting the Brain: Overcoming Barriers and Enhancing Therapeutic Efficacy.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018474663260907142216},
pmid = {42764574},
issn = {1875-5704},
abstract = {The blood-brain barrier (BBB) is critical in CNS pharmacotherapy; it blocks the entry of 98 per cent of small-molecule compounds and almost all macromolecules into the brain parenchyma via tight junction complexes, efflux transporter action, and enzymatic breakdown. This review focuses on the mechanistic basis of BBB resistance and analyses the current landscape of new drug delivery systems developed to overcome this barrier. We elaborate on polymeric nanocarriers, lipid-based nanocarriers, exosomes, dendrimers, and metallic nanoparticles, including surface engineering, the possibility of receptor-mediated transcytosis via transferrin, LRP1, and glucose transporter receptors, and known preclinical efficacy in glioblastoma, Alzheimer's disease, and Parkinson's disease. Non-invasive delivery through the nose is evaluated as intranasal delivery because it utilises olfactory and trigeminal receptors to circumvent systemic delivery. BBB modulation mediated by focused ultrasound is mentioned as one of the physical adjuncts to enhance CNS penetration. Clinical translation is poor, even where the preclinical data are positive. Most late-stage failures can be attributed to protein corona formation, anti-PEG immunogenicity, interpatient heterogeneity in the BBB, and manufacturing scalability. These obstacles are critically evaluated with the help of recent clinical trial evidence, where preclinical models cannot be used as predictors of human outcomes. In the future, AI-based nanocarrier design, machine-learning-driven prediction of BBB permeability, and patient-centred nanomedicine platforms will provide a viable pathway to customised CNS therapeutic approaches. Multimodal strategies integrating RMT, stimuli-responsive carriers, and CRISPRbased gene delivery may collectively overcome the translational gap that single-platform approaches have consistently failed to bridge.},
}

@article {pmid42764659,
year = {2026},
author = {Taş, NA and Taş, R and Celebioglu, HU and Taslimi, P and Kaya, S and Berisha, A},
title = {Eco-Friendly Zinc Oxide Nanoparticles from Trachystemon orientalis L.: Examination of Their Antibacterial, Anti-Alzheimer, and Antidiabetic Potentials.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673493377260828095834},
pmid = {42764659},
issn = {1875-533X},
abstract = {INTRODUCTION: This study aimed to biogenically synthesize and characterize Zinc Oxide Nanoparticles (ZnONPs) using the Trachystemon orientalis L. plant extract. It also aimed to evaluate the antibacterial potential and metabolic enzyme-inhibitory activities of these green-synthesized nanoparticles for medical and industrial applications.

METHODS: Nanoparticles were synthesized using a green chemistry approach, where the plant extract acted as a reducing agent for zinc ions. The structural and morphological properties of ZnONPs were analyzed using X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Energy-dispersive X-ray Spectroscopy (EDX). Antibacterial efficacy was evaluated by determining the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) against Staphylococcus aureus and Escherichia coli. Additionally, the inhibitory effects on α-glycosidase, Acetylcholinesterase (AChE), and Butyrylcholinesterase (BChE) enzymes were investigated to determine the inhibition constant (Ki) values. All experiments were conducted in triplicate, and the results are expressed as mean ± standard deviation.

RESULTS: XRD analysis confirmed the crystalline metallic structure of ZnONPs, SEM imaging revealed a predominantly rod-shaped morphology, and EDX analysis verified that the elemental composition was predominantly zinc, consistent with ZnO nanoparticle formation. FTIR spectra confirmed the successful capping of the nanoparticles by plant-derived bioactive compounds. Antibacterial assays showed significant activity, with MIC values of 125 μg/mL for S. aureus and 250 μg/mL for E. coli. Enzyme inhibition studies yielded potent results, with Ki values of 47.10 ± 3.72 μM for α-glycosidase, 3.55 ± 0.43 μM for BChE, and 15.47 ± 1.24 μM for AChE, all of which outperformed standard inhibitors such as tacrine and acarbose.

DISCUSSION: The results demonstrate that the biogenic synthesis of ZnONPs using T. orientalis is an effective and eco-friendly method for producing nanoparticles with high biological activity. The superior enzyme inhibition and antibacterial performance compared to conventional standards suggest that these nanoparticles possess unique surface properties owing to the plant-derived organic shell, enhancing their interaction with biological targets.

CONCLUSION: This study successfully synthesized rod-shaped zinc oxide nanoparticles with significant antimicrobial and enzyme-inhibitory properties. These findings highlight the potential of biogenically synthesized ZnONPs as multifunctional agents in the development of new therapeutic strategies for managing bacterial infections and metabolic disorders.},
}

@article {pmid42764670,
year = {2026},
author = {Thabtah, F and Kamalov, F and Spencer, R and Abdelhamid, N and Nami, M and , },
title = {Plasma biomarker and machine learning modeling of clinical progression in cognitively normal individuals at risk for Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17582024.2026.2731194},
pmid = {42764670},
issn = {1758-2032},
abstract = {AIMS: To evaluate whether plasma biomarkers can distinguish cognitively normal (CN) individuals who remain clinically stable from those who subsequently develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) and to test the predictive performance of classification data‑driven models.

MATERIALS AND METHODS: Plasma biomarker follow-up data from initially CN participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed across Elecsys, Lumipulse, Precivity, and SIMOA assays. Feature selection was done using chi-square, information gain ratio, and ReliefF. K-nearest neighbors (kNN), logistic regression, support vector machine (SVM), and Extreme Gradient Boosting (XGBoost) classifiers were tested using cross-validation. Synthetic Minority Over-sampling Technique (SMOTE) was applied to alleviate class imbalance.

RESULTS: pTau217, pTau181, Aβ40, NfL, and assay-specific amyloid/tau ratios have relatively high feature importance. Class imbalance significantly reduced sensitivity in unbalanced models. Following data balancing, the best‑performing SVM model with selected Elecsys features achieved an accuracy of 71.6%, while the highest sensitivity of all models was 56%.

CONCLUSIONS: Baseline plasma biomarker data, combined with follow-up plasma biomarkers visits can help us identify patterns that are associated with subsequent clinical progression from CN to MCI/AD. However, predictive performance was moderate, and external validation in larger and more diverse cohorts is needed before clinical applications.},
}

@article {pmid42764767,
year = {2026},
author = {Wenxin, S and Youmao, Z and Wenhua, H},
title = {Basic Research on the Lymphatic System and Exploratory Research in LVA Surgery for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050503391260907045733},
pmid = {42764767},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Its characteristic pathological features include Aβ plaque deposition and abnormal tau protein aggregation. Biomarker testing has improved AD diagnosis. However, current treatments are primarily symptomatic, and no effective therapies are available to slow disease progression.

MATERIALS AND METHODS: In this review, PubMed, CNKI, Wanfang Data, and the Chinese Medical Journal Full-text Database were searched using core terms including lymphatic system, Alzheimer's disease, and deep cervical lymphatic-venous anastomosis with supplementary synonyms. After deduplication and two-round screening, irrelevant, duplicate, low-quality, and non-full-text articles were excluded, and eligible literature was systematically summarized.

RESULTS: The proposal of the glymphatic system has refined the theory of cerebral fluid circulation and waste clearance. Its dysfunction is closely associated with neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), providing a novel target for AD treatment. Deep cervical Lymphatic-Venous Anastomosis (LVA), as an emerging surgical approach with potential to alleviate AD symptoms, has been initially validated for its short-term efficacy. However, it is still in the early stage of clinical exploration, and further systematic research is required for its successful clinical translation.

DISCUSSION: The glymphatic system mediates brain fluid circulation and waste clearance, providing new insights into AD pathogenesis and treatment. Building on this understanding, deep cervical Lymphatic-Venous Anastomosis (LVA) has emerged as a promising surgical intervention to alleviate AD pathology. Nevertheless, the considerable technical demands and incompletely elucidated mechanism of LVA severely limit its clinical translation, rendering these challenges a central research priority.

CONCLUSION: Breakthroughs in the central lymphatic system have provided an important direction for exploring the pathological mechanisms of AD and developing innovative therapeutic strategies. Clarifying the theoretical basis and technical evolution of LVA surgery, as well as addressing relevant controversial issues, constitutes a key focus to advance the basic research and clinical translation of AD treatment.},
}

@article {pmid42760484,
year = {2026},
author = {Wei, X and Shao, R and Rolland, Y and Vellas, B and de Souto Barreto, P},
title = {Alzheimer's disease biomarkers in relation to non-cognitive domains within the intrinsic capacity framework: a narrative review.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42760484},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) biomarkers may be associated with decline in non-cognitive domains of intrinsic capacity (IC), but such evidence has not been synthesized. This narrative review, based on a structured PubMed search (last search: December 31, 2025), included 119 human studies examining associations of core AD biomarkers (e.g., amyloid-beta (Aβ) and tau protein) and biomarkers of non-specific processes involved in AD pathophysiology (including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), structural magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET)) with composite IC scores and non-cognitive IC domains. Among included studies, 2 investigated composite IC scores, 49 depressive symptoms, 30 locomotion, 29 hearing impairment, 19 vitality, and 1 vision impairment. The very limited longitudinal evidence on composite IC scores suggests that lower IC was associated with increased p-tau181 levels and that higher baseline NfL predicted steeper IC decline, whereas plasma Aβ42/Aβ40 showed no clear association. At the IC domains' level, higher cerebral Aβ deposition was associated with poorer locomotion, especially slower gait, more consistently than other biomarker modalities. Higher levels of tau biomarkers and NfL were more often associated with lower or declining handgrip strength. Depressive symptoms represented the most investigated non-cognitive IC domain, showing consistent longitudinal associations with lower fluid Aβ42, greater cerebral amyloid deposition, and subsequent brain atrophy. Hearing impairment was linked mainly to higher tau and NfL, reduced glucose metabolism, and brain atrophy; evidence for vision impairment was almost totally absent. Overall, the pattern of associations varied by biomarker modality, IC domain, and study design, suggesting that AD-related pathology and neurodegeneration have functional correlates beyond cognition. Methodological quality, formally appraised with the Newcastle-Ottawa Scale and the JBI checklist, was acceptable for most included studies.},
}

@article {pmid42760588,
year = {2026},
author = {Abdelhamid, M and Padhi, P and Gifani, M and Beck, JS and Thomas, JP and Khadse, G and Kudela, C and Phillips, GJ and Kanthasamy, AG and Counts, SE},
title = {Bioengineered microbiotic levodopa therapy improves cognition and reduces pathology in a rat model of Alzheimer's disease.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70670},
pmid = {42760588},
issn = {1476-5381},
support = {R01AG060731//National Institutes of Health (NIH)/ ; U01AG074960//National Institutes of Health (NIH)/ ; //Johnny Isakson Endowed Chair, Coach Mark Rich Endowment/ ; //Georgia Research Alliance Eminent Scholar funds/ ; },
abstract = {BACKGROUND AND PURPOSE: Degeneration of the pontine noradrenergic and midbrain dopaminergic systems contributes to cognitive-behavioural disturbances during the prodromal stages of Alzheimer's disease (AD). We developed a genetically engineered, programmable probiotic Escherichia coli Nissle 1917 strain (EcN[rha] L-DOPA) capable of producing L-3,4-dihydroxyphenylalanine (L-DOPA) in a sustained and titratable manner, thus offering a novel gut-brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD.

EXPERIMENTAL APPROACH: We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine-β-hydroxylase IgG-saporin immunotoxin into the prefrontal cortex of 6-months-old Tg344-19 AD rats. The animals then received EcN[rha] L-DOPA/benserazide or placebo by daily gavage for 6 weeks. We assessed cognitive-behavioural function prior to postmortem assessments of amyloid-β plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L-DOPA, dopamine, noradrenaline and metabolite levels, were also measured.

KEY RESULTS: EcN[rha] L-DOPA displayed stable gut colonization and resulted in sustained therapeutic levels of L-DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN[rha] L-DOPA reduced anxiety-like behaviour improved spatial and working memory. The treatment reduced forebrain Aβ plaque and MHC-II antigen-presenting microglial load. Additionally, EcN[rha] L-DOPA increased protein levels of the dendritic spine marker PSD95.

CONCLUSIONS AND IMPLICATIONS: This translational study suggests that EcN[rha] L-DOPA modifies AD by boosting brain catecholamine production, reducing Aβ accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN[rha] L-DOPA as a promising preclinical engineered gut microbiome-based therapeutic strategy for early-stage AD.},
}

@article {pmid42760755,
year = {2026},
author = {Lee, M and Wang, K and Lee, HJ},
title = {How temporal caregiving demands shape mental health among older East Asian dementia caregivers.},
journal = {Ethnicity & health},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13557858.2026.2729317},
pmid = {42760755},
issn = {1465-3419},
abstract = {Objective: Dementia caregiving is associated with elevated psychological distress, yet limited research has examined how caregiving demands shape mental health among East Asian American caregivers, a rapidly growing but understudied population. Guided by the stress process framework, this study examined three temporal dimensions of objective caregiving demands - time intensity, frequency, and chronicity - and their associations with subjective caregiving demands and depressive symptoms among older East Asian American caregivers of individuals living with Alzheimer's disease and related dementias (AD/ADRD).Design: Survey data were collected from 82 East Asian American caregivers aged 50 years or older who were providing care to individuals with dementia in the United States. Participants were recruited through community-based organizations and ethnic community settings. Ordinary least squares regression models were estimated to examine associations among temporal caregiving demands, subjective caregiving demands, and depressive symptoms. An exploratory post hoc structural equation model was also estimated to examine indirect associations.Result: Caregivers in this sample reported substantial caregiving involvement, averaging more than 10 hours of care per day, five days per week, over a period exceeding five years. In adjusted regression models, time intensity and chronicity were not directly associated with depressive symptoms, while caregiving frequency was negatively associated with depressive symptoms. Subjective caregiving demands were strongly and positively associated with depressive symptoms. Temporal caregiving demands were positively associated with subjective caregiving demands when examined separately. An exploratory post hoc analysis suggested that chronicity was indirectly associated with depressive symptoms through subjective caregiving demands.Conclusion: Findings suggest that the mental health implications of dementia caregiving may depend less on objective time exposure alone and more on caregivers' subjective appraisal of caregiving demands. Culturally and linguistically responsive interventions should address perceived caregiving burden, improve access to formal support, and attend to the long-term caregiving experiences of East Asian American dementia caregivers.},
}

@article {pmid42761049,
year = {2026},
author = {Reus, LM and Jiang, C and Vilor-Tejedor, N and Boltz, T and Yigit, A and Gobom, J and Vos, SJB and Blennow, K and Zetterberg, H and Martinez-Lage, P and Tainta, M and Popp, J and Tsolaki, M and Vandenberghe, R and Frölich, L and Freund-Levi, Y and Dobricic, V and Braber, AD and van Harten, AC and Ophoff, RA and Holstege, H and van der Flier, WM and van der Lee, SJ and Teunissen, CE and Bertram, L and Visser, PJ and Tijms, BM},
title = {CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {40},
pmid = {42761049},
issn = {3059-4944},
abstract = {BACKGROUND: Despite the identification of numerous genetic risk variants for Alzheimer's disease (AD), mechanisms through which these variants act remain unclear. Identifying specific proteins levels affected by genetic variation can provide valuable insights into the underlying biological pathways implicated in AD.

METHODS: To gain more insight into effects of genetic variation on AD-related processes, we conducted a genome-wide protein pQTL study using untargeted TMT mass spectrometry in cerebrospinal fluid (CSF) of 2,215 proteins across 487 individuals. Replication was assessed in the independent EMIF-AD MBD cohort of 242 individuals.

RESULTS: We identified 399 independent CSF pQTL signals (P Bonferroni < 2.26 × 10⁻11) associated with 222 proteins, 69% of which were novel. Findings included gene-protein links such as RPS23P10/HSPA6 with CSF FCGR2A, BIN2 with CSF GALNT6, APOE with CSF HS3ST1, and the HLA-region with CSF HLA-DPB1 and PLXDC2. We replicated 230 of 270 gene-protein associations. A proteome-wide association study identified genetically predicted CSF protein levels to be associated with AD, including SIRPA, PLXDC2, and GALNT6. Many AD pQTLs in CSF were enriched in neuroimmune activation, suggesting a genetic basis for neuroimmune dysregulation in AD.

CONCLUSIONS: This study highlights how genetic variation shapes protein expression in the central nervous system, offering mechanistic insight into AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1186/s44477-026-00048-7.},
}

@article {pmid42761308,
year = {2026},
author = {Lee, S and Ju, IG and Lee, M and Kim, JH and Choi, Y and Baek, C and Kim, C and Moon, K and Moon, M and Kim, YJ and Oh, MS},
title = {Alismatis Rhizoma prevents AβO-induced neuronal cell death and synaptic loss in Alzheimer's disease models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1898356},
pmid = {42761308},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disease characterized by abnormal accumulation of amyloid-β (Aβ), which leads to memory impairment, synaptic dysfunction, and neuronal loss. This study investigated whether Alismatis Rhizoma (AR) could prevent Aβ oligomer (AβO)-induced synaptic dysfunction, neuronal cell death, and consequent memory decline.

METHODS: For in vitro studies, HT22 cells and human embryonic stem cells (hESC)-derived hippocampal neurons exposed to AβO were treated with AR. For in vivo studies, we administrated AR orally at 50 and 200 mg/kg to mice intrahippocampally injected with AβO and memory function was assessed using behavioral tests. Cellular and hippocampal tissue samples were analyzed by Western blotting and immunostaining.

RESULTS: In AβO-injected mice, AR, particularly at 200 mg/kg, attenuated memory deficits, reduced hippocampal neuronal degeneration, preserved synaptic protein immunoreactivity and increased markers of hippocampal cell proliferation and immature neurons. These effects were accompanied by changes in PI3K/Akt/GSK-3β and ERK/CREB signaling, increased mature BDNF levels, and reduced cleaved caspase-3 levels. AR at 30 and 300 μg/mL protected HT22 cells and hESC-derived hippocampal neurons against AβO-induced loss of viability, while 300 μg/mL AR additionally reduced cleaved caspase-3 levels and increased inhibitory GSK-3β Ser9 phosphorylation in HT22 cells.

CONCLUSION: Collectively, AR attenuated AβO-induced neuronal and synaptic injury and the associated memory impairment in acute experimental models. These findings provide promising preclinical evidence for the neuroprotective potential of AR and support its further evaluation in chronic and progressive AD models.},
}

@article {pmid42761424,
year = {2026},
author = {Stovner, LJ and Skrindo Knudsen, AK and Lien, L and Peersen, H and Gilhus, NE},
title = {The burden of brain disorders in Norway: an analysis of data from the global burden of disease study 2023.},
journal = {The Lancet regional health. Europe},
volume = {70},
number = {},
pages = {101857},
pmid = {42761424},
issn = {2666-7762},
abstract = {BACKGROUND: The term 'Brain disorders' encompasses conditions affecting the brain and nervous system and includes neurological, mental, neurosurgical and substance use disorders. No study has previously estimated the combined burden of brain disorders in Norway.

METHODS: Data source was the Global Burden of Disease database on prevalence, incidence, Years Lived with Disability (YLDs), Years of Life Lost (YLLs), and Disability-Adjusted Life Years (DALYs), for brain disorders in Norway in 2023, with changes from 1990 to 2023.

FINDINGS: Brain disorders accounted for 26·64% of all DALYs, 30·77% of all YLDs and 22·31% of all YLLs in Norway in 2023, no uncertainty intervals (UIs) given. The highest burden in terms of DALYs was observed for Alzheimer's disease (AD) and dementias (3·82% of all DALYs, UI: 1·72-7·87), anxiety disorders (3·79%, UI: 2·77-4·97), stroke (3·43%, UI: 3·04-3·89), headache (2·5%, UI: 1·94-3·18), and depressive disorders (2·22%, UI: 1·71-2.90). Leading causes of YLDs were anxiety (7·35%, UI: 5·35-9·65), headache (4·91%, UI: 3·91-5·88), and depression (4·29%, UI: 3·47-5.42), while AD and dementias (5·47%, UI: 1·35-13·54), stroke (5·46%, UI: 4·75-5·95), and self-harm (3·51%, UI: 3·17-3·97) were important causes of YLLs. Age-standardized DALYs decreased over the 34 years for stroke, meningitis, and alcohol use disorders, whereas Parkinson's disease, anxiety, depressive, eating, and drug use disorder increased.

INTERPRETATION: Brain disorders are causing more than a quarter of all disease burden in Norway, which is of importance for prioritizing resources to health services and to research. Although there are concerning trends for some disorders, others have become considerably less burdensome since 1990, likely due to improvements in general health, prevention, and effective new treatments and rehabilitation.

FUNDING: The Gates foundation and Norwegian Institute of Public Health.},
}

@article {pmid42761463,
year = {2026},
author = {Xin, Y and Liao, Y and Cao, X and Zhu, X and Wang, J},
title = {IL-34 in neurological homeostasis and its multifaceted roles in central nervous system diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1860233},
pmid = {42761463},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Homeostasis ; *Central Nervous System Diseases/metabolism/immunology ; *Interleukins/metabolism/immunology ; Microglia/immunology/metabolism ; *Central Nervous System/immunology/metabolism ; Signal Transduction ; Macrophages/immunology/metabolism ; },
abstract = {Interleukin-34 (IL-34), a ligand for the macrophage colony-stimulating factor receptor (CSF1R), plays an indispensable role in the development and homeostasis maintenance of the central nervous system (CNS). This review systematically outlines the core mechanisms by which the IL-34/CSF1R signaling axis regulates the development, colonization, and functional differentiation of CNS-resident immune cells-including microglia and border-associated macrophages (BAMs). It highlights its role in critical physiological processes such as synaptic pruning, neural circuit maturation, and maintenance of blood-brain barrier integrity. Beyond its physiological functions, IL-34 modulates diverse neurological disorders-such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, ischemic stroke-with context dependent outcomes. It can confer neuroprotective effects but also drive disease progression under different conditions, providing new insights into CNS homeostasis balance and the complexity of pathological mechanisms.},
}

Humans
Animals
*Homeostasis
*Central Nervous System Diseases/metabolism/immunology
*Interleukins/metabolism/immunology
Microglia/immunology/metabolism
*Central Nervous System/immunology/metabolism
Signal Transduction
Macrophages/immunology/metabolism

@article {pmid42761489,
year = {2026},
author = {Vallés, AS and Barrantes, FJ},
title = {Common metabolic, environmental, and molecular mechanisms underlying neurodevelopmental and neurodegenerative disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860052},
pmid = {42761489},
issn = {1664-2295},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/etiology ; Animals ; *Neurodevelopmental Disorders/metabolism/etiology ; Developmental Origins of Health and Disease ; Neurodevelopment ; },
abstract = {Several neurodevelopmental disorders and neurodegenerative diseases share common pathogenic mechanisms that unfold across the lifespan, blurring the distinction between the two nosological entities. Environmental factors, particularly those shaping metabolic health during critical developmental time windows, have emerged as key modulators of long-term brain liabilities. This review critically evaluates the experimental, epidemiological, and mechanistic evidence linking early-life metabolic and environmental insults with the establishment of latent vulnerability. We propose that this status may remain clinically silent for decades until activated by aging and cumulative stressors, ultimately leading to neurodegeneration. Specifically, we analyze how early metabolic alterations disrupt mitochondrial function, redox signaling, synaptogenesis, and glial programming, particularly in microglia, thereby shaping long-term neuroinflammatory tone and dysfunctional neural circuit maturation. The review highlights the role of the α7 nicotinic acetylcholine receptor (α7nAChR) as a strategic molecular bridge onto which metabolic and inflammatory signals converge. We further discuss how early dysregulatory stressors manifest later in life as dysmetabolism, vascular impairment, and defective energy sensing, all of which accelerate neurodegenerative pathophysiological processes. This life-course perspective reframes these disorders as a continuum and highlights critical prophylactic and/or therapeutic opportunities through early nutritional, metabolic, and environmental interventions.},
}

Humans
*Neurodegenerative Diseases/metabolism/etiology
Animals
*Neurodevelopmental Disorders/metabolism/etiology
Developmental Origins of Health and Disease
Neurodevelopment

@article {pmid42761554,
year = {2026},
author = {Aponte, C and Jimenez-Marín, A and Razkin, M and Gómez, JFO and Erramuzpe, A and Diez, I and Aguillón-Niño, D and Tobón, C and Cortés, JM},
title = {Subregional Functional Connectivity of the Precuneus as a Preclinical Biomarker in Alzheimer's Disease.},
journal = {Neurology research international},
volume = {2026},
number = {},
pages = {7281786},
pmid = {42761554},
issn = {2090-1852},
abstract = {INTRODUCTION: The precuneus (Pc) is a central hub integrating diverse brain functions, and it is early involved in Alzheimer's disease (AD) pathophysiology, yet its subregional vulnerability remains poorly understood. This study aims to delineate the differential involvement and vulnerability of these subdivisions in the early stages of AD.

METHODS: We conducted a resting-state FC analysis of Pc subregions in 32 cognitively unimpaired carriers of the PSEN1 E280A mutation compared to 25 noncarriers using seed-based analyses.

RESULTS: As compared to noncarriers, we found that the group of asymptotic carriers had increased connectivity from the 7Am subregion toward the entorhinal cortex, superior temporal gyrus, insula-operculum, dlPFC, and somatosensory areas. Moreover, the POS2 subregion significantly decreased connectivity with the anterior insula and dlPFC. Higher MoCA scores correlated with increased connectivity within and between the Pc and frontoparietal networks.

DISCUSSION: These results reveal distinct patterns of early functional reorganization and support the subregional Pc analysis in identifying sensitive biomarkers for preclinical AD, often overlooked in conventional whole-region analyses.},
}

@article {pmid42761630,
year = {2026},
author = {Cote, S and Ruitenberg, MFL and van der Geest, JN and Frost, NA and King, JB and Duff, K and Koppelmans, V},
title = {White matter microstructure and motor function in amnestic mild cognitive impairment and Alzheimer's dementia.},
journal = {Neuroimage. Reports},
volume = {6},
number = {4},
pages = {100405},
pmid = {42761630},
issn = {2666-9560},
abstract = {INTRODUCTION: Up to 30% of amnestic mild cognitive impairment (aMCI) subjects exhibit motor dysfunction. However, the relationship between white matter microstructural connectivity (SC) and motor function across the Alzheimer's disease (AD) spectrum remains unclear. This study investigated 1) white matter microstructural differences among cognitively unimpaired (CU) individuals, those with aMCI, and those with mild AD; and 2) associations between white matter microstructure and motor performance.

METHODS: Participants (CU = 68, aMCI = 44, AD = 34) underwent diffusion- and T1-weighted MRI. Whole-brain SC was assessed using weighted streamline count from probabilistic tractography between regions of the Brainnetome atlas. A subset (n = 103) also completed motor assessments (finger tapping, grip strength, spiral tracing, sequence learning). Group differences and AFD-motor associations were evaluated using threshold-free network-based statistics, corrected for multiple comparisons.

RESULTS: Compared with CU participants, those with AD exhibited reduced SC in 268 connections, predominantly involving the temporal lobe, thalamus, and hippocampus. Compared with aMCI, AD participants showed reduced SC in three connections linking frontal, parietal, and temporal regions. No significant SC differences were observed between CU and aMCI, and SC was not associated with motor performance.

CONCLUSION: White matter SC is affected in AD, particularly in medial temporal lobe regions that are known to be affected early in the disease. Absence of differences between CU and aMCI, and small differences between aMCI and AD suggests that SC changes appear later in the disease course. The lack of SC-motor associations could reflect lack of variation in motor behavior in the sample.},
}

@article {pmid42761709,
year = {2026},
author = {Shahzad, M and Mushtaq, A and Rochais, C and Naseer, MM},
title = {Isatin derivatives as potent cholinesterase inhibitors: recent developments and future challenges.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42761709},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal loss, primarily associated with β-amyloid plaque deposition, tau hyperphosphorylation, and cholinergic dysfunction. Since the disruption of cholinergic neurotransmission is a key pathological feature of AD, the cholinesterase (ChE) inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) remain the mainstay of symptomatic treatment by enhancing synaptic acetylcholine levels. However, the currently approved small molecules, including tacrine, donepezil, rivastigmine, and galantamine, are limited by their modest efficacy, poor selectivity, and adverse effects, necessitating the development of improved therapeutic agents. Among emerging scaffolds, isatin (1H-indole-2,3-dione) has attracted considerable research attention owing to its structural versatility, synthetic accessibility, and favorable pharmacological properties. Recent studies have reported diverse isatin-based derivatives, including hydrazones, Schiff bases, thiosemicarbazones, spirooxindoles, and molecular hybrids, exhibiting potent AChE and BChE inhibitory activities, often in the submicromolar or nanomolar ranges. Structure-activity relationship studies have revealed the critical influence of electronic effects, linker optimization, N-substitution, and molecular hybridization on inhibitory potency and selectivity. This review summarizes the most promising isatin-based cholinesterase inhibitors reported from 2020 to the present, highlighting their biological activities, structure-activity relationships, and potential for the development of next-generation anti-Alzheimer therapeutics.},
}

@article {pmid42758114,
year = {2026},
author = {Ran, J and Wei, Q and Lu, T and Liao, X and Pang, X and Zhu, Q and Zhou, H and He, X},
title = {Cognitive-enhancing effects of a herbal combination on D‑galactose‑induced memory impairment.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {1-6},
doi = {10.14715/cmb/2026.72.5.1},
pmid = {42758114},
issn = {1165-158X},
mesh = {Animals ; *Galactose ; *Memory Disorders/drug therapy/chemically induced ; Cognitive Enhancement ; Acetylcholinesterase/metabolism ; Male ; Mice ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; Maze Learning/drug effects ; Signal Transduction/drug effects ; Malondialdehyde/metabolism ; Hippocampus/drug effects/pathology/metabolism ; Oxidative Stress/drug effects ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, for which effective pharmacological interventions remain limited. This study investigated the cognitive-enhancing effects of an optimized six‑herbal combination (HC) comprising Polygonati Rhizoma (PR), Lycium barbarum polysaccharides (LBPs), Green Tea (GT), Jujube Seeds (JS), Fructus hippophae (FH), and Mori Folium (MF). Using the Ellman method, we evaluated the acetylcholinesterase (AChE) inhibitory activities of individual herbs and HC. An L25(4[6]) orthogonal design was employed to determine the optimal proportions of the six herbs, with AChE inhibition as the evaluation index. The optimal HC composition (PR 9 g, LBPs 6 g, GT 3 g, JS 3 g, FH 3 g, MF 5 g) exhibited 88.11% AChE inhibition at 2000 μg/mL, which was significantly higher than that of any individual herb (p < 0.05). Network pharmacology analysis revealed 682 common targets between HC and AD, with significant enrichment in the PI3K‑Akt signaling pathway, lipid metabolism, and chemical carcinogenesis‑receptor activation pathways, suggesting multi‑target mechanisms of action. In a D‑galactose‑induced subacute aging mouse model (3.5 g·kg[-1], 70 days), HC treatment (0.75, 1.5, and 3.0 g·kg[-1], 28 days) significantly improved spatial learning and memory in the Morris water maze. Specifically, HC at 1.5 g·kg[-1] significantly reduced escape latency (p < 0.01 vs. D‑galactose group), increased superoxide dismutase (SOD) and glutathione (GSH) levels (p < 0.05), and decreased malondialdehyde (MDA) and monoamine oxidase (MAO) levels (p < 0.01), while ameliorating hippocampal neuronal damage, as confirmed by hematoxylin and eosin staining. These findings demonstrate that HC exhibits potent anti‑cholinesterase activity, modulates oxidative stress, and protects against neuronal injury, positioning it as a promising multi‑target botanical candidate for further development in the prevention and management of AD.},
}

Animals
*Galactose
*Memory Disorders/drug therapy/chemically induced
Cognitive Enhancement
Acetylcholinesterase/metabolism
Male
Mice
Cholinesterase Inhibitors/pharmacology/therapeutic use
Maze Learning/drug effects
Signal Transduction/drug effects
Malondialdehyde/metabolism
Hippocampus/drug effects/pathology/metabolism
Oxidative Stress/drug effects
*Drugs, Chinese Herbal/pharmacology/therapeutic use

@article {pmid42758358,
year = {2026},
author = {Abdi, K and Amiri, M and Asadalizadeh, M and Khanmirzaei, A and Javanmard, AR and Rezaeimirghaed, O and Hajiesmaeili, M and Ghaderian, SMH},
title = {LncRNA Loc646329 modulates Alzheimer's disease-related phenotypes through the miR-150/WNT/β-catenin axis in cellular and APP/PS1 mouse models.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42758358},
issn = {1573-4978},
mesh = {*MicroRNAs/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; Animals ; *Wnt Signaling Pathway/genetics ; Humans ; Mice ; Disease Models, Animal ; beta Catenin/metabolism/genetics ; Apoptosis/genetics ; *RNA, Long Noncoding/genetics/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Presenilin-1/genetics/metabolism ; Phenotype ; Neurons/metabolism ; Hippocampus/metabolism ; Cell Line, Tumor ; Cell Survival/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuronal apoptosis, and amyloid‑β (Aβ) deposition. Dysregulation of the WNT/β‑catenin signaling pathway contributes to AD pathogenesis, yet the upstream regulatory mechanisms, particularly those involving long non‑coding RNAs (lncRNAs), remain unclear. This study investigated the neuroprotective role and molecular mechanism of lncRNA Loc646329 in AD models.

METHODS AND RESULTS: Analysis of publicly available human Alzheimer's disease sequencing datasets was performed to examine the expression patterns of Loc646329 and miR-150 in AD and control brain sample. Subcellular localization and interaction with miR‑150 were examined using fluorescence in situ hybridization, AGO2‑RNA immunoprecipitation, and dual‑luciferase reporter assays in SH‑SY5Y cells. Functional assays, including CCK-8, EdU incorporation, Annexin V-FITC/PI flow cytometry, and TUNEL staining, demonstrated that Loc646329 overexpression improved cell viability and reduced apoptosis under Aβ1-42-induced neurotoxic conditions. Mechanistically, Loc646329 localized predominantly in the cytoplasm and directly interacted with miR-150. MiR-150 mimic experiments further indicated that the effects of Loc646329 on GSK3β phosphorylation, β-catenin stabilization, and WNT/β-catenin signaling were at least partly miR-150-dependent. In APP/PS1 mice, stereotaxic injection of AAV‑Loc646329 into the hippocampus improved spatial learning and memory in the Morris water maze, reduced Aβ plaque burden, and increased β‑catenin activation.

CONCLUSIONS: These findings provide preclinical evidence that the Loc646329/miR-150/WNT signaling axis contributes to neuronal survival and modulates AD-related pathological changes. Loc646329 may therefore represent a candidate molecular regulator for further investigation; however, additional validation in primary or human-derived neuronal models and clinical samples is required before its therapeutic relevance can be established.},
}

*MicroRNAs/genetics/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
Animals
*Wnt Signaling Pathway/genetics
Humans
Mice
Disease Models, Animal
beta Catenin/metabolism/genetics
Apoptosis/genetics
*RNA, Long Noncoding/genetics/metabolism
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism
Male
Presenilin-1/genetics/metabolism
Phenotype
Neurons/metabolism
Hippocampus/metabolism
Cell Line, Tumor
Cell Survival/genetics

@article {pmid42758365,
year = {2026},
author = {Ke, J and Xuekelati, S and Maimaitiwusiman, Z and Halan, B and Xu, Q and Guo, S and Xu, L and Wang, H},
title = {A multimodal model for clinically defined MCI integrating plasma biomarkers and brain microstructural features: a dual-cohort external validation study.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42758365},
issn = {1590-3478},
support = {2022E02120//Science and Technology Department of Xinjiang Uygur Autonomous Region/ ; BL202601//Science and Technology Department of Xinjiang Uygur Autonomous Region/ ; },
mesh = {Humans ; *Cognitive Dysfunction/blood/diagnostic imaging/pathology ; Diffusion Tensor Imaging ; Biomarkers/blood ; Male ; Female ; *tau Proteins/blood ; Aged ; *Glial Fibrillary Acidic Protein/blood ; *Neurofilament Proteins/blood ; Cohort Studies ; *White Matter/diagnostic imaging/pathology ; *Brain/diagnostic imaging/pathology ; Alzheimer Disease/diagnostic imaging/blood ; Aged, 80 and over ; Random Forest ; },
abstract = {OBJECTIVE: Mild cognitive impairment (MCI) is clinically and etiologically heterogeneous. We aimed to develop and externally validate a multimodal model for distinguishing clinically defined MCI from normal cognition using plasma biomarkers and diffusion tensor imaging (DTI)-derived white-matter features.

METHODS: We analyzed 310 participants from a local discovery cohort (n = 153; 80 MCI and 73 cognitively normal [NC]) and an independent Alzheimer's Disease Neuroimaging Initiative phase 4 (ADNI4) validation cohort (n = 157; 68 MCI and 89 NC). Plasma phosphorylated tau 217 (p-tau217), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) were log-transformed and standardized using parameters estimated exclusively from NC participants in the local discovery cohort and then frozen for application to ADNI. Twenty-seven tract-level fractional anisotropy (FA) measures were considered as candidate imaging predictors. DTI feature selection used L1-penalized logistic regression with the 1-SE rule, with feature selection repeated within nested 10-fold cross-validation. Logistic regression (LR), support vector machine (SVM), random forest (RF), and XGBoost models were developed using local data, and the finalized pipelines were subsequently applied to ADNI4 without feature reselection, hyperparameter tuning, or recalibration.

RESULTS: Plasma p-tau217, NFL, and GFAP were higher in MCI than NC in both cohorts (all cohort-specific P ≤ 0.005). LASSO selected fornix (FX) and cingulum hippocampus (CGH) FA, and both features were retained in all 10 outer cross-validation folds. Nested internal AUCs ranged from 0.791 to 0.839. Under strict external validation, RF achieved the highest AUC of 0.829 (95% CI 0.762-0.889), followed by SVM with an AUC of 0.802 (95% CI 0.730-0.870), XGBoost with an AUC of 0.790 (95% CI 0.714-0.860), and LR with an AUC of 0.770 (95% CI 0.688-0.843). Relative to plasma biomarkers plus demographics, the full multimodal models significantly improved external discrimination across all four classifiers (all P ≤ 0.004). Improvements relative to DTI plus demographics were smaller and classifier-dependent; only RF showed a statistically significant increment (ΔAUC = 0.063, 95% CI 0.004-0.125; P = 0.036). RF had the lowest external Brier score (0.171). In the local cohort, lower FX and CGH FA remained associated with MCI after adjustment for available vascular and metabolic risk factors.

CONCLUSION: A multimodal signature combining two selected DTI features with three prespecified plasma biomarkers and demographic covariates showed reproducible discrimination of clinically defined MCI across independent cohorts. The findings support further evaluation of this approach as an adjunctive MCI risk-stratification strategy but do not establish Alzheimer's disease (AD)-specific etiology or clinical readiness. Prospective validation incorporating amyloid/tau status, longitudinal conversion outcomes, and real-world calibration is required.},
}

Humans
*Cognitive Dysfunction/blood/diagnostic imaging/pathology
Diffusion Tensor Imaging
Biomarkers/blood
Male
Female
*tau Proteins/blood
Aged
*Glial Fibrillary Acidic Protein/blood
*Neurofilament Proteins/blood
Cohort Studies
*White Matter/diagnostic imaging/pathology
*Brain/diagnostic imaging/pathology
Alzheimer Disease/diagnostic imaging/blood
Aged, 80 and over
Random Forest

@article {pmid42758418,
year = {2026},
author = {Ye, Z and Xu, J and Zhang, T and Zhu, Y and Lu, Y and Chen, X and Yang, Z and Yuan, Z and Huang, S and Weng, Y and Yang, D},
title = {Multi-omics Insights into Oxidative Stress-related Genes and Neurodegenerative Diseases: From Epigenetic Regulation to Pathogenic Pathways.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42758418},
issn = {1559-1166},
support = {No. 25ywb102//the Science and Technology Plan Project of Taizhou/ ; No. 82302081//the National Natural Science Foundation of China/ ; No. LQ24H090003//the Zhejiang Provincial Natural Science Foundation of China/ ; },
mesh = {*Neurodegenerative Diseases/genetics/metabolism ; Humans ; *Oxidative Stress/genetics ; *Epigenesis, Genetic ; Quantitative Trait Loci ; DNA Methylation ; Genome-Wide Association Study ; },
abstract = {Oxidative stress (OS) is critically implicated in the onset and progression of neurodegenerative diseases (NDDs), yet its genetic determinants remain insufficiently elucidated. This study aims to delineate the putative causal relationships between OS-related genes (OSRGs) and NDDs, along with the potential regulatory and pathogenic mechanisms. Summary-data-based Mendelian randomization (SMR) was conducted to explore the putative causal associations of 936 OSRGs with NDDs, integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) data, using a multi-cohort design with blood eQTLs for discovery and replication, followed by brain eQTL validation. Subsequently, colocalization analysis was used to verify putative causal inferences in SMR. In addition, DNA methylation regulation and pathway enrichment analyses were applied to explore potential regulatory and pathogenic mechanisms. Genetically predicted levels of 15 genes were found to be significantly associated with the risk of NDDs. Higher genetically predicted expression of ACE and TP53INP1 was associated with decreased Alzheimer's disease risk, whereas higher TSFM expression was associated with increased multiple sclerosis risk; these associations were consistently supported by replication cohort and brain eQTL validation for ACE and TSFM, while TP53INP1 showed brain-level consistency without replication. Among 15 genes, the expression levels of ACE, TP53INP1, and other 5 genes were regulated by DNA methylation. Pathway enrichment analysis showed specific enrichment in autophagy-apoptosis and mitochondrial pathways. These findings provide genetic evidence supporting a putative causal role of OSRGs on NDDs, offering mechanistic insights and potential therapeutic targets, and substantially advance the pathobiological understanding of NDDs.},
}

*Neurodegenerative Diseases/genetics/metabolism
Humans
*Oxidative Stress/genetics
*Epigenesis, Genetic
Quantitative Trait Loci
DNA Methylation
Genome-Wide Association Study

@article {pmid42758469,
year = {2026},
author = {Lena, O and Todri, J},
title = {Global Postural Reeducation in Mild Alzheimer's Disease: A Secondary Analysis of an RCT.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261489372},
doi = {10.1177/15333175261489372},
pmid = {42758469},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/rehabilitation/therapy ; Female ; Male ; Aged ; Secondary Data Analysis ; Aged, 80 and over ; *Postural Balance/physiology ; Depression ; Neuropsychological Tests ; Quality of Life ; },
abstract = {BackgroundDepression and neuropsychiatric symptoms are common in Alzheimer's disease (AD) and may contribute to functional decline and reduced quality of life.MethodsThis secondary analysis used data from a randomized controlled trial (NCT03732053). Fifty-eight participants were analyzed: 36 received supervised GPR twice weekly for 24 weeks and 22 received usual care. Outcomes included the Geriatric Depression Scale (GDS), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), Barthel Index, and Performance-Oriented Mobility Assessment (POMA). Repeated-measures ANOVA and baseline-adjusted analyses were performed.ResultsAt 24 weeks, GDS scores were lower with GPR than usual care (4.72 ± 2.36 vs. 8.41 ± 2.15; p < 0.001). Significant group × time effects were observed for NPI, MMSE, Barthel Index, and POMA (all p < 0.001).ConclusionGPR may provide complementary benefits across psychological, cognitive, and functional outcomes in mild AD, although baseline imbalance and differential attrition warrant cautious interpretation.},
}

Humans
*Alzheimer Disease/rehabilitation/therapy
Female
Male
Aged
Secondary Data Analysis
Aged, 80 and over
*Postural Balance/physiology
Depression
Neuropsychological Tests
Quality of Life

@article {pmid42758499,
year = {2026},
author = {Anderer, S},
title = {FDA Approves 2 New Alzheimer Disease Blood Tests.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.14721},
pmid = {42758499},
issn = {1538-3598},
}

@article {pmid42758504,
year = {2026},
author = {Ouyang, F and Pogoda, TK and Reisman, J and Li, R and Pradhan, R and Moradi, Y and Mez, J and Liu, W and Zhang, Y and Sultana, S and Qian, J and Yao, Z and Mitra, A and Yu, H},
title = {Posttraumatic Stress Disorder, Health-Related Social Needs, and Cognitive Outcomes in US Veterans.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2634839},
doi = {10.1001/jamanetworkopen.2026.34839},
pmid = {42758504},
issn = {2574-3805},
mesh = {Humans ; *Stress Disorders, Post-Traumatic/epidemiology/psychology/complications ; *Veterans/psychology/statistics & numerical data ; United States/epidemiology ; Male ; Aged ; Retrospective Studies ; Middle Aged ; Female ; *Cognitive Dysfunction/epidemiology/psychology ; Aged, 80 and over ; *Alzheimer Disease/epidemiology ; },
abstract = {IMPORTANCE: Posttraumatic stress disorder (PTSD) and health-related social needs (HRSNs) have been associated with cognitive decline, but their joint associations with mild cognitive impairment (MCI), Alzheimer disease (AD), and AD-related dementias (ADRD) are unclear.

OBJECTIVE: To evaluate the independent and joint associations of PTSD and HRSNs with incident MCI, AD, and ADRD and to assess additive and multiplicative interaction.

Retrospective cohort study using 2015 to 2024 National Veterans Health Administration (VHA) electronic health record data. Participants were veterans aged 55 to 100 years with a qualifying VHA encounter in 2015 and no preindex MCI, AD, or ADRD, followed up through December 31, 2024.

EXPOSURES: Time-varying PTSD, defined by at least 2 coded encounters on different dates, and time-varying HRSNs across 9 domains identified from structured data and clinical notes using natural language processing.

MAIN OUTCOMES AND MEASURES: The primary outcome was incident composite MCI, AD, or ADRD; secondary outcomes were each component separately. Time-varying Cox models estimated adjusted hazard ratios (aHRs) and 95% CIs. Multiplicative interaction was assessed using a PTSD × HRSN product term, and additive interaction using the relative excess risk due to interaction (RERI) and attributable proportion (AP).

RESULTS: The cohort included 3 817 970 veterans (mean [SD] age, 70.3 [9.1] years; 3 664 349 [96.0%] male), of whom 270 282 (7.1%) met the composite outcome with median (IQR) follow-up of 8.84 (5.02-9.03) years for the composite outcome. PTSD (aHR, 1.33; 95% CI, 1.32-1.35) and HRSNs (aHR, 2.17; 95% CI, 2.13-2.20) were independently associated with the composite outcome. Compared with neither exposure, aHRs were 2.14 (95% CI, 2.11-2.17) for HRSNs only, 1.13 (95% CI, 1.07-1.19) for PTSD only, and 2.87 (95% CI, 2.82-2.92) for both exposures. Multiplicative interaction was observed for the composite outcome (aHR, 1.19; 95% CI, 1.13-1.26), with positive additive interaction (RERI, 0.61; 95% CI, 0.54-0.67; AP, 0.21; 95% CI, 0.19-0.23). Additive interaction was observed for MCI and ADRD but not AD; multiplicative interaction was observed for ADRD but not MCI or AD.

CONCLUSIONS AND RELEVANCE: In this cohort study, PTSD and HRSNs were independently associated with incident cognitive outcomes, and co-occurring PTSD and HRSNs may identify veterans with higher observed hazards of cognitive impairment and dementia.},
}

Humans
*Stress Disorders, Post-Traumatic/epidemiology/psychology/complications
*Veterans/psychology/statistics & numerical data
United States/epidemiology
Male
Aged
Retrospective Studies
Middle Aged
Female
*Cognitive Dysfunction/epidemiology/psychology
Aged, 80 and over
*Alzheimer Disease/epidemiology

@article {pmid42758690,
year = {2026},
author = {Kokorelias, KM and Simpson, R and Beleno, R and Cameron, J and Dove, E and Kuluski, K and McAiney, C and Munce, SEP and Quinn, K and Saragosa, M and Wasilewski, M and Yous, ML and Zhu, L and Wu, J and Stall, N},
title = {Conceptualizations of compassion in the context of dementia caregiving: A scoping review protocol.},
journal = {PloS one},
volume = {21},
number = {9},
pages = {e0357411},
doi = {10.1371/journal.pone.0357411},
pmid = {42758690},
issn = {1932-6203},
mesh = {Humans ; *Empathy ; *Dementia/psychology/nursing ; *Caregivers/psychology ; Scoping Reviews as Topic ; },
abstract = {BACKGROUND: Compassion is widely recognized as a vital component of dementia caregiving, yet its conceptualization, definition, and operationalization remain inconsistent across contexts. In dementia caregiving, compassion is often conflated with empathy, emotional labor, and relational care, obscuring its unique characteristics and applications. Clarifying how compassion is understood and applied, particularly among unpaid family caregivers, is essential for advancing research, policy, and practice.

OBJECTIVE: This paper outlines a scoping review protocol to map and synthesize empirical studies examining the conceptualizations, definitions, and operationalization of compassion in dementia caregiving by unpaid family caregivers. The forthcoming review will identify how compassion is framed and measured across diverse care settings and caregiver populations, providing a foundation to inform future compassion-based interventions and assessment tools.

METHODS: Following Joanna Briggs Institute (JBI) methodology and the PRISMA-ScR reporting guidelines, this forthcoming review will systematically search CINAHL, EMBASE, MEDLINE, and PsycINFO. Eligible studies include qualitative, quantitative, and mixed-method empirical research focused on family caregivers of persons living with dementia. Studies exploring compassion or self-compassion conceptualization, definition, or operationalization will be included. Non-empirical works, reviews, and paid caregiving roles are excluded. Screening and data extraction will be conducted independently by two reviewers using a form informed by the Compassion-Focused Care Framework (CFCF), which emphasizes Affiliative relationships, Bidirectional communication, Compassionate partnerships, and the structural supports of Compassionate Design, Education, and systemic Call to Action. Data will be synthesized using descriptive statistics and qualitative content analysis.

Caregiver partners from Alzheimer's Societies and Ontario Health Teams will contribute throughout the review process, including study selection, interpretation, and dissemination. Engagement is structured according to the Ontario Brain Institute framework and CIHR principles, ensuring inclusiveness, mutual respect, support, and co-building. A peer-researcher with lived caregiving experience will lead patient engagement efforts.

DISCUSSION: This review will provide a comprehensive synthesis of how compassion is understood and applied in family dementia caregiving, addressing a critical gap in the literature. By identifying existing measures and conceptual frameworks, the findings will inform the development of more nuanced, caregiver-centered interventions and policies aimed at enhancing compassionate care. Ultimately, this work seeks to support caregivers' well-being and improve care quality for people living with dementia.},
}

Humans
*Empathy
*Dementia/psychology/nursing
*Caregivers/psychology
Scoping Reviews as Topic

@article {pmid42758805,
year = {2026},
author = {Li, C and Mao, Y and Liu, X and Hao, W},
title = {Data-driven modeling of spatiotemporal dynamics using multimodal imaging data.},
journal = {PLoS computational biology},
volume = {22},
number = {9},
pages = {e1014751},
doi = {10.1371/journal.pcbi.1014751},
pmid = {42758805},
issn = {1553-7358},
abstract = {Understanding how biological systems evolve across space and time remains a fundamental challenge, particularly when dynamic processes vary substantially across individuals. We present a personalized graph-based dynamical modeling framework for characterizing spatiotemporal biological dynamics from longitudinal multimodal imaging data. The framework constructs individualized brain graphs from MRI and PET measurements and learns patient-specific dynamical parameters governing regional structural and molecular changes. Applied to 1,891 participants from the Alzheimer's Disease Neuroimaging Initiative, the model captures the coordinated evolution of amyloid-β, tau, neurodegeneration, and cognition and accurately predicts their future trajectories, outperforming established clinical and neuroimaging benchmarks. Patient-specific dynamical parameters reveal distinct patterns of biological progression and provide improved prediction of future cognitive decline compared with standard biomarkers. Sensitivity analysis further identifies regional network features associated with the propagation of pathological and structural changes, recovering known temporolimbic and frontal vulnerability patterns. These results demonstrate how data-driven dynamical modeling can integrate multimodal longitudinal measurements to uncover individualized spatiotemporal patterns and latent mechanisms of biological change. The framework provides a quantitative approach for studying complex biological dynamics across heterogeneous individuals and establishes a foundation for personalized modeling of progressive biological processes.},
}

@article {pmid42758826,
year = {2026},
author = {Park, T and Chang, L and Chung, SW and Lee, S and Bae, S and Condello, C and Kim, YH and Lee, J and Kim, HJ and Kwon, HK and Suh, M},
title = {Targeting glial PD-1/PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model.},
journal = {Science advances},
volume = {12},
number = {38},
pages = {eadx0731},
doi = {10.1126/sciadv.adx0731},
pmid = {42758826},
issn = {2375-2548},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/etiology/drug therapy ; *Microglia/metabolism/pathology/drug effects ; *B7-H1 Antigen/metabolism/genetics/antagonists & inhibitors ; Mice ; *Programmed Cell Death 1 Receptor/metabolism/genetics/antagonists & inhibitors ; Disease Models, Animal ; *Homeostasis ; *Neurons/metabolism/pathology ; Humans ; Astrocytes/metabolism ; *Neuroglia/metabolism ; Signal Transduction ; Mice, Transgenic ; },
abstract = {Alzheimer's disease (AD) involves complex neuroimmune dysregulation, and the role of immune checkpoint pathways in regulating neuro-glial interactions and intrinsic glial homeostasis remains unclear. In AD, glial expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) is elevated in mouse models and human patients, suggesting involvement of immune checkpoint signaling in glial function. To define the role of this pathway in the AD brain, we locally modulated PD-1/PD-L1 signaling by intracortical anti-PD-L1 injection in 8-10-month-old 5xFAD mice, combined with in vivo two-photon imaging and quantitative functional analyses. Brain-intrinsic PD-L1 blockade reshaped the local glial microenvironment, restoring impaired microglial process convergence and increasing P2RY12 expression, a key marker of homeostatic function, with concomitant attenuation of aberrant neuronal hyperactivity. Astrocyte-specific PD-L1 knockdown produced similar effects, indicating a key role of astrocytic PD-L1 in regulating microglia-neuron interactions. These findings suggest that the glial PD-1/PD-L1 axis functions as a brain-intrinsic regulator of glial homeostasis linked to neuronal dysfunction in AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/etiology/drug therapy
*Microglia/metabolism/pathology/drug effects
*B7-H1 Antigen/metabolism/genetics/antagonists & inhibitors
Mice
*Programmed Cell Death 1 Receptor/metabolism/genetics/antagonists & inhibitors
Disease Models, Animal
*Homeostasis
*Neurons/metabolism/pathology
Humans
Astrocytes/metabolism
*Neuroglia/metabolism
Signal Transduction
Mice, Transgenic

@article {pmid42759160,
year = {2026},
author = {Calemi, C and Bruffaerts, R and Ellender, T},
title = {The effect of neurodegeneration on ultrasonic vocalisations (USV) and their neuronal substrates in mice and rats: A systematic review.},
journal = {Neurobiology of aging},
volume = {169},
number = {},
pages = {69-87},
doi = {10.1016/j.neurobiolaging.2026.09.006},
pmid = {42759160},
issn = {1558-1497},
abstract = {Neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Frontotemporal Degeneration, significantly impair communication abilities in humans. Animal models, particularly rats and mice, are widely used to study the underlying mechanisms of these disorders. Ultrasonic vocalisations (USVs) play a crucial role in signalling emotional states during social interaction, mating, and distress and may reflect low versus high arousal and/or a positive versus negative affective state of the animal, making them valuable behavioural biomarkers for neurological dysfunction. This systematic review synthesises the existing literature on USVs in rodent models of neurodegeneration. Specifically, it compares USV alterations across disease models, summarises the experimental paradigms used to elicit USVs, and reviews the neurobiological findings reported alongside these vocal changes. By integrating findings across studies, this review highlights consistent patterns, methodological differences, and current knowledge gaps to guide future research. Studying USV impairments in animal models may help to neurobiologically validate biomarkers based on the detection of acoustic changes in the vocal output of patients with neurodegenerative diseases. By bridging the gap between preclinical and clinical research, this review aims to contribute to the growing field of neurobehavioral biomarkers, which could ultimately improve early diagnosis and intervention in human neurodegenerative conditions.},
}

@article {pmid42759232,
year = {2026},
author = {Pocknell, C and Dinius, C and Foley, R and Commins, S and McHugh Power, J and Roche, R},
title = {Tracing dementia: Reminiscence therapy in and from place.},
journal = {Health & place},
volume = {102},
number = {},
pages = {103744},
doi = {10.1016/j.healthplace.2026.103744},
pmid = {42759232},
issn = {1873-2054},
abstract = {Across different disciplines, there has been increasing interest in the relationships between early-stage dementia, place and different forms of treatment. Reminiscence therapy has demonstrated benefits in stalling the progression of dementia, especially in its early-stage, and within such therapies, relationships between place memory and the beneficial triggering effect of place-based events and personal narratives have become important aspects. Promoting physical activity outdoors is associated with better management of dementia that additionally recognises a potential role for meaningful local places and spaces. Much of this place-based research, including go-alongs, are informed by mobile methodologies, with new spatial technologies (beyond risk-informed tracking) having much potential when used directly with patients within and outside their home places. However, there remain questions about the feasibility of using such methodologies for the purposes of place-based intervention among individuals with early-stage dementia. We document a recent proof-of-concept study, AIM-WARM, that investigated the potential impact of combining the exercise of walking and reminiscence therapy, in early Alzheimer's disease groups, to explore how such technologically-enabled place-based tools worked. Instrumental and walkability measures were augmented by digital mapping and a spatial video app, Ubipix, to capture go-alongs across familiar routes traced out within the town of Maynooth (Ireland). Specific findings identified positive results in relation to four distinct aspects of the study: walkability, cognitive instruments, the capturing of place-traces and a positive narrative response to being and moving outdoors. Additional methodological reflection considered the value of go-alongs to capture traces of people's past within their current everyday neighbourhoods, to help better understand and represent the voice of people living with dementia within community settings.},
}

@article {pmid42759280,
year = {2026},
author = {Kusi-Mensah, K and Jones, N and Haroon, H and Veldic, M and Choi, DS},
title = {Mechanistic link of obesity to depression and cognitive decline in Alzheimer's disease.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {106979},
doi = {10.1016/j.neubiorev.2026.106979},
pmid = {42759280},
issn = {1873-7528},
abstract = {The global rise in obesity and metabolic dysfunction has heightened concern about their links to depression, cognitive impairment, and Alzheimer's disease (AD)-related pathology. High-fat diet (HFD) exposure, excess adiposity, and metabolic dysfunction may each contribute to these outcomes, but they represent biologically distinct conditions that should not be treated as interchangeable. Epidemiological evidence suggests links between these conditions, yet the molecular pathways connecting them remain poorly characterized. This systematic review synthesizes current evidence on how HFD exposure, excess adiposity, and metabolic dysfunction may engage overlapping mechanisms associated with depression-related outcomes, cognitive impairment, and AD-related pathology. We propose an integrated biomechanistic model illustrating how HFD exposure may contribute to depression-related outcomes, cognitive impairment, and AD-related pathology through partially overlapping mechanisms. It is presented as a molecular formulation of the classical stress-diathesis perspective, highlighting how dietary exposures may interact with preexisting vulnerabilities, including genetic, epigenetic, and environmental factors, to compromise the brain's adaptive capacity to various stressors. Finally, we discuss translational implications, identifying potential targets for interventions-dietary, pharmacological, and lifestyle-with relevance to shared mechanisms underlying depression-related and cognitive outcomes, while highlighting critical gaps in understanding-such as sex-specific effects, developmental timing, and human translational evidence-that warrant further research. Human evidence remains largely observational and does not establish that these mechanisms operate equivalently in clinically diagnosed depression or AD. Future longitudinal studies integrating dietary exposure, metabolic and inflammatory biomarkers, neuroimaging, cognitive assessment, and clinical diagnoses are needed to define human vulnerability better and to provide targeted prevention and intervention strategies.},
}

@article {pmid42759390,
year = {2026},
author = {Cai, Y and Hou, Q and Cheng, Z and Cheng, Y and Zhang, E and Li, Y and Zhang, X and Wang, C and Hu, T and Tian, G and Zheng, W and Shen, J},
title = {Lipid-conjugated siRNA targeting SARM1 enables CNS silencing and mitigates alzheimer-like phenotypes.},
journal = {Bioorganic chemistry},
volume = {182},
number = {},
pages = {110526},
doi = {10.1016/j.bioorg.2026.110526},
pmid = {42759390},
issn = {1090-2120},
abstract = {RNA interference (RNAi) therapeutics have achieved clinical success in liver disease, but their application to central nervous system (CNS) disorders remains limited. Here, we developed a lipid-conjugated siRNA to silence sterile alpha and TIR motif-containing protein 1 (SARM1), a key executor of axon degeneration associated with neuroinflammatory injury, and evaluated it in an Alzheimer-like model. siRNAs targeting conserved regions of human SARM1 and mouse Sarm1 were designed and screened in neural cells, and C16 lipid conjugation together with a 5'-(E)-vinylphosphonate (5'-VP) modification was used to support in vivo delivery. In mice, intracisterna magna (ICM) administration reduced Sarm1 mRNA in the hippocampus at the two-week time point. In the intracerebroventricular streptozotocin (STZ-ICV) model, two ICM doses of VD07C attenuated hyperlocomotion and partially improved selected spatial-memory-related endpoints. VD07C also reduced hippocampal SARM1 protein and cADPR, increased NAD[+], and was associated with lower p-Tau, glial activation markers, and NF-κB/TNF-α expression. These findings provide convergent evidence of molecular and functional target engagement and support further evaluation of lipid-conjugated SARM1 siRNAs in progressive neurodegeneration models.},
}

@article {pmid42759392,
year = {2026},
author = {Ozcan, I and Erdogan, T and Taslimi, P and Sadeghian, N and Tahtaci, H},
title = {Synthesis, characterization and biological evaluation of novel imidazothiazole-based chalcone derivatives as cholinesterase inhibitors through computational and experimental approaches.},
journal = {Bioorganic chemistry},
volume = {182},
number = {},
pages = {110540},
doi = {10.1016/j.bioorg.2026.110540},
pmid = {42759392},
issn = {1090-2120},
abstract = {In this study, fifteen imidazothiazole-based chalcone derivatives (6-20) were synthesized and evaluated as potential cholinesterase inhibitors through computational and experimental approaches. Fourteen of these compounds are reported for the first time, while the previously known derivative (8) was newly assessed for its AChE and BChE inhibitory activities in relation to Alzheimer's disease (AD). In silico studies, including density functional theory (DFT) calculations, molecular docking, molecular dynamics simulations, binding free energy calculations, and ADMET analyses, suggested that these compounds could act as dual cholinesterase inhibitors. The compounds were synthesized via a three-step route and structurally characterized by [1]H NMR, [13]C NMR, FT-IR, and mass spectrometry. Their inhibitory activities against AChE and BChE were evaluated using the Ellman method, and kinetic parameters were determined through nonlinear regression and Lineweaver-Burk analyses. All derivatives exhibited inhibitory activity in the picomolar range. Among them, compounds 6, 12, and 20 were the most potent AChE inhibitors, whereas compounds 18, 19, and 6 showed the highest potency against BChE. Notably, compound 6 exhibited potent dual inhibition against both enzymes. Kinetic studies indicated a mixed-type inhibition mechanism, suggesting interactions with both catalytic and peripheral binding sites. Overall, these findings identify imidazothiazole-based chalcone derivatives as promising dual cholinesterase inhibitors and provide a basis for further optimization and investigation as potential therapeutic candidates for AD.},
}

@article {pmid42759510,
year = {2026},
author = {Qu, J and Yang, J and Li, W and Zeng, X and He, X and Guo, H and Lu, J and Jiang, X and Zhuang, X and Qian, C and Liu, Z and Huang, J and Wang, H and Xu, H and Li, H and Gao, Z and Kang, L and Hu, H and Ma, H},
title = {A miR-10a-5p-γCaMKII axis links periphery-to-brain signaling to cognitive vulnerability during female midlife.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.08.022},
pmid = {42759510},
issn = {1097-4199},
abstract = {Although women live longer, they paradoxically face heightened susceptibility to cognitive and systemic decline emerging in midlife-an underexplored transition from resilience to vulnerability. Here, we investigate biological processes associated with this female-biased vulnerability and their molecular regulation. Senescence-associated features were preferentially elevated in middle-aged females in human brain and spleen tissues, with similar changes in mice. In female mice, epigenetic upregulation of the X-linked RNA-binding protein RBMX promoted midlife increases in splenic miR-10a-5p, while complementary in vivo approaches supported a peripheral contribution to cerebral miR-10a-5p abundance. miR-10a-5p repressed calcium/calmodulin-responsive kinase γCaMKII, and modulation of this axis influenced mitochondrial function, cellular senescence, and memory in mice. In neurons derived from Alzheimer's disease patients and in model mice, miR-10a-5p inhibition attenuated disease-associated phenotypes, supporting relevance to pathological aging. Together, these findings link periphery-to-brain communication to emerging brain vulnerability during female midlife and indicate that this transition may remain amenable to intervention.},
}

@article {pmid42759574,
year = {2026},
author = {Li, X and Guo, RL and Teng, ZQ and Liu, PP and Liu, CM},
title = {Histone Modifications and Chromatin Landscapes in Microglial Function: Developmental Imprinting and Disease-Associated Reprogramming.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103377},
doi = {10.1016/j.arr.2026.103377},
pmid = {42759574},
issn = {1872-9649},
abstract = {Microglia, the brain's resident immune cells, rely on histone modifications and chromatin remodeling to sculpt their identity across the trajectory from development through aging. Recent studies have identified enhancer rewiring and metabolic-epigenetic coupling-exemplified by histone lactylation-as central drivers of microglial plasticity. Disruption of this regulatory balance drives the transition from homeostatic microglia toward disease-associated microglia (DAM) in Alzheimer's and Parkinson's diseases. This Review examines emerging concepts such as trained innate immunity, state-specific enhancer landscapes, and regional heterogeneity, and posits that epigenetic reprogramming is a central mechanism governing microglial functional transitions. These insights reveal promising therapeutic targets; however, a pressing prerequisite for clinical translation is to rigorously establish the causality of these epigenetic changes across diverse model systems, sexes, and brain regions.},
}

@article {pmid42759687,
year = {2026},
author = {Dulong, C and Trunfio-Sfarghiu, AM and Lazar, AN and Bernoud-Hubac, N},
title = {Effects of fine particulate matter on neuroblastoma cell line: metabolic and lipid deregulations and their consequences on the onset of neurological diseases.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.09.011},
pmid = {42759687},
issn = {1638-6183},
abstract = {Particulate Matter (PM) contained in atmospheric pollution can interact with pulmonary, cardiac and nervous systems. Recent studies focus on the impact of PM2.5 on the brain and on their potential role in the onset of neurodegenerative diseases (ND) such as Alzheimer's disease. Using human neuroblastoma SH-SY5Y cell line as an in vitro neurodegenerative model, multiple interconnected cellular dysfunctions induced by PM2.5 exposure have been highlighted. This includes mitochondrial damages, reticulum endoplasmic stress, oxidative stress, calcium dyshomeostasis and lipid dysregulation. These alterations activate multiple cell death pathway though apoptosis and autophagy-dependent ferroptosis. This review aims to provide an integrated overview of these mechanisms, to better understand the association between PM2.5 exposure and cell degeneration. A particular attention is given to lipid peroxidation and oxidative damage as emerging drivers of neuronal degeneration. Despite significant advances, important gaps remain regarding the translation of in vitro findings to in vivo models and particularly to human pathology. A better understanding of key molecular events is essential to identify therapeutic targets to mitigate or prevent pollution-related neurodegenerative processes.},
}

@article {pmid42759802,
year = {2026},
author = {Junwu, F and Xiangqian, R and Chengyong, Y and Dai, K and Wang, J and Xiang, X and Guoqing, Z},
title = {Alzheimer's disease-associated transcriptional signatures define prognostic subtypes in glioma.},
journal = {Brain research},
volume = {},
number = {},
pages = {150525},
doi = {10.1016/j.brainres.2026.150525},
pmid = {42759802},
issn = {1872-6240},
abstract = {BACKGROUND: Gliomas are molecularly heterogeneous central nervous system tumors with marked variation in clinical outcome. Alzheimer's disease (AD)-associated transcriptional alterations may capture neural and immune programs relevant to glioma biology, but they do not by themselves establish a direct mechanistic relationship between AD and glioma.

METHODS: AD-associated differentially expressed genes were identified from GSE132903 and evaluated in TCGA/GTEx and CGGA glioma datasets. Consensus clustering, enrichment analysis, Cox and LASSO modeling, immune deconvolution, and mutation analyses were performed. The incremental prognostic value of the AD-Driven score (ADDs) was tested after adjustment for age, sex, WHO grade, IDH status, 1p/19q codeletion, and MGMT promoter methylation. Protein-expression and glioma survival annotations for the 14 model genes were reviewed in the Human Protein Atlas (HPA).

RESULTS: We identified 470 CE-associated differentially expressed genes enriched in synaptic, calcium-signaling, and neurotransmitter pathways. A 14-gene ADDs model stratified survival in the discovery and validation cohorts. Among 554 complete cases with 147 deaths, continuous standardized ADDs remained associated with overall survival after molecular and clinicopathological adjustment (HR per SD = 1.76, 95 % CI 1.26-2.44, P = 0.0008), improving model fit (likelihood-ratio P = 0.0008) but only modestly increasing the C-index (0.876 to 0.880). HPA review provided directionally supportive glioma survival annotations for seven model genes.

CONCLUSION: The ADDs captures prognostically relevant neural and immune transcriptional variation in glioma and provides incremental information beyond established molecular variables when modeled continuously. The cross-cancer IMvigor210 analysis remains exploratory and does not establish prediction of immunotherapy benefit in glioma. HPA observations provide orthogonal public-database support for selected signature components, while independent tissue-based, mechanistic, and glioma-specific treatment-response validation remain necessary.},
}

@article {pmid42759807,
year = {2026},
author = {Sekizar, S and Holt, K and Meyers, S and Tzioras, M and King, D and Tulloch, J and Jackson, RJ and Spires-Jones, TL},
title = {Astrocytic synapse engulfment is differentially controlled by APOE genotype.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.09.026},
pmid = {42759807},
issn = {1873-7544},
abstract = {APOE gene variants encoding the apolipoprotein E (ApoE) protein are strong genetic modifiers of risk of Alzheimer's disease (AD) with the APOE ε4 allele (APOE4) associated with substantially increased disease risk, APOE ε2 allele (APOE2) associated with decreased risk and APOE ε3 allele (APOE3) considered neutral. Recently the Christchurch variant of APOE3 (APOE3CH) has been shown to protect people from familial AD. Despite this strong evidence for APOE mediating AD risk, the exact biological mechanisms through which APOE influences pathogenesis remain unknown. Our previous work implicates APOE in synapse degeneration in AD with exacerbated plaque-associated synapse loss, increased accumulation of amyloid beta in synapses, and increased ingestion of synapses by glia around plaques observed in APOE4 carriers. Here we used a cell culture system to test the hypothesis that APOE isoforms would differentially regulate phagocytosis of synapses isolated from human post-mortem AD brain tissue. Human APOE expressing mouse astrocyte cell lines exhibited isoform-dependent differences in phagocytic activity with APOE2 < APOE3 < APOE4 as would be expected if APOE genotype mediated risk at least in part through synapse phagocytosis. Interestingly, astrocytes with the protective APOE3CH allele phagocytosed synapses similarly to APOE4 astrocytes indicating this variant does not likely protect from AD by reducing astrocyte phagocytosis of synapses. These findings indicate that APOE isoforms differentially regulate astrocytic engulfment of AD-associated synaptic material. These isoform-specific effects are not explained by differences in phosphatidylserine recognition, suggesting the involvement of additional mechanisms underlying ApoE-dependent modulation of astrocyte function.},
}

@article {pmid42759971,
year = {2026},
author = {Leaning, IE and Costanzo, A and Jagesar, R and Knol, L and Tjeerdsma, S and Tyborowska, A and Ikani, N and Reus, LM and Visser, PJ and Kas, MJ and Beckmann, CF and Ruhé, HG and Marquand, AF},
title = {Did you miss me? Making the most of digital phenotyping data by imputing missingness with point process models: observational study.},
journal = {BMJ health & care informatics},
volume = {33},
number = {1},
pages = {},
doi = {10.1136/bmjhci-2026-102079},
pmid = {42759971},
issn = {2632-1009},
mesh = {Humans ; *Smartphone ; *Phenotype ; Hidden Markov Models ; Alzheimer Disease ; Digital Media ; Poisson Distribution ; },
abstract = {OBJECTIVES: Smartphone-based digital phenotyping can provide low-burden behavioural measures for mental disorder monitoring. However, progress in making inferences from these data is challenged by the common occurrence of missing data. We propose a method to impute missingness using non-homogeneous Poisson point process models (PPPMs), where activities (overall phone, social media, communication app usage, outgoing/incoming calls) are modelled as 'points'.

METHODS: We evaluate personalised PPPMs for imputation and investigate their influence on downstream analysis. In a ground truth evaluation (in and out-of-sample), we evaluate time-varying covariates ('hour of the day', 'day of the week'; encoded using one-hot encoding and sine-cosine transformation) to model behavioural patterns in participants from SMARD (depression; n=26). We train a hidden Markov model (HMM) on data simulated by the PPPMs and compare this to a ground truth HMM. We then perform a replication of a prior HMM analysis in PRISM (Alzheimer's disease, schizophrenia, healthy controls; n=65) and Hersenonderzoek studies (Alzheimer's disease, memory complaints, healthy controls; n=283).

RESULTS: In the ground truth evaluation, 'hour' was consistently significant in in-sample likelihood ratio tests and 'day' was less commonly significant. PPPMs including one-hot encoded hour generally provided the highest out-of-sample likelihood. Using this PPPM variant, HMM properties were preserved, and prior findings were replicated.

DISCUSSION: Personalised PPPMs provide behavioural simulations that can be used for temporal imputation. These models capture average patterns and could be extended to include further temporal components.

CONCLUSION: Non-homogeneous PPPMs are a promising imputation tool that may contribute to improved utility of digital phenotyping by providing realistic temporal imputations.},
}

Humans
*Smartphone
*Phenotype
Hidden Markov Models
Alzheimer Disease
Digital Media
Poisson Distribution

@article {pmid42760257,
year = {2026},
author = {Wu, Y and Park, CM and Chen, X and Luo, L and Kim, EG and Shi, SM and Kim, DH and McCarthy, EP},
title = {Performance of Claims-based Alzheimer's Disease and Related Dementias Algorithms in Medicare Advantage and Fee-for-Service Populations.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag237},
pmid = {42760257},
issn = {1758-535X},
abstract = {BACKGROUND: Evidence comparing the performance of claims-based dementia algorithms across Medicare Advantage (MA) and fee-for-service (FFS) populations remains limited. We evaluated the validity of two claims-based algorithms across MA and FFS populations.

METHODS: We used nationally representative, linked National Health and Aging Trends Study (NHATS)-Medicare data to identify community-dwelling participants with continuous enrollment in MA or FFS during Round 7 (2017; n = 5,018), Round 9 (2019; n = 4,018), and Round 11 (2021-2022; n = 3,086). Using NHATS probable dementia as reference standard, we validated the Bynum-Standard and Chronic Condition Warehouse (CCW) dementia algorithms across three time points.

RESULTS: Overall, both algorithms demonstrated comparable performance in MA and FFS populations, with high specificity (>97.9%) and negative predictive value [NPV] (>92.9%). The Bynum algorithm showed similar sensitivity between MA and FFS in Rounds 7 (30.2% vs. 29.1%) and 11 (25.6% vs. 23.9%), but lower sensitivity in MA for Round 9 (25.0% vs. 36.4%). Positive predictive value [PPV] was similar between MA (62.7%-70.6%) and FFS (62.1%-70.4%) across all rounds. The CCW algorithm demonstrated greater MA-FFS differences, with lower sensitivity in MA for Rounds 9 (30.8% vs. 46.9%) and 11 (35.0% vs. 49.3%) and similar sensitivity for Round 7 (40.4% vs. 42.2%). PPV varied across rounds in both MA and FFS [(Round 7: 76.3% vs. 71.2%) to (Round 11: 68.5% vs. 76.4%)]. Both algorithms identified participants with more severe dementia.

CONCLUSION: Claims-based dementia algorithms demonstrate broadly consistent performance in MA and FFS populations, with high specificity and moderate PPV but comparable or lower sensitivity in MA, informing case ascertainment across Medicare plan type.},
}

@article {pmid42760306,
year = {2026},
author = {},
title = {Cognitive resilience helps to predict Alzheimer's dementia.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42760306},
issn = {1476-4687},
}

@article {pmid42760345,
year = {2026},
author = {Grinberg, LT and Murray, ME},
title = {Atypical Alzheimer disease: a multi-axis framework toward defining heterogeneity.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42760345},
issn = {1759-4766},
abstract = {Alzheimer disease (AD) is defined biologically by the presence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain; however, these pathologies do not affect all brain regions equally. Typical AD usually presents with memory impairment, whereas atypical forms of AD, including posterior cortical atrophy, logopenic variant primary progressive aphasia, behavioural and dysexecutive AD, and corticobasal syndrome, manifest with prominent non-memory symptoms. Aβ biomarkers usually confirm that AD pathology is present, whereas regional tau, neurodegeneration and dysfunction more closely track the affected network and the presenting symptoms. The atypical variants, which tend to present at a younger age than typical AD, provide human models to study selective vulnerability of neurons and circuits. They also help us to test whether immune-glial, vascular, protein-handling, synaptic or genetic factors shape regional vulnerability and rate of progression beyond total Aβ and tau burden. In this Review, we integrate clinical, neuropathological, imaging, genetic and molecular evidence to describe atypical AD within the broader AD spectrum. We propose a practical multi-axis framework comprising clinical phenotype, AD biological context (AD pathology plus co-pathologies and molecular modifiers), network topography (regional patterns) and tempo (rate of clinical and biomarker progression). This framework could reduce diagnostic mismatches, make cohorts more comparable and support trials that include outcomes tailored to the affected brain networks.},
}

@article {pmid42751784,
year = {2026},
author = {Mamangam, S and Dhanabalan, AK and Verma, K and Prasanth, MI and Brimson, S and Brimson, JM},
title = {Neuroprotective Effects of Two N-Benzylamides in Models of Oxidative Stress, Neurite Outgrowth and Neurodegeneration.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e3092494},
doi = {10.1155/omcl/3092494},
pmid = {42751784},
issn = {1942-0994},
support = {N42A670287//National Research Council of Thailand/ ; //Chulalongkorn University/ ; },
mesh = {*Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Humans ; *Neuronal Outgrowth/drug effects ; Receptors, sigma/metabolism ; Sigma-1 Receptor ; Mice ; *Benzamides/pharmacology ; Molecular Docking Simulation ; Reactive Oxygen Species/metabolism ; Caenorhabditis elegans ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Oxidative stress is a central pathological mechanism in neurodegenerative diseases (NDDs), contributing to mitochondrial dysfunction, impaired proteostasis, and progressive neuronal loss. The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident chaperone that coordinates cellular stress responses and has emerged as a promising therapeutic target for neuroprotection. In this study, we investigated the neuroprotective properties and mechanisms of the structurally related N-benzylamides, N-benzylcinnamide (NBCA) and N-benzylbenzamide (NBBA) using complementary in vitro, in vivo and in silico approaches. Neuroprotective activity was initially evaluated using glutamate-induced oxidative injury in HT22 hippocampal neurones and H2O2-induced oxidative stress in SH-SY5Y neuroblastoma cells. Both compounds significantly attenuated oxidative injury, although NBCA consistently showed greater efficacy and was therefore selected for detailed mechanistic investigation. NBCA reduced intracellular reactive oxygen species (ROS) production and lipid peroxidation while restoring endogenous antioxidant enzyme activities, mitochondrial membrane potential, ATP production, and cholinergic homeostasis. Immunofluorescence analysis showed that NBCA modulated nuclear factor erythroid 2-related factor 2 (NRF2) and S1R immunoreactivity after oxidative stress. NBCA also promoted neurite outgrowth in wild-type (WT) Neuro-2a cells, whereas these effects were absent in S1R knockout cells, supporting the involvement of S1R-associated signalling. Molecular docking predicted favourable interactions between NBCA and the stress-response proteins S1R, BiP and TMEM97, suggesting modulation of interconnected cellular stress-response networks. In Caenorhabditis elegans, NBCA improved resistance to oxidative stress, preserved learning and memory, delayed amyloid-β-induced paralysis, and reduced amyloid deposition in transgenic Alzheimer's disease (AD) models. Collectively, these findings demonstrate that NBCA exerts neuroprotective effects across multiple experimental models by preserving redox homeostasis, mitochondrial function, and neuronal integrity. The convergence of pharmacological, genetic, imaging, computational, and whole-organism evidence supports the involvement of S1R-associated signalling in NBCA's biological activity. Together, these findings demonstrate that modulation of S1R-associated cellular stress-response networks is a promising strategy for preserving neuronal function during oxidative stress and neurodegeneration and identify NBCA as a valuable lead compound for future mechanistic and therapeutic investigation.},
}

*Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Humans
*Neuronal Outgrowth/drug effects
Receptors, sigma/metabolism
Sigma-1 Receptor
Mice
*Benzamides/pharmacology
Molecular Docking Simulation
Reactive Oxygen Species/metabolism
Caenorhabditis elegans
*Neurodegenerative Diseases/drug therapy/pathology/metabolism
Cell Line, Tumor
Membrane Potential, Mitochondrial/drug effects

@article {pmid42752160,
year = {2026},
author = {Abo Foul, Y and Shamay-Tsoory, S},
title = {Empathy on the edge: A neurocognitive model of empathy in aging and dementia.},
journal = {Psychology and aging},
volume = {},
number = {},
pages = {},
doi = {10.1037/pag0001025},
pmid = {42752160},
issn = {1939-1498},
abstract = {Empathy, the ability to understand others' perspectives (cognitive empathy) and share their emotions (emotional empathy), is critical for social functioning across the lifespan. Although empathy changes with age and is often disrupted in neurodegenerative disease, prior research has largely examined isolated components or focused narrowly on healthy aging or specific disorders. This systematic review addresses this gap by synthesizing behavioral and neuroimaging evidence on empathy across typical and pathological aging, from healthy older adulthood and mild cognitive impairment to Alzheimer's disease and behavioral variant frontotemporal dementia. We reviewed empirical studies published between January 2015 and October 2025 that examined cognitive and/or emotional empathy in healthy older adults or individuals with mild cognitive impairment, Alzheimer's disease, or behavioral variant frontotemporal dementia. We propose an integrative model suggesting that cognitive and emotional empathy follow distinct trajectories across aging. Based on the model, cognitive empathy gradually declines, likely reflecting changes in prefrontal regions and large-scale brain networks, with this process beginning in normal aging and continuing through mild cognitive impairment and dementia. In contrast, emotional empathy is relatively preserved in aging and early disease stages, although it becomes more context-dependent with clearer impairment in behavioral variant frontotemporal dementia. We conclude that understanding these trajectories has important implications for early diagnosis, caregiving, and designing targeted interventions to support empathic functioning in older adults and individuals with neurodegenerative diseases. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42752570,
year = {2026},
author = {Liu, Y and He, Y and Wei, Y and Wang, P and Huang, C and Tao, Q and Zhu, L and Xu, X and Liu, L and Liu, S and Han, L and Zhang, J and Wang, L},
title = {A Molecularly Anchored Spatial Transcriptomic Framework for Precise CA1-Subiculum Parcellation and Region-Resolved Analysis in Alzheimer's Disease.},
journal = {GigaScience},
volume = {},
number = {},
pages = {},
doi = {10.1093/gigascience/giag094},
pmid = {42752570},
issn = {2047-217X},
abstract = {BACKGROUND: The precise molecular delineation of the interface between the Subiculum (Sub) and cornu ammonis 1 (CA1) is a challenge in hippocampal research, as conventional cytoarchitectural boundaries are often ambiguous and limit reproducible regional annotation. Here, we developed a molecularly anchored spatial transcriptomic framework to define CA1-Sub regional identities using high-definition spatial transcriptomics (Stereo-seq) and single-nucleus RNA sequencing (snRNA-seq) references.

FINDINGS: Using a human hippocampal Stereo-seq dataset from 12 donors, we established a data-driven parcellation framework that defines reproducible molecular features distinguishing CA1 and Sub while capturing the transition between these regions. FN1 was identified as a Sub-enriched marker in a subset of EX_Sub and, together with ETV1 and additional regional markers, enabled molecular assignment of CA1 and Sub identities across datasets. The Sub association of FN1 and ETV1 was further supported by human 10X Genomics spatial transcriptomics, mouse in situ hybridization data, and a mouse spatial transcriptomic dataset. Applying this framework to Alzheimer's disease (AD) tissues revealed region-specific transcriptional alterations across CA1 and Sub, including enrichment of mitochondrial energy metabolism-related transcripts in the Sub, suggesting exploratory transcriptional associations of altered metabolic function.

CONCLUSIONS: This study provides a molecularly anchored framework for human CA1-Sub parcellation that complements conventional annotation. By defining regional molecular states while preserving the biological continuum across CA1-Sub interface, this approach enables more consistent regional analysis of human hippocampus tissue across donors, datasets, and disease conditions.},
}

@article {pmid42752707,
year = {2026},
author = {Santos, DH and da Silva, AMP},
title = {Amyloid-beta-targeting monoclonal antibodies in early Alzheimer's disease: a cochrane review summary and appraisal for the neurological community.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42752707},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/immunology/metabolism ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Seven amyloid-beta-targeting monoclonal antibodies have been trialled in early Alzheimer's disease. They differ in epitope and in how much plaque they clear; only two have traditional approval. A 2026 Cochrane Review pooled all seven as one class. We ask what that average tells us about any one drug.

METHODS: We summarise the review in mild cognitive impairment or mild dementia due to Alzheimer's disease and report its estimates and certainty ratings unchanged. Our appraisal sits in a separate section and draws on the pivotal trials and regulatory assessments.

RESULTS: Seventeen trials (20,342 participants) were included. At 18 months the pooled standardised mean difference was -0.11 (95 % confidence interval -0.16 to -0.06) for cognition and -0.12 (-0.24 to 0.00) for dementia severity; three functional scales favoured treatment (0.09 to 0.23). Amyloid-related imaging abnormalities with oedema affected 119 versus 12 per 1,000 (risk ratio 10.02, 7.49 to 13.41). Four of the seven antibodies cleared no plaque or cleared it incompletely, so the pooled result cannot test whether clearance produces benefit. In the two approved agents dementia severity differed by 0.45 and 0.67 points, larger than the class average but below thresholds of clinical importance.

CONCLUSIONS: The class average is not an estimate for any single agent. These antibodies clear amyloid and produce small differences on trial scales at 18 months, against a tenfold rise in amyloid-related oedema. Counselling should rest on agent-specific figures and a biomarker-confirmed diagnosis, and should weigh APOE ε4 genotype and antithrombotic use before the first infusion.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
*Amyloid beta-Peptides/immunology/metabolism
Cognitive Dysfunction/drug therapy

@article {pmid42752750,
year = {2026},
author = {Jantaratnotai, N and McLarnon, JG},
title = {The Roles of Transcription Factor Ets-1 in Neurological Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42752750},
issn = {1559-1182},
mesh = {Humans ; *Proto-Oncogene Protein c-ets-1/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; },
abstract = {Ets-1 is a member of the Ets family of transcription factors that regulates diverse biological processes including cellular proliferation, development, and immune response. At present, few studies have examined the actions of Ets-1 in brain neurological disorders. One exception is brain tumors where evidence suggests that elevated levels of Ets-1 could induce abnormalities in angiogenic activity in promoting tumor growth. In this review we summarize evidence for the involvement of Ets-1 in brain neurological disorders including brain tumors, stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuropathic pain, and depression. Overall findings suggest that Ets-1 is a critical switch in balancing vascular remodeling and neuroinflammation across various neuropathologies; however, whether Ets-1 exerts detrimental or beneficial effects is context- and time-dependent. At present, published work has largely concerned ancillary, rather than primary, roles of Ets-1 in brain with little focus on disorders other than brain tumors. Resolving these divergent and time-dependent roles of Ets-1 will advance its utility as both a diagnostic biomarker and a viable therapeutic target in neurological diseases.},
}

Humans
*Proto-Oncogene Protein c-ets-1/metabolism
Animals
*Nervous System Diseases/metabolism/pathology

@article {pmid42752765,
year = {2026},
author = {Zhang, T and Chen, X and Wang, Y and Wang, Y},
title = {A Lipoylation-PDH-TCA Transcriptional Deficit in the Alzheimer's Disease Cortex - Donor-level Multi-cohort Evidence with Neuronal-composition, Disease-specificity and Matched-null Controls.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42752765},
issn = {1559-1166},
mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; Humans ; *Neurons/metabolism ; Lipoylation ; *Prefrontal Cortex/metabolism/pathology ; *Citric Acid Cycle ; Male ; Cuproptosis ; },
abstract = {Cuproptosis, a copper-dependent form of regulated cell death acting through lipoylated tricarboxylic acid (TCA) cycle proteins, has been proposed as a molecular link between type 2 diabetes and Alzheimer's disease. We asked whether cuproptosis effector genes are dysregulated in a cell-type-specific manner in the human Alzheimer's disease cortex, and whether any such signal survives controls for neuronal composition and disease specificity. Single-nucleus data from 21 prefrontal cortex donors were aggregated to donor-level pseudobulk within each cell type. Four independent bulk cohorts, each contributing one observation per donor, entered a random-effects meta-analysis. Adjustment for estimated neuronal content, competitive and expression-matched null gene-set testing, and comparison against Huntington's disease and vascular dementia were applied as controls. The donor was the unit of replication throughout. No gene-cell-type pair survived correction across the 75 prespecified tests; PDHA1 in inhibitory neurons showed the largest nominal reduction (- 0.418, q = 0.829). In donor-level meta-analysis PDHA1 was lower in Alzheimer's disease in all four cohorts (- 0.457, 95% CI - 0.712 to - 0.201, I[2 ]= 0%) but did not survive correction (q = 0.086). A post hoc lipoylation/pyruvate dehydrogenase/TCA module did reach the adjusted threshold (- 0.245, 95% CI - 0.363 to - 0.127, q = 0.035), whereas the copper modules pooled to zero and moved in opposite directions across cohorts. Comparable reductions occurred in Huntington's disease and vascular dementia, and the disease-control contrasts were not significant. These transcriptional associations do not demonstrate cuproptosis, are not specific to Alzheimer's disease, and are hypothesis-generating only.},
}

*Alzheimer Disease/metabolism/genetics/pathology
Humans
*Neurons/metabolism
Lipoylation
*Prefrontal Cortex/metabolism/pathology
*Citric Acid Cycle
Male
Cuproptosis

@article {pmid42752992,
year = {2026},
author = {Li, X and Liu, X and Song, X and Zhou, Y and Yang, D and Wang, Y and Mao, S and Rang, X and Hong, X and Wang, X and Yue, H and Wang, D and Zhang, X},
title = {Bioinformatics-Driven Discovery of Aβ-Targeted Therapeutics and Diagnostic Biomarkers for Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e8975137},
pmid = {42752992},
issn = {2314-6141},
support = {LH2020H052//Heilongjiang Provincial Natural Science Foundation/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; *Biomarkers/metabolism ; Molecular Docking Simulation ; *Computational Biology/methods ; Curcumin/pharmacology/chemistry ; Molecular Dynamics Simulation ; Resveratrol/pharmacology ; Apigenin/pharmacology/chemistry ; Gene Regulatory Networks ; Protein Binding ; },
abstract = {The deposition of amyloid-β (Aβ) plaque is widely recognized as one of the core pathological events of Alzheimer's disease (AD). This study focused on uncovering potential diagnostic biomarkers and small-molecule candidates potentially modulating Aβ-associated pathways in AD. Weighted gene coexpression network analysis (WGCNA) and machine learning identified the hub gene. Single-nucleus RNA sequencing (snRNA-seq) identified high-expression cell clusters. We identified potential Aβ-binding small-molecule candidates and calculated their binding affinities using molecular docking techniques. Based on molecular docking, we further evaluated the binding stability and conformational dynamics of the protein-ligand complex through molecular dynamics (MD) simulations. NFKBIA was identified as a hub diagnostic gene. Three small molecules, resveratrol, curcumin, and apigenin, demonstrated strong binding affinities for NFKBIA. These findings clarify the priority candidate gene and feasible strategic directions, which are expected to be translated into practical pathways for precision diagnosis and treatment of AD.},
}

*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy
Humans
*Amyloid beta-Peptides/metabolism
*Biomarkers/metabolism
Molecular Docking Simulation
*Computational Biology/methods
Curcumin/pharmacology/chemistry
Molecular Dynamics Simulation
Resveratrol/pharmacology
Apigenin/pharmacology/chemistry
Gene Regulatory Networks
Protein Binding

@article {pmid42753025,
year = {2026},
author = {Aydın, AC},
title = {Exosomes in Alzheimer's Disease: From Pathological Mechanisms to Biomarker Potential and Therapeutic Applications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42753025},
issn = {1559-1182},
mesh = {Humans ; *Exosomes/metabolism ; *Alzheimer Disease/therapy/pathology/metabolism ; *Biomarkers/metabolism ; Animals ; Microglia/metabolism/pathology ; },
abstract = {Exosomes are small extracellular vesicles that mediate communication between cells by carrying proteins, lipids, nucleic acids, and other biologically active molecules. In Alzheimer's disease (AD), their role appears to be complex and context-dependent. Evidence suggests that exosomes may contribute to disease progression by supporting the intercellular spread of amyloid-β and tau pathology. At the same time, they are increasingly being investigated as blood-based biomarkers and as potential therapeutic delivery systems. This review summarizes current evidence on the involvement of exosomes in AD biology. Particular attention is given to their role in amyloid-β and tau propagation, microglia-driven neuroinflammation, and the Pellino-1 (Peli1)-related communication between microglia and astrocytes. The review also discusses the diagnostic value of neuron- and astrocyte-derived exosomes as minimally invasive biomarkers. In addition, the therapeutic potential of mesenchymal stem cell-derived exosomes is evaluated, especially in relation to amyloid clearance, neuroinflammation, synaptic repair, and blood-brain barrier crossing. Although preclinical and early clinical findings are encouraging, several barriers still limit clinical translation. These include the lack of standardized isolation methods, cargo heterogeneity, large-scale production difficulties, and insufficient long-term safety and efficacy data. Overall, exosome-based strategies represent a promising but still developing field in AD research, with potential relevance for early diagnosis, disease monitoring, and future therapeutic applications.},
}

Humans
*Exosomes/metabolism
*Alzheimer Disease/therapy/pathology/metabolism
*Biomarkers/metabolism
Animals
Microglia/metabolism/pathology

@article {pmid42753051,
year = {2026},
author = {Pellikka, E and Vauhkonen, PK and Oura, P},
title = {Neuropathological diagnoses and age-related differences in Finnish medico-legal autopsies of individuals aged 65 years and older.},
journal = {Forensic science, medicine, and pathology},
volume = {},
number = {},
pages = {},
pmid = {42753051},
issn = {1556-2891},
abstract = {As populations worldwide continue to grow older, an increase in cases involving aged individuals is also to be expected in medico-legal autopsies. The aim of this study was to report the neuropathological diagnoses of individuals aged ≥ 65 years, and to compare the findings across three age groups: youngest-olds (65-74 years of age), middle-olds (75-84) and oldest-olds (≥ 85). The sample comprised all Finnish medico-legal autopsies of individuals aged ≥ 65 years whose autopsy included a full neuropathological examination performed by a neuropathologist over the period 2016-2022 (n = 629). Neuropathological diagnoses were obtained from the neuropathologists' reports, and background characteristics were collected from medico-legal cause-of-death investigation documents. Of all cases, 97.1% received at least one neuropathological diagnosis. The prevalences of many neurodegenerative diseases increased with age; Alzheimer's disease neuropathological change (30.5%) and cerebral amyloid angiopathy (14.0%) were the most common ones. However, some rarer neurodegenerative diseases were more frequent among youngest-olds. While the prevalence of acute infarcts remained relatively consistent across the age groups (12.4-14.5%), old infarcts and subarachnoid haemorrhages were most common among oldest-olds (22.1% and 16.6%, respectively). The age-related increase in subarachnoid haemorrhage diagnoses appeared to be primarily driven by the male sex. The prevalences of acute and old traumatic brain injuries were rather low (5.7-6.2% and 5.1%, respectively) and remained relatively stable across the age groups. In conclusion, our data suggest that neuropathological diagnoses are highly prevalent among aged individuals undergoing medico-legal autopsy, and many diagnoses become more frequent towards oldest-olds.},
}

@article {pmid42753133,
year = {2026},
author = {Misra, SR and Das, R},
title = {Beyond Oral Hygiene: Medication Burden, Oral Function, and Dysphagia in Alzheimer's Disease.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {5},
pages = {e70255},
doi = {10.1111/scd.70255},
pmid = {42753133},
issn = {1754-4505},
}

@article {pmid42753291,
year = {2026},
author = {Tamiz, AP and Baran, SW and Hartung, T and Wu, WW},
title = {New approach methodologies in neurotherapeutics development.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01056},
doi = {10.1016/j.neurot.2026.e01056},
pmid = {42753291},
issn = {1878-7479},
abstract = {New Approach Methodologies (NAMs) offer substantial opportunities to transform neurotherapeutics discovery, optimization, and development, reducing the timeline to translate central nervous system (CNS) innovations to patients. Strategically deployed, NAMs enhance the predictive value of preclinical studies for human outcomes while reducing reliance on animal models. Current scientific community interest focuses particularly on human-based and -derived systems, in silico and AI-driven models, and advanced microphysiological platforms, reflecting a shift toward human-centric drug development paradigms. Despite this momentum, significant challenges remain, including NAM reproducibility and validation, the establishment of standardized performance criteria, data sharing, and the evolution of regulatory frameworks needed to enable consistent adoption across the neurotherapeutics continuum. Nevertheless, there is a rich history of developing and adopting methodologies, particularly for improving the prediction of neurotherapeutic safety profiles while reducing animal use, and for advancing understanding of drug delivery across the blood-brain barrier, and the assessment of adverse neurological effects. These advances have begun to influence regulatory decision-making and are increasingly reflected in guidance and review practices. Furthermore, NAMs are showing concrete impact in neurological disorders, including Epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, where human-relevant models and computational approaches support more precise characterization of disease mechanisms and therapeutic responses. In this paper, we examine the current and emerging roles of NAMs in neurotherapeutics development from government, academia, and industry perspectives, highlight key opportunities and limitations, and discuss the scientific, technical, and regulatory steps required to fully realize their potential in accelerating safe and effective CNS therapies.},
}

@article {pmid42753292,
year = {2026},
author = {Nam, MH and Park, HJ and Lee, HY and Chen, ZY and Yun, HD and Kim, Y and Lee, JY and Shin, CH and Ha, JY and Seo, YK},
title = {40 Hz vibrotactile stimulation ameliorates amyloid pathology and cognitive deficits in 5xFAD mice and is associated with alterations in Piezo1, ERK, and GSK-3β/p65 signaling.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01077},
doi = {10.1016/j.neurot.2026.e01077},
pmid = {42753292},
issn = {1878-7479},
abstract = {40 Hz vibrotactile stimulation (VTS) is an emerging non-invasive therapy for Alzheimer's disease (AD), yet its specific mechanisms regarding amyloid-beta (Aβ) metabolism remain unclear. Six-month-old 5xFAD mice received daily 40 Hz VTS for four weeks. We assessed cognitive function, Aβ pathology, and underlying molecular pathways. VTS improved spatial learning and recognition memory, whereas no significant improvement was observed in short-term spatial working memory. VTS reduced hippocampal Aβ plaque burden and cortical soluble Aβ40 and Aβ42 levels, accompanied by decreased expression of APP, BACE1, and PS1 and increased expression of ADAM10 and IDE. It further attenuated neuroinflammation, oxidative stress and produced changes in cholinergic and synaptic plasticity-associated proteins. VTS increased hippocampal Piezo1 expression and ERK phosphorylation, increased inhibitory phosphorylation of GSK-3β at Ser9, decreased p65 phosphorylation, and reduced tau phosphorylation. 40 Hz VTS ameliorates several cognitive and neuropathological features of AD in 5xFAD mice. These improvements are associated with the modulation of Piezo1, ERK, and GSK-3β/p65 signaling pathways, highlighting its potential as a promising non-invasive AD therapeutic strategy.},
}

@article {pmid42753425,
year = {2026},
author = {Orzeł, U and Wójcik, E and Filipek, S and Moreira, IS},
title = {ACE2 dysregulation and lipid metabolism: Mechanistic interplay between COVID-19 and neurodegeneration.},
journal = {Molecular aspects of medicine},
volume = {112},
number = {},
pages = {101519},
doi = {10.1016/j.mam.2026.101519},
pmid = {42753425},
issn = {1872-9452},
abstract = {Angiotensin-converting enzyme 2 (ACE2) is the primary cellular receptor of SARS-CoV-2. It is a key regulator of the renin-angiotensin system (RAS) and modulates blood pressure and inflammatory pathways. ACE2 converts pro-inflammatory angiotensin II into the vasoprotective peptide, angiotensin (1-7). This is strongly influenced by the lipid composition of the plasma membrane. Cholesterol-rich lipid rafts play an important role in determining receptor localisation and viral accessibility. Dyslipidaemia, which is common in obesity, diabetes, and metabolic syndrome, has been associated with an increased susceptibility to severe COVID-19 and may amplify systemic inflammation. Aberrant lipid metabolism also contributes to neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, which drive neuroinflammation, synaptic dysfunction, and blood-brain barrier impairment. Notably, similar disturbances and systemic inflammation are increasingly recognised in patients with Long COVID, suggesting overlapping mechanisms that may exacerbate or accelerate neurodegenerative processes. This review explores the interplay between ACE2 regulation, lipid metabolism, and systemic inflammation in COVID-19, with a particular focus on their implications for neurological health. Uniquely, we highlighted the intersection of ACE2 and lipid-related alterations in patients with Long COVID and their potential contribution to the progression of neurodegenerative diseases. In addition, we reviewed therapeutic strategies targeting ACE2, including recombinant soluble ACE2, ACE2-based nanotherapeutics, and lipid-focused interventions, aimed at mitigating acute infection, systemic inflammation, and persistent neurological sequelae. Understanding these mechanisms is essential to prevent long-term neurological consequences of the COVID-19 pandemic.},
}

@article {pmid42753449,
year = {2026},
author = {Xi, L and Wan, J and Hua, Y and Guo, M and Du, J and Luo, X and Yu, H},
title = {Effects of ketogenic diet on cognitive impairment in older adults: a systematic review and meta-analysis.},
journal = {Archives of gerontology and geriatrics},
volume = {151},
number = {},
pages = {106409},
doi = {10.1016/j.archger.2026.106409},
pmid = {42753449},
issn = {1872-6976},
abstract = {BACKGROUND: Cognitive impairment in older adults is associated with substantial functional decline and care burden. The ketogenic diet (KD) may improve cognition, but evidence in older adults with cognitive impairment remains inconsistent. This study evaluated the effects of KD, including related ketogenic dietary strategies, on cognitive outcomes and metabolic markers.

METHODS: PubMed, Web of Science, Embase, the Cochrane Library, CNKI, Wanfang, and VIP were searched from inception to July 2025 for randomized controlled trials of KD or related ketogenic dietary strategies in older adults with cognitive impairment. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Meta-analysis was performed using Review Manager 5.4.

RESULTS: Twelve randomized controlled trials involving 707 participants were included. Compared with control interventions, KD-related dietary strategies improved overall cognitive function [SMD = 0.34, 95% CI (0.16 to 0.52), p < 0.01]. Domain-specific analyses showed significant improvements in memory [SMD = 0.53, 95% CI (0.10 to 0.96), p = 0.01] and language function [SMD = 0.43, 95% CI (0.16 to 0.70), p = 0.002], whereas no significant effects were observed for attention or executive function. KD-related strategies increased acetoacetate and β-hydroxybutyrate concentrations, indicating effective ketone production. Regarding metabolic safety, KD-related interventions increased total cholesterol and LDL-C, while triglycerides and HDL-C remained unchanged.

CONCLUSIONS: KD and related ketogenic dietary strategies may improve cognitive performance and enhance ketone body production in older adults with mild cognitive impairment or Alzheimer's disease. The potential metabolic implications associated with lipid changes should be considered alongside cognitive benefits.},
}

@article {pmid42753521,
year = {2026},
author = {Chen, F},
title = {Bioinformatics-driven discovery and cross-cohort validation of a two-gene signature (RPH3A and HIGD1B) associated with Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109417},
doi = {10.1016/j.compbiolchem.2026.109417},
pmid = {42753521},
issn = {1476-928X},
abstract = {BACKGROUND: Transcriptomic biomarker discovery for Alzheimer's disease (AD) has yielded numerous candidate signatures, yet many fail independent external validations due to overfitting or cohort-specific confounders. We aimed to identify a minimal reproducible gene signature and evaluate its generalizability under locked-model validation.

METHODS: Three GEO datasets were analyzed: GSE118553 (training), GSE122063 (internal validation), and GSE5281 (external validation). Differentially expressed genes were identified in the training set, followed by LASSO and Random Forest feature selection, and intersecting genes were filtered for concordant fold-change direction and P < 0.05 across cohorts. An elastic net model was evaluated using locked training parameters by ROC, calibration, and decision curve analyses,with exploratory threshold optimization performed to assess model performance.

RESULTS: Four genes overlapped between machine-learning methods, but only RPH3A and HIGD1B passed the consistency filter. The locked model achieved AUCs of 0.818 and 0.974 in the internal and external cohorts, respectively. Internal validation showed calibration drift (intercept -2.697, slope 0.705), resulting in 0.000 specificity at the locked threshold. Cohort-specific threshold optimization increased specificity to 1.000 with 0.607 sensitivity. External validation showed good calibration (intercept 1.065, slope 1.203) and favorable decision-curve performance.

CONCLUSION: RPH3A and HIGD1B constitute a reproducible AD-associated molecular signature with robust discrimination across independent postmortem brain cohorts, regions, and platforms. As all datasets were postmortem brain tissue, these findings reflect disease-associated molecular alterations. Calibration, confusion matrix, and decision curve analyses further support model performance and translational relevance.},
}

@article {pmid42753807,
year = {2026},
author = {Shi, H},
title = {Word-Form and Lemma Dependency Networks of Connected Speech in Probable Alzheimer's Disease: Morphological Impacts on Syntactic Topological Metrics.},
journal = {Seminars in speech and language},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2954-9654},
pmid = {42753807},
issn = {1098-9056},
abstract = {BACKGROUND: Alzheimer's disease causes progressive cognitive and linguistic deterioration. Few studies investigate how morphological inflections shape syntactic network topology by comparing word-form and lemma networks.

METHOD: Spontaneous language samples were collected by the Cookie Theft picture description task from 68 individuals with probable Alzheimer's disease (PA) and 68 healthy controls.

RESULTS: In both groups, lemma networks had fewer nodes/edges, higher average degree, density, and clustering coefficient, and shorter average path length than word-form networks. All networks showed small-world properties; only healthy networks obeyed scale-free rules, whereas patient networks deviated slightly. Controls had more nodes and edges, while patients demonstrated higher density and clustering coefficients. Intergroup average degree differences were limited to lemma networks (higher in controls). Average path length and diameter were similar across groups. Significant topological differences were accompanied by modest effect sizes (r = 0.21-0.29), likely arising from variability in spontaneous speech. Function words and basic verbs formed core nodes in both network types.

CONCLUSION: This study identifies quantitative syntactic network biomarkers for linguistic impairments in early PA. Such topological measures may combine with clinical indicators for risk prediction and inform targeted early cognitive interventions.},
}

@article {pmid42753883,
year = {2026},
author = {Lee, JH and Jeong, JH and Mun, BR and Jang, JK and Choi, YM and Baek, JH and Choi, WS},
title = {The phenyl carbamates JBPOS0101 and JBPOS0607 attenuate rotenone-induced dopaminergic neuronal death in mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150555},
doi = {10.1016/j.brainres.2026.150555},
pmid = {42753883},
issn = {1872-6240},
abstract = {Parkinson's disease (PD) is a progressive neurodegenerative disease that causes motor abnormalities such as tremors, rigidity, and posture imbalance. The loss of dopaminergic neurons and Lewy bodies containing the aggregation of α-synuclein are the main neuropathological features of PD. Rotenone, a widely used pesticide and mitochondrial complex I inhibitor, induces dopaminergic neuronal death and is used to model PD in rodents. We previously reported that JBPOS0101, a phenyl carbamate compound, attenuates amyloid β accumulation and memory impairment in the 5xFAD mouse model of Alzheimer's disease. In this study, we investigated the effect of JBPOS0101 and its derivative, JBPOS0607, in rotenone-administered mice as a PD model. Both drugs significantly attenuated the loss of dopaminergic neurons induced by rotenone in mice. Furthermore, the rotenone-induced accumulation of phosphorylated α-synuclein in dopaminergic neurons was also attenuated by the drugs. Additionally, both drugs alleviated rotenone-induced activation of astrocytes and microglia compared to the group treated with rotenone alone. These results indicate that the phenyl carbamates JBPOS0101 and JBPOS0607 attenuate rotenone-induced dopaminergic neurodegeneration in mice. Both compounds preserved nigral dopaminergic neurons and attenuated alpha-synuclein phosphorylation, glial activation, and pro-inflammatory cytokine levels in the striatum, and JBPOS0607 was also effective in restoring the anti-inflammatory cytokine IL-10, striatal dopamine levels, and motor performance, supporting the therapeutic potential of phenyl carbamates in Parkinson's disease.},
}

@article {pmid42753897,
year = {2026},
author = {Green, J and Liu, Z and Timis, S and Nelson, C and Pedin, A and Guo, C and Wang, XY and Zhang, S and Sun, D},
title = {Deletion of NLRP3 gene blocks traumatic brain injury induced abnormal immune response in mice with a genetic background for AD.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116030},
doi = {10.1016/j.expneurol.2026.116030},
pmid = {42753897},
issn = {1090-2430},
abstract = {Traumatic brain injury (TBI) is a significant risk factor for the development of Alzheimer's disease (AD) and related dementia. In both TBI and AD, inflammation plays a pivotal role. It is known that the NLRP3 inflammasome plays an important role in AD pathogenesis while TBI triggers activation of the NLRP3 inflammasome in the brain. To evaluate the importance of the NLRP3 inflammasome in mediating the TBI-induced immune response in animals with a genetic background for AD, we have examined immune profiles in the brain using a novel transgenic mouse line at 3xTg background with the NLRP3 gene deleted. Briefly, a group of 4 months old male and female 3xTg and 3xTg/NLRP3[-/-] mice received a moderate lateral fluid percussive injury or sham. Immune cell phenotypes and cytokine gene expression were assessed at 3- and 7-days post injury (dpi). We found that NLRP3 gene deletion counteracted injury-induced alteration of the immune response in 3xTg mice with a significant sex-related difference. Specifically, TBI induced a significant brain infiltration of neutrophils, macrophages and γδ T-cells in 3xTg mice in both sexes at 3dpi, and NLRP3 gene deletion blocked this injury effect only in males not in females. NLRP3 gene deletion also blocked injury-enhanced IL-1β, TNF-α gene expression in male mice, but not in female mice. In conclusion, our study has confirmed that TBI significantly alters the immune response in 3xTg mice and NLRP3 inflammasome is important in mediating these TBI-induced changes with significant sex-related differences.},
}

@article {pmid42753898,
year = {2026},
author = {Guo, F and Li, T and He, XB},
title = {Dynamic contributions of astrocytes in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116032},
doi = {10.1016/j.expneurol.2026.116032},
pmid = {42753898},
issn = {1090-2430},
abstract = {In Alzheimer's disease, pathological stimuli reshape astrocyte functions, which in turn act on neurons, making astrocytes critical modulators of disease progression. A comprehensive understanding of how astrocytes dynamically shift from physiology to pathology across multiple functional domains remains to be established. This review synthesizes recent findings across four key domains: proteostasis, gliotransmission/synapse regulation, blood-brain barrier integrity and metabolism, and microglial crosstalk. For each domain, we compare homeostatic and pathological functions, analyze how supportive roles turn detrimental, and discuss effects on neuronal fate. We also examine signaling pathways that govern astrocyte reactivity and the potential of astrocyte-derived biomarkers. By tracing these dynamic transitions, we aim to refine Alzheimer's disease mechanisms and identify state-targeted therapeutic opportunities.},
}

@article {pmid42753958,
year = {2026},
author = {Peck, BD and O'Hare, NR and Ferris, CF and Pinals, RL and Ebong, EE},
title = {Fragment morphometry analysis and same-color-channel separation enable reproducible quantification across BBB models.},
journal = {Methods (San Diego, Calif.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymeth.2026.09.003},
pmid = {42753958},
issn = {1095-9130},
abstract = {Quantifying blood-brain barrier (BBB) integrity from fluorescence microscopy remains limited by subjective scoring and categorical classification methods that lack reproducibility. For reproducible BBB phenotyping, we present two semi-automated image-analysis pipelines that replace manual scoring with quantitative, continuous-variable measurements. Our in vitro pipeline, implemented in Python, quantifies the connectivity of tight junction structures by measuring discrete ZO-1 fragment objects within manually traced junction regions. It outputs continuous metrics including average fragment area, total junctional area, and a junctional fragmentation ratio that captures degree of ZO‑1 continuity. In human brain microvascular endothelial cells subjected to glycocalyx component knockdown, the pipeline detected significantly reduced fragment area (37% decrease for both CD44 and syndecan-1 (SDC1) knockdown, p = 0.0148 and 0.0084) and junctional fragmentation ratio (p = 0.0061 and 0.0137). Our in vivo pipeline integrates ilastik-based pixel classification with FIJI macro automation to quantify vascular marker colocalization and to separate vessel signal from microglial contamination within a single fluorescence channel, eliminating the need for dedicated counterstains. Applied across four mouse cohorts [young, aged, Alzheimer's, traumatic brain injury (TBI)] and three brain regions [prefrontal cortex (PFC), hippocampus, midbrain], the pipeline detected concurrent ZO-1 loss and ICAM-1 elevation in the PFC and hippocampus of aged and Alzheimer's cohorts, which were statistically indistinguishable, with eNOS nearly doubling in the Alzheimer's PFC (p = 0.0013). TBI mice showed persistent ZO-1 loss with transient ICAM-1 and eNOS changes. Both deterministic pipelines are available on GitHub and designed for adoption beyond the specific markers and systems analyzed here.},
}

@article {pmid42754468,
year = {2026},
author = {Thomas, ML},
title = {A caution in interpreting reliable cognitive decline in older adults at risk for Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100272},
doi = {10.1016/j.inpsyc.2026.100272},
pmid = {42754468},
issn = {1741-203X},
abstract = {Repeated cognitive screening of functionally independent older adults may help identify decline before performance crosses conventional thresholds for cognitive impairment, but interpreting longitudinal change requires distinguishing true change from measurement error. The Reliable Change Index (RCI) is commonly used for this purpose. Conventional RCI methods based on classical test theory (CTT), however, typically assume that measurement error is constant across examinees, an assumption that may be particularly problematic for screening instruments such as the Mini-Mental State Examination (MMSE), which often show pronounced ceiling effects. We compared conventional CTT- and difference-score-based item response theory (IRT) RCIs in 1136 cognitively unimpaired older adults with elevated brain amyloid from the A4 clinical trial. The two approaches were strongly correlated overall (r = .83). However, among the 92 participants identified as showing reliable decline by at least one method, 44 (47.8%) received discordant classifications. Thus, substantial overall correspondence between CTT- and IRT-based RCIs can co-occur with meaningful disagreement about which individuals have experienced reliable cognitive decline. These findings highlight the importance of accounting for variation in measurement precision when interpreting longitudinal change on cognitive screening measures in older adults. They also provide an important cautionary note for clinicians who rely on repeated cognitive screening, as detection of reliable decline may be particularly challenging among individuals with relatively preserved cognition who may be in the earliest stages of cognitive deterioration.},
}

@article {pmid42754545,
year = {2026},
author = {Nanna, MG and Cohen, AB and Erickson, AC and Sun, B and Rossi, R and Akman, Z and Krishnaswami, A and Damluji, AA and Leggett, CG and Staiger, DO and Agha, L},
title = {Days Alive at Home After Emergency Department STEMI Visits Among Medicare Beneficiaries With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70705},
pmid = {42754545},
issn = {1532-5415},
support = {P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; NIA P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; K23-HL153771-01/HL/NHLBI NIH HHS/United States ; K76AG088428/AG/NIA NIH HHS/United States ; P01AG019783/AG/NIA NIH HHS/United States ; //American College of Cardiology Foundation/ ; /PCORI/Patient-Centered Outcomes Research Institute/United States ; P30AG021342//Yale Claude D. Pepper Older Americans Independence Center/ ; },
abstract = {BACKGROUND: As the population of older adults with Alzheimer's disease and related dementias (ADRD) increases, a growing number are presenting with acute cardiovascular events, including ST-elevation myocardial infarction (STEMI). Patient-centered outcomes following treatment for STEMI in this population are not well understood.

METHODS: This retrospective cohort study used Medicare fee-for-service claims from a 100% national sample to identify beneficiaries aged 65 years or older who presented to the emergency department (ED) with STEMI between 2017 and 2022 and underwent cardiac catheterization. Patients were stratified by ADRD status and nursing home admission source. The primary outcome was adjusted days alive at home in the year following the index ED visit. Secondary outcomes included 1-year survival, percent of alive days spent at home, and long-term nursing home care use (≥ 100 days). Multivariable linear regression models controlled for age, sex, and comorbidities.

RESULTS: Of 117,318 patients, 7348 (6.3%) had ADRD and 2617 (2.2%) were admitted from a nursing home. Among community-dwelling patients, those with ADRD had moderately lower adjusted days at home than those without ADRD (225.1 vs. 299.4; adjusted difference -37.8 days; 95% CI, -41.1 to -34.5), but more than half spent over 300 days at home. Among patients admitted from a nursing home, ADRD was associated with markedly worse outcomes (adjusted difference -71.9 days; 95% CI, -84.0 to -59.8), and 1-year survival was 42.4%.

CONCLUSION: Many community-dwelling older adults with ADRD experienced meaningful survival and time at home following cardiac catheterization for STEMI. Dementia status alone should not deter appropriate STEMI care. Treatment decisions should be individualized based on cognitive status, admission source, and patient goals.},
}

@article {pmid42754555,
year = {2026},
author = {Alcaide-Prados, MDC and Gómez-Moreno, G and Leizaola-Cardesa, IO and Moreu, G and Roa-López, A and Aguilar-Salvatierra, A},
title = {Periodontal disease and Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488806},
doi = {10.1177/13872877261488806},
pmid = {42754555},
issn = {1875-8908},
abstract = {BackgroundPeriodontitis is a host-mediated inflammatory disease of microbial origin that results in the loss of periodontal attachment. Its effects are not limited to the oral cavity, as association with systemic diseases, including Alzheimer's disease (AD), has been widely reported.ObjectiveTo evaluate the evidence regarding the potential relationship between periodontitis and AD through a systematic review.MethodsA bibliographic search was conducted in PubMed, Scopus, and WOS. Studies published within the last five years evaluating the biological association between both diseases were selected. The methodological quality and risk of bias of the included studies were assessed using the NOS and ROBINS-I tool, according to the study design.ResultsEleven studies were included. Eight studies analyzed biological samples obtained from brain tissue, blood/serum, saliva, gingival crevicular fluid, and cerebrospinal fluid. Patients with AD exhibited higher levels of periodontopathogenic bacteria, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia, and an association between bacterial load and systemic inflammatory markers. Although most studies reported an association between periodontitis and AD, the findings were not consistent across studies, as some failed to identify statistically significant differences. Periodontal treatment was associated with a reduction in the AD Score, a neuroimaging surrogate marker of preclinical AD, whereas no effect was observed on brain age gap.ConclusionsEvidence suggests a possible association between periodontitis and AD through inflammatory and neurodegenerative mechanisms. Methodological limitations and study heterogeneity preclude establishing causality, underscoring the need for longitudinal studies and alternative methodological approaches.},
}

@article {pmid42754556,
year = {2026},
author = {Wiseman, FK},
title = {New mouse models for Down syndrome Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488873},
doi = {10.1177/13872877261488873},
pmid = {42754556},
issn = {1875-8908},
abstract = {In this issue Ishihara and colleagues report the development and characterization of new mouse models for Down syndrome Alzheimer's disease, the most commonly occurring genetic cause of dementia worldwide. These new models add to the growing portfolio of in vivo models of Down syndrome. In particular, the new Ts1Kei-APPswe/PS1[dE9] model may be highly useful for the study and identification of novel treatment targets for late onset myoclonic epilepsy of Down syndrome. This seizure disorder is a common comorbidity of Down syndrome Alzheimer's disease affecting around half of all people with the condition and is associated with particularly adverse clinical outcomes.},
}

@article {pmid42754558,
year = {2026},
author = {Zou, C and Chung, AS and Tadigiri, M and Namjoshi, A and Shah, T and Kulshreshtha, A},
title = {Mobile application-based interventions for subjective memory decline and mild cognitive impairment: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488814},
doi = {10.1177/13872877261488814},
pmid = {42754558},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) and mild cognitive impairment (MCI) are early clinical markers along the continuum from normal aging to dementia. Both conditions are associated with an elevated risk of progression to Alzheimer's disease and related dementias. With SCD affecting up to 25% and MCI up to 25.2% of older adults, there is growing interest in non-pharmacological, multidomain interventions to address modifiable risk factors, reduce progression, and enhance quality of life. Mobile application-based interventions offer a promising avenue for older populations due to their convenience, reduced need for travel, and personalized engagement.ObjectiveThis systematic review aimed to evaluate the effectiveness of mobile application-based interventions on cognitive performance in individuals with SCD and/or MCI.MethodsA systematic review of randomized controlled trials was conducted to identify mobile application-based interventions targeting SCD and MCI from 2010 to 2025. We conducted a comprehensive search in PubMed, Web of Science, and Scopus databases following PRISMA guidelines.ResultsA total of 3140 abstracts were screened, of which 19 (0.6%) met the inclusion criteria. Seven studies focused on SCD, while the majority targeted patients with MCI. All but one study reported improvements in at least one cognitive outcome following the intervention.ConclusionsMobile application-based interventions show promising benefits for individuals with SCD and MCI, with most studies reporting improvements in cognitive outcomes, particularly in memory. However, further research with larger samples and more extended follow-up periods is needed to confirm these findings and optimize intervention strategies.},
}

@article {pmid42754564,
year = {2026},
author = {Zhang, H and Liang, B and Chang, Y and Zhang, Z and Wang, Z and Zhu, W and Song, B and Zhang, H},
title = {Exosomal miR-223-3p, associated with NLRP3-related neuroinflammation, as a potential biomarker for mild cognitive impairment in patients with type 2 diabetes mellitus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487620},
doi = {10.1177/13872877261487620},
pmid = {42754564},
issn = {1875-8908},
abstract = {BackgroundNeuroinflammation has been implicated in diabetic cognitive dysfunction, with the NLRP3 playing an important role.ObjectiveThis study aimed to elucidate the regulatory role of miR-223-3p in NLRP3 associated neuroinflammation and its potential as a biomarker for mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM).MethodsDiabetic mouse models were generated by 24 weeks of high-fat diet feeding, with cognitive impairment verified by behavioral assessments. Hippocampal tissues were analyzed by microRNA sequencing and validated for miR-223-3p expression. NLRP3-mediated neuroinflammation was examined in vivo, while in vitro assays using BV2 cells assessed mechanistic pathways. BV2 cells with miR-223-3p knockdown and overexpression to evaluate its effects on NLRP3. Clinically, plasma exosomal miR-223-3p was quantified in T2DM patients with and without MCI and correlated with neuropsychological test scores.ResultsDiabetic mice exhibited cognitive decline, reduced hippocampal miR-223-3p, microglial activation, and elevated NLRP3 and pro-inflammatory cytokines. miR-223-3p knockdown and overexpression induced and attenuated neuroinflammation, respectively. Luciferase reporter gene assays confirmed the direct regulatory of miR-223-3p on NLRP3. Clinically, exosomal miR-223-3p levels were significantly lower in T2DM patients with MCI (n = 98) compared with cognitive normal patients (n = 147), correlating with global cognition, and immediate memory performance. ROC analysis demonstrated that, when using the threshold of 0.7565, miR-223-3p achieved a diagnostic specificity of 71.4% and a sensitivity of 68.7% for identifying MCI.ConclusionsmiR-223-3p exerts neuroprotective effects by suppressing NLRP3-mediated neuroinflammation. Its downregulation contributes to cognitive impairment in diabetes, and circulating exosomal miR-223-3p represents a potential biomarker for identifying MCI in T2DM.},
}

@article {pmid42754623,
year = {2026},
author = {Wang, J and Pan, P and Zhang, J and Wang, Y},
title = {Several methodological issues in the systematic review "PD-1/PD-L1 blockade in Alzheimer's disease".},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42754623},
issn = {1476-5578},
}

@article {pmid42754830,
year = {2026},
author = {Castellani, RJ},
title = {Traumatic brain injury and Alzheimer's disease: The null hypothesis wins.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489299},
doi = {10.1177/13872877261489299},
pmid = {42754830},
issn = {1875-8908},
abstract = {The theory that traumatic brain injury initiates Alzheimer's disease owes much of its existence to classical studies on boxers. It now appears that both the complexity of postmortem neuropathology and the clinical syndrome were not fully appreciated. Large scale studies linking epidemiology and biology continue to show that chronic effects of traumatic brain injury and Alzheimer's disease pathophysiology are biologically distinct. Researchers are encouraged to look beyond conventional protein precipitates for explanations of clinical deterioration following traumatic brain injury.},
}

@article {pmid42754972,
year = {2026},
author = {Pillai, JA and Zhu, A and Ma, C and Wang, M and Yang, Y and Bekris, LM and Khrestian, M and DiFilippo, FP and Nasrallah, M and Burberry, A and Leverenz, JB and Hou, Y and Cheng, F and Rao, SM},
title = {Cerebrospinal Fluid Over Plasma Links Analytes to Cognitive Decline in Older Adults at Risk for Alzheimer's Disease.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70532},
pmid = {42754972},
issn = {2328-9503},
support = {K23AG055685//National Institute on Aging (NIA), National Institutes of Health/ ; P30AG072959//National Institute on Aging (NIA), National Institutes of Health/ ; R01AG022304//National Institute on Aging (NIA), National Institutes of Health/ ; R01AG078763//National Institute on Aging (NIA), National Institutes of Health/ ; },
abstract = {OBJECTIVE: To identify inflammatory analytes in cerebrospinal fluid (CSF) and plasma associated with cognitive decline in cognitively normal (CN) older adults at risk for Alzheimer's disease (AD).

METHODS: In a longitudinal study of 118 CN older adults (65-80 years, 54% APOE ε4, 26% preclinical AD), 1331 CSF and 1501 plasma analytes were quantified at baseline and 2-year follow-up using SomaLogic, with key inflammatory findings validated on the Luminex platform. Linear models (Limma), adjusted for age, sex, APOEε4, and amyloid-positive status, identified pathology-associated analytes. Co-expression network and multivariable modeling defined hub analytes and enriched pathways. To assess robustness, a targeted panel of 94 inflammation-related analytes was analyzed using best subsets regression to derive parsimonious models based on adjusted R[2] improvement (≥ 0.01) and ≥ 5 observations per predictor. Subgroup analyses by amyloid and APOE ε4 status were performed, and a two-stage elastic-net approach additionally validated analyte selection.

RESULTS: CSF proteomics revealed stronger APOEε4 and amyloid-associated analyte signatures than plasma. Forty-four CSF analytes were co-regulated by APOEε4 and amyloid-positive status, forming central network hubs (e.g., EFNB2, NPTN, UNC5D) enriched in axon guidance, synaptic signaling, and extracellular matrix pathways. In contrast, inflammatory analytes including eotaxin-1 and IL-17 pathway-related molecules were associated with longitudinal cognitive decline, with stronger effects observed in females. Eotaxin-1 demonstrated the most consistent predictive performance across analytic methods, subsets, and assay platforms, whereas network hub analytes were not predictive of cognitive outcomes.

INTERPRETATION: CSF reflects strong APOEε4/amyloid related proteomic network alterations linked to cognitive decline, while plasma provides weaker but complementary signals. CSF inflammatory signaling, particularly eotaxin-1, may serve as a correlate of longitudinal cognitive decline in cognitively normal older adults at risk for AD.},
}

@article {pmid42755059,
year = {2026},
author = {Lee, SK and Han, M and Park, S and Song, J and Park, SJ and Kim, H and Kim, J and Lee, H and Shin, HY and Kim, KH and Park, SM},
title = {Impact of Changes in Physical Activity on Dementia Risk Among Cancer Survivors: A Nationwide Cohort Study Comparing Chemotherapy and Non-Chemotherapy Groups.},
journal = {Cancer research and treatment},
volume = {},
number = {},
pages = {},
doi = {10.4143/crt.2026.0451},
pmid = {42755059},
issn = {2005-9256},
abstract = {PURPOSE: Chemotherapy-associated cognitive decline is well recognized; however, the role of changes in physical activity in reducing dementia risk among cancer survivors remains unclear. This study evaluated the association between physical activity changes and dementia risk.

MATERIALS AND METHODS: This nationwide retrospective cohort study used health screening and claims data from the Korean National Health Insurance Service. A total of 260,659 adults diagnosed with cancer between 2009 and 2015 who survived ≥3 years and underwent both pre- and post-diagnosis health examinations were included. Individuals with prior dementia or missing data were excluded. Physical activity was assessed as metabolic equivalent task-minutes per week at two time points and categorized as decreased, maintained, or increased. The primary outcome was incident all-cause dementia (ICD-10 codes F00-F03, G30). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, stratified by chemotherapy exposure.

RESULTS: Decreased physical activity was associated with increased dementia risk compared with maintaining high activity (aHR, 1.46; 95% CI, 1.31-1.62), whereas maintaining or increasing activity was associated with reduced risk (aHR, 0.82; 95% CI, 0.75-0.91). The protective association was stronger among chemotherapy-treated patients (aHR, 0.80; 95% CI, 0.72-0.90). No significant association was observed among those not receiving chemotherapy.

CONCLUSION: Maintaining or increasing physical activity after cancer diagnosis was associated with lower dementia risk, particularly among chemotherapy-treated patients.},
}

@article {pmid42755290,
year = {2026},
author = {Xu, L and Wei, N and Ran, Y},
title = {The dynamic connectome in Alzheimer's disease: From static snapshots to a symphony in time-A hypothesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488872},
doi = {10.1177/13872877261488872},
pmid = {42755290},
issn = {1875-8908},
abstract = {The static functional connectivity (sFC) model has established Alzheimer's disease (AD) as a large-scale brain network disorder, yet it rests on a questionable assumption of temporal stationarity. This assumption obscures the brain's intrinsic dynamics, which are essential for flexible cognition. Here, we advance the hypothesis that the core deficit in AD is not merely a weakening of average connections, but a fundamental loss of the brain's capacity for temporal coordination, adaptive reconfiguration, and metastable dynamics-a state we term dynamic network dysrhythmia. Synthesizing evidence from dynamic functional connectivity (dFC) studies across the AD continuum, from subjective cognitive decline to mild cognitive impairment and AD dementia, we argue that the AD brain exhibits a progressive collapse in temporal flexibility: reduced state transition frequency, diminished connectivity variability, and entrapment in inefficient network configurations. These dynamic abnormalities correlate with molecular pathology, structural disconnection, and domain-specific cognitive deficits, positioning dFC metrics as sensitive, systems-level digital biomarkers. We further outline methodological challenges and translational opportunities for dFC in early detection, prognostic stratification, and treatment monitoring. This hypothesis reframes AD from a static disconnection syndrome to a dynamic dysrhythmia, with profound implications for both mechanistic understanding and clinical practice.},
}

@article {pmid42755349,
year = {2026},
author = {Wittlinger, M and Jevtic, S and Teimann, S and Scherbaum, N and Wiltfang, J and Benninghoff, J},
title = {The potential of nature exposure to reduce agitation: lessons from a naturalistic observational study in a stage-adaptive, dementia-friendly therapy garden.},
journal = {BJPsych open},
volume = {12},
number = {5},
pages = {e242},
doi = {10.1192/bjo.2026.12093},
pmid = {42755349},
issn = {2056-4724},
abstract = {BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD), particularly agitation, are common among people living with dementia, negatively affecting their psychological well-being and quality of life. Non-pharmacological interventions such as therapeutic gardens may offer a holistic approach to managing these symptoms.

AIMS: This study aimed to investigate whether participation in a multimodal, dementia-specific therapeutic garden intervention could reduce BPSD, with a particular focus on agitation, and improve psychological well-being among people with dementia.

METHODS: A naturalistic observational study was conducted with 24 residents of a dementia-friendly garden. Participants engaged in tailored, nature-based therapy over 6 months. The intervention was adapted to individual cognitive and physical abilities and included motor, sensory and social activities within the participants' familiar living environment. Standardised assessments of BPSD and psychological well-being were administered, including evaluations reported by relatives.

RESULTS: The intervention was associated with a significant reduction in agitation, as measured by the non-cognitive subscales of the Alzheimer's Disease Assessment Scale (p < 0.05). Furthermore, reduced agitation was linked to improved psychological well-being among participants.

CONCLUSIONS: The findings suggest that multimodal therapeutic gardens can serve as an effective non-pharmacological intervention in reducing agitation and supporting psychological well-being in people with dementia. This study adds to the growing evidence that therapeutic gardens could contribute to the functional and emotional health of individuals living with dementia.},
}

@article {pmid42755454,
year = {2026},
author = {Wang, Y and Wu, W and Yan, L and Zhang, B and Li, Q and Zhou, Y},
title = {Synaptic mitochondrial dysfunction and Alzheimer's disease: from molecular mechanisms to therapeutic strategies.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1849218},
pmid = {42755454},
issn = {1663-9812},
abstract = {The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies-disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission/fusion, and defective autophagy-converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood-brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.},
}