@article {pmid42372237,
year = {2026},
author = {Marschner, RA and da Silva, FM and Crispim, D and Saraiva Gonçalves, CA},
title = {Muscle-Brain Crosstalk in Alzheimer's Disease: Exercise-Associated FNDC5/Irisin Pathways in Preclinical Models - A Systematic Review.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0427},
pmid = {42372237},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, neuroinflammation, and altered amyloid-β processing. Growing evidence suggests that physical exercise exerts neuroprotective effects partly mediated by myokines released from skeletal muscle. Among these, irisin, a cleavage product of fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a potential component of muscle-brain communication involved in neuroplasticity and memory-related pathways. This systematic review summarizes evidence from preclinical in vivo studies investigating exercise-induced FNDC5 expression and irisin-related signaling pathways in experimental models of AD. A literature search was conducted in PubMed and EMBASE following PRISMA guidelines to identify studies evaluating the effects of physical exercise on FNDC5 expression, irisin-related pathways, and cognitive outcomes in animal models of AD. Ten preclinical studies met the inclusion criteria and were included in the qualitative synthesis, encompassing both behavioral and mechanistic evidence. Overall, the evidence indicates that physical exercise was associated with increased FNDC5 expression, activation of irisin-related pathways, and downstream neuroprotective mechanisms including PPARGC1A, AMPK, SIRT1, and BDNF signaling. These molecular adaptations were associated with improvements in synaptic plasticity, reductions in neuroinflammation and oxidative stress, and attenuation of amyloid-related pathology. Behavioral assessments across multiple paradigms also demonstrated improvements in learning and memory following exercise interventions. Collectively, the available preclinical evidence suggests that FNDC5/irisin-related signaling is associated with neuroprotective effects of physical exercise in experimental models of AD as part of a broader exercise-induced response. Further studies are needed to clarify the underlying mechanisms and translational relevance of this pathway in AD.},
}

@article {pmid42372338,
year = {2026},
author = {Ersözlü, E and Preis, L and Aktuz, A and Droste, L and Erman, A and Gref, D and Strentz, KS and Hellmann-Regen, J and , },
title = {Drawing a line: Differentiating mild from moderate dementia using the functional activities questionnaire.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100630},
doi = {10.1016/j.tjpad.2026.100630},
pmid = {42372338},
issn = {2426-0266},
abstract = {BACKGROUND: Accurate differentiation between mild and moderate dementia is increasingly important, particularly as amyloid-targeting therapies are restricted to early disease stages. Functional impairment in instrumental activities of daily living is a hallmark of progression beyond mild dementia. The informant-based Functional Activities Questionnaire (FAQ) is widely used, but empirically validated cut-offs distinguishing mild from moderate dementia remain insufficiently defined.

METHODS: The optimal cut-off score was derived from the entire National Alzheimer's Coordinating Center (NACC) Uniform Data Set as a discovery cohort (n = 34,513) and validated in two independent multicentric cohorts (Alzheimer's Disease Neuroimaging Initiative (ADNI) n = 381 and Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) n = 74). The dementia staging was based on the Clinical Dementia Rating (CDR) global score. Functional impairment was assessed using the 10-item FAQ. Receiver operating characteristic analyses in NACC identified optimal thresholds, which were applied unchanged in validation cohorts. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and discordant cases were examined to identify factors associated with misclassification.

RESULTS: In NACC, the FAQ demonstrated excellent discrimination of moderate dementia (AUC=0.947, 95% CI 0.944-0.949). A cut-off value of ≥18 maximized discrimination (sensitivity 96%, specificity 87%). A higher threshold of ≥23 improved specificity (92%), while maintaining sensitivity (83%). In ADNI and FTLDNI, the sensitivity of ≥18 threshold yielded 92% and 94%, respectively. Moreover, older age and lower cognitive performance were associated with higher odds of misclassification.

CONCLUSIONS: The FAQ robustly differentiates mild from moderate dementia across diverse cohorts. A threshold of ≥18 prioritizes sensitivity, whereas ≥23 favors specificity, supporting context-dependent functional staging in clinical and research settings. Individuals with FAQ scores between 18 and 22 may benefit from more detailed clinical staging.},
}

@article {pmid42372723,
year = {2026},
author = {Tyagi, M and de Hoog, E and Grega, M and Sullivan, KR and Walker, AC and Chadha, R and Northrop, A and Fábián, B and Hummer, G and Fuxreiter, M and Hyman, BT and Shepherd, JD},
title = {Arc mediates intercellular tau transmission via extracellular vesicles.},
journal = {Cell},
volume = {},
number = {},
pages = {},
pmid = {42372723},
issn = {1097-4172},
abstract = {Tau pathology spreads cell to cell, but the mechanisms of intercellular tau transmission remain unclear. We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain EVs purified from transgenic rTg4510 mutant tau mice (rTg[WT]) crossed with Arc knockout mice (rTg[Arc KO]) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTg[Arc KO] mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.},
}

@article {pmid42372923,
year = {2026},
author = {Lin, Z and Hu, L and Liu, Y and Ning, W and Wang, S and Fu, ZY and Guan, L},
title = {Rational design, synthesis, and biological evaluation of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene as anti- Alzheimer's agents.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130716},
doi = {10.1016/j.bmcl.2026.130716},
pmid = {42372923},
issn = {1464-3405},
abstract = {A series of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene were designed, synthesized and evaluated their inhibitory activities against cholinesterase (ChE). All compounds displayed good inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, compound 2e displayed the most inhibitory activity against AChE, BChE and β-amyloid (Aβ42) with IC50 values 7.01, 5.39 and 4.47 μM, respectively. Meanwhile, 2e was found anti-Alzheimer's disease (AD) effect by significantly alleviating lipopolysaccharide (LPS)/Aβ-induced neurotoxicity, reducing the levels of reactive oxygen species (ROS), pro-inflammatory cytokines, and exert anti-inflammatory effects by regulating the NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. Furthermore, the molecular modeling studies showed that 2e target both catalytic active site as well as peripheral anionic site of AChE, BChE and Aβ42, and possess strong bind affinity. In addition, in silico ADMET and toxicity predictions demonstrated favorable oral absorption and potential blood-brain barrier (BBB) permeability for 2e. The rationale remains partly overstated. The novelty claim should more precisely distinguish this scaffold from previously reported chalcone, piperazine, thiophene, and multitarget ChE/Aβ inhibitors. The phrase "anti-Alzheimer's agents" should be softened, because the data are limited to enzyme assays, Aβ assays, BV-2 cellular models, docking, and computational predictions.},
}

@article {pmid42372976,
year = {2026},
author = {Price, TM and Tucker, AE and Funk, KE},
title = {Molecular and Environmental Drivers of Tau Post-Translational Modifications and Tau Pathology.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103223},
doi = {10.1016/j.arr.2026.103223},
pmid = {42372976},
issn = {1872-9649},
abstract = {Tau is an intrinsically disordered protein that functions to support cytoskeletal stability by binding microtubules in neuronal axons. While tau is involved in healthy neuronal function, it can become pathogenic by forming protein aggregates leading to neurologic diseases collectively known as tauopathies, which include Alzheimer's disease, frontotemporal dementia, and chronic traumatic encephalopathy. Post-translational modifications, including phosphorylation, O-GlcNAcylation, acetylation, methylation, ubiquitination, and protein truncation are molecular drivers that promote tau aggregation and subsequent disease development. There is a growing, but incomplete, understanding of the complex crosstalk that occurs among distinct modifications and how they orchestrate tau pathogenesis in concert. The drivers of tau post-translational modifications are not fully understood, but environmental factors, such as traumatic brain injuries, microbial infections, alcohol abuse, chronic stress, and heavy metal pollutants, increase risk of tau pathology formation. In this article we review the current literature describing the molecular changes that increase tau aggregation propensity, the environmental factors that promote those changes, and the multifactorial crosstalk that modulates tau pathogenesis. Our goal is to outline the biological pathways and molecular factors that drive tau pathogenesis in order to identify potential points of behavioral and/or therapeutic intervention for tauopathies.},
}

@article {pmid42373039,
year = {2026},
author = {Gao, K and Bao, J and Song, Y and Lin, CP and Iturria-Medina, Y and Biswal, BB and Wang, P},
title = {Beyond gray matter: unveiling the critical role of white matter in Alzheimer's disease.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111816},
doi = {10.1016/j.pnpbp.2026.111816},
pmid = {42373039},
issn = {1878-4216},
abstract = {Alzheimer's disease (AD) has traditionally been regarded as a disorder primarily affecting gray matter, while growing evidence highlights the significant role of white matter pathology in its progression. This review aims to assess the current state of knowledge regarding white matter abnormalities and elucidate the potential impact of white matter on the pathogenesis and progression of AD. White matter alterations, including inflammation, hyperintensities, structural and functional changes, often precede gray matter atrophy and cognitive decline during AD progression. Advanced imaging and histopathological studies suggest that white matter degeneration is not merely a downstream consequence of gray matter pathology; it may represent an independent, perhaps initiating, pathological pathway in AD progression. Moreover, white matter lesions in individuals with AD may be modifiable by both pharmacological and non-pharmacological interventions, supporting the potential for reducing white matter damage and improving cognitive functions.},
}

@article {pmid42373045,
year = {2026},
author = {Bulycheva, I and Watanabe, Y and Kitamura, K and Kabasawa, K and Saito, T and Takahashi, A and Kobayashi, R and Oshiki, R and Yamazaki, O and Watanabe, K and Takachi, R and Murai, U and Tsugane, S and Nakamura, K},
title = {Association between high dietary polyphenol intake and reduced risk of dementia: a 12-year cohort study.},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {103438},
doi = {10.1016/j.clnesp.2026.103438},
pmid = {42373045},
issn = {2405-4577},
abstract = {BACKGROUND & AIMS: Dietary polyphenols may play a modifiable role in reducing the risk of dementia; however, current evidence remains limited and inconclusive. This study aimed to investigate whether dietary polyphenol intake, taking caffeine intake into account, is associated with dementia risk in middle-aged and older people.

METHODS: Participants of this 12-year cohort study were 13,473 community-dwelling individuals aged 40-74 years (51.9% female). Dietary intake data were collected from 2011 to 2013 using a validated food frequency questionnaire. Polyphenol intake was adjusted for energy intake using the residual method. The outcome was incident dementia determined using Japan's long-term care insurance database. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Covariates included demographic factors, body size, lifestyle habits, and disease history (myocardial infarction, stroke, diabetes mellitus). An additional multivariable analysis was conducted, further adjusting for energy-adjusted caffeine intake.

RESULTS: The mean age of participants was 59.1 years. During follow-up, 337 males and 331 females developed dementia. Higher polyphenol intake was associated with a lower risk of dementia (multivariable-adjusted P for trend <0.0001), with the highest quintile (Q5) having a reduced risk of dementia (HR = 0.62, 95%CI: 0.49-0.78) compared to the lowest quintile (Q1, reference). After further adjusting for energy-adjusted caffeine intake, this association remained significant (P for trend = 0.0149), with Q5 having an HR of 0.70 (95%CI: 0.52-0.95). In males, higher polyphenol intake was associated with a lower hazard of dementia (multivariable-adjusted P for trend = 0.0002), with Q4 and Q5 having a lower hazard (Q4: HR = 0.59, 95% CI: 0.42-0.83; Q5: HR = 0.55, 95%CI: 0.40-0.76) compared to Q1. In females, higher polyphenol intake was associated with a lower hazard of dementia (multivariable-adjusted P for trend = 0.0106), with Q5 having a lower hazard (HR = 0.68, 95%CI: 0.49-0.96) compared to Q1.

CONCLUSION: High polyphenol intake is robustly associated with a decreased risk of dementia in middle-aged and older individuals, with the association remaining even after accounting for caffeine intake.},
}

@article {pmid42373097,
year = {2026},
author = {Chen, X and Wang, Z and Wang, J and Kong, D and Wang, X and Lu, L and Nelson, PT and Zhou, FM and Liao, FF},
title = {Distinctly altered TRPC3 and TRPC6 expression patterns in human Alzheimer's disease cortex and hippocampus.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70118},
doi = {10.1111/bpa.70118},
pmid = {42373097},
issn = {1750-3639},
support = {R01-NS120327/NH/NIH HHS/United States ; R01-AG072703/NH/NIH HHS/United States ; P01 AG078116/NH/NIH HHS/United States ; P30 AG072946/NH/NIH HHS/United States ; 2023Y9286//Joint Funds for the Innovation of Science and Technology, Fujian province, China/ ; 2024J011004//Fujian Provincial Natural Science Foundation/ ; //Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare, China/ ; },
abstract = {Calcium dysregulation is increasingly recognized as a convergent mechanism underlying neuronal vulnerability and glial overactivation in Alzheimer's disease (AD). Transient Receptor Potential Canonical (TRPC) channels are potential key modulators of Ca[2+] signaling in multiple cell types in central nervous system (CNS), mediating different pathophysiological roles. However, their cell type-specific remodeling and cellular origins of these changes in human AD tissue remain poorly defined. This study investigated their expression patterns with main focus on the two closely related members of TRPC3 and TRPC6 across human AD brains and two relevant mouse models. Formalin-fixed paraffin-embedded cortical and hippocampal tissues from AD patients and age-matched controls were examined using immunohistochemistry. Spatial relationships between TRPC3/TRPC6 and glial fibrillary acidic protein (GFAP)-positive astrocytes were assessed in adjacent serial sections. TRPC3 expression was markedly increased in AD cortex and hippocampus whereas TRPC6 was significantly reduced primarily in pyramidal neurons. TRPC3-positive regions showed close spatial correspondence with reactive astrocytes, particularly in the hippocampal and subcortical white matter regions, suggesting a partial astrocytic origin. TRPC6 exhibited negligible overlap with GFAP. These observations were reproduced in brain sections of both 5xFAD and PS19 transgenic (Tg) mice compared to their littermate controls. Our findings reveal a conserved pattern of divergent TRPC remodeling across human and mouse models with AD pathology. In addition, TRPC1 expression was significantly reduced in AD samples while TRPC4 and TRPC5 had no significant change in expression. Taken together, selected TRPC family members may undergo differential remodeling during AD pathogenesis, with TRPC3 and TRPC6 showing the most prominent and consistent alterations.},
}

@article {pmid42373113,
year = {2026},
author = {Weiss, SM and Watt, JA and Ewa, V and Straus, SE},
title = {Lecanemab use for early Alzheimer disease in Canada.},
journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne},
volume = {198},
number = {25},
pages = {E973-E976},
doi = {10.1503/cmaj.260193},
pmid = {42373113},
issn = {1488-2329},
}

@article {pmid42373496,
year = {2026},
author = {Wang, AM and Wang, YX and Ma, YH and Yang, XY and Guo, GY and Song, WC and Wang, SZ and Shi, FY},
title = {[Study on the risk factors of development for mild cognitive impairment to Alzheimer's disease based on the competitive risk joint model].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {47},
number = {6},
pages = {1158-1164},
doi = {10.3760/cma.j.cn112338-20251013-00718},
pmid = {42373496},
issn = {0254-6450},
support = {81803337, 81872719//National Natural Science Foundation of China/ ; ZR2023MH313//Natural Science Foundation of Shandong Province/ ; 2019-10-156//Shandong Provincial Higher Education Youth Talent Introduction and Cultivation Program/ ; },
mesh = {*Alzheimer Disease ; Humans ; *Cognitive Dysfunction ; Risk Factors ; Boosting Machine Learning Algorithms ; Disease Progression ; Random Forest ; Female ; },
abstract = {Objective: To identify the risk factors for the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) using a competing risks joint model. Methods: This study was based on the Alzheimer's Disease Neuroimaging Initiative database. Three gradient boosting tree algorithm, namely CatBoost, XGBoost, and LightGBM, were employed to reduce the dimensionality of the high-dimensional lipoprotein and metabolite data (including 250 amino acids, lipids, and energy metabolism-related components, etc.). A random survival forest model (RSF) was used to screen out key demographic, cognitive function scores and metabolic variables. A competing risk joint model was constructed to identify the risk factors for the progression from MCI to AD. Results: A total of 8 lipoprotein and metabolite variables were identified by the three algorithms [creatinine, lactate, glycine, large high-density lipoprotein phospholipids percent (L_HDL_PL_PCT), acetic acid, tyrosine, β-hydroxybutyric acid and valine]. The RSF model identified 14 main variables, including cognitive function indicators [Functional Activities Questionnaire (FAQ), Alzheimer's Disease Assessment Scale-13 items (ADAS13), Alzheimer's Disease Assessment Scale word recognition item 4 (ADASQ4), and Alzheimer's Disease Assessment Scale-11 items (ADAS11)], lipoprotein and metabolites (acetic acid, L_HDL_PL_PCT, β-hydroxybutyrate, glycine, and creatinine), and baseline characteristics [age, years of education, marital status, retirement status, and apolipoprotein E ε4 allele (APOE-ε4)]. The univariate competing risk joint model showed that the longitudinal changes of ADAS11, ADAS13, ADASQ4, FAQ, and glycine, as well as baseline age, marital status, and APOE-ε4, were positively associated with the progression of MCI to AD (P<0.05). The results of the multivariate competing risk joint model further indicated that the longitudinal changes of ADAS13, ADASQ4, FAQ, and glycine, as well as baseline age, marital status, and APOE-ε4 were positively associated with AD incidence (P<0.05). Conclusions: Longitudinal increases in ADAS13, ADASQ4, FAQ, and glycine, as well as older age, unfavorable marital status, and APOE-ε4 carriage at baseline, were all risk factors for progression from MCI to AD.},
}

*Alzheimer Disease
Humans
*Cognitive Dysfunction
Risk Factors
Boosting Machine Learning Algorithms
Disease Progression
Random Forest
Female

@article {pmid42373580,
year = {2026},
author = {Lee, J and Olafson, E and Toth, B and Casavant, E and Schauer, S and Bittner, T and Meyer, MR and Verghese, PB and Venkatesh, V and West, T and Braunstein, JB and Biever, A and Calderon, E and Mandl, M and Bayfield, A and Hoogenraad, CC and Teng, E and Monteiro, C and Anania, VG and Bohórquez, SMS and Yeh, FL},
title = {Evaluation of CSF and plasma tau species as fluid surrogate candidates for tau PET in prodromal to moderate Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71604},
pmid = {42373580},
issn = {1552-5279},
support = {//Genentech Inc/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/blood/metabolism ; *Positron-Emission Tomography ; Female ; Biomarkers/cerebrospinal fluid/blood ; Male ; Aged ; Prodromal Symptoms ; Middle Aged ; Phosphorylation ; },
abstract = {INTRODUCTION: Positron emission tomography (PET) is a valuable tool for assessing tau pathology in Alzheimer's disease (AD), but it is not widely accessible. Clarifying the relationship between fluid tau species and tau PET in AD may allow for the identification of fluid biomarkers that could serve as more accessible surrogates for tau PET.

METHODS: Cerebrospinal fluid (CSF) and plasma tau species levels were assessed across prodromal to moderate AD subjects (CSF: n = 53, plasma: n = 181) via immunoassays and liquid chromatography-mass spectrometry. Fluid measures were correlated with [[18]F]GTP1 tau PET at baseline for head-to-head comparisons across analytes.

RESULTS: CSF C2N-eMTBR-tau243, tau phosphorylated at threonine 205 (p-tau205), p-tau217, and a peptide from the tau-441 microtubule-binding region (MTBR) (MTBR/243-254) exhibited the highest correlations with [[18]F]GTP1 standardized uptake value ratio. Plasma p-tau181 and p-tau217 demonstrated correlation rankings with tau PET similar to those observed with corresponding CSF analytes.

DISCUSSION: CSF C2N-eMTBR-tau243, MTBR/243-254, p-tau205, and p-tau217 demonstrated comparable strong correlations with tau PET. These findings may guide future development of plasma biomarker surrogates for tau PET.},
}

Humans
*tau Proteins/cerebrospinal fluid/blood/metabolism
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/blood/metabolism
*Positron-Emission Tomography
Female
Biomarkers/cerebrospinal fluid/blood
Male
Aged
Prodromal Symptoms
Middle Aged
Phosphorylation

@article {pmid42373784,
year = {2026},
author = {Li, Y and Ulrich, JD and Holtzman, DM},
title = {Adaptive immunity in the pathogenesis of neurodegeneration.},
journal = {Nature immunology},
volume = {27},
number = {7},
pages = {1375-1389},
pmid = {42373784},
issn = {1529-2916},
support = {AG085374//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG069701//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG078106//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG083977//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; NS090934//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Adaptive Immunity/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; Animals ; Microglia/immunology ; *Central Nervous System/immunology/pathology ; Astrocytes/immunology ; Immunity, Innate ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression. Advances in genetic, neuropathological and experimental studies also underscore the potential role of the adaptive immune system in disease pathogenesis. Here we summarize the current understanding of how adaptive immunity can shape the progression of neurodegenerative diseases and highlight cross-disease parallels and potentially shared mechanisms. We also examine cellular events leading to the recruitment of peripheral immune cells to the CNS, as well as candidate antigens driving the adaptive immune response. Last, we discuss potential therapeutic strategies to treat neurodegeneration via the manipulation of adaptive immune cells.},
}

Humans
*Adaptive Immunity/immunology
*Neurodegenerative Diseases/immunology/pathology/therapy
Animals
Microglia/immunology
*Central Nervous System/immunology/pathology
Astrocytes/immunology
Immunity, Innate

@article {pmid42373786,
year = {2026},
author = {Guo, AX and Fisher, TM and Comandante-Lou, N and De Jager, PL and Liddelow, SA},
title = {Innate immune signaling and functions in astrocytes.},
journal = {Nature immunology},
volume = {27},
number = {7},
pages = {1364-1374},
pmid = {42373786},
issn = {1529-2916},
support = {AARF-24-1313800/ALZ/Alzheimer's Association/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; },
mesh = {*Astrocytes/immunology/metabolism ; Humans ; *Immunity, Innate/immunology ; Animals ; *Signal Transduction/immunology ; Toll-Like Receptors/metabolism/immunology ; Innate Immunity Recognition ; Inflammasomes/metabolism/immunology ; },
abstract = {Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.},
}

*Astrocytes/immunology/metabolism
Humans
*Immunity, Innate/immunology
Animals
*Signal Transduction/immunology
Toll-Like Receptors/metabolism/immunology
Innate Immunity Recognition
Inflammasomes/metabolism/immunology

@article {pmid42373968,
year = {2026},
author = {Gardner, KL and Lange, TE and Perna, MK and Wells, SI and Williams, MT and Vorhees, CV and Cox, M and Solomon, MB and Privette Vinnedge, LM},
title = {DEK Loss Induces Task-specific Deficits in Learning and Memory and Reprograms the Hippocampal Transcriptome in Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42373968},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism ; Male ; *Poly-ADP-Ribose Binding Proteins/deficiency/metabolism/genetics ; *Chromosomal Proteins, Non-Histone/deficiency/metabolism/genetics ; Female ; *Oncogene Proteins/deficiency/metabolism/genetics ; *Transcriptome/genetics ; Mice, Knockout ; *Memory/physiology ; Mice, Inbred C57BL ; Mice ; Maze Learning ; Behavior, Animal ; DNA-Binding Proteins ; },
abstract = {DEK is an estrogen-responsive chromatin-remodeling protein broadly expressed in the murine and human brain, with high expression in memory-relevant regions such as the hippocampus. Prior work from our group and others has linked DEK loss to cellular features associated with Alzheimer's disease and Alzheimer's disease-related dementias. Notably, our group has demonstrated that DEK expression declines with increasing dementia severity in women, but not in age-matched men, suggesting a sex-specific relationship between DEK loss and cognitive vulnerability. Together, these findings support a potential neuroprotective role for DEK; however, functional consequences of DEK loss in vivo were unknown. Here, we examined behavioral and molecular consequences of Dek loss using male and female constitutive knockout (cKO) mice assessed across cognitive, sensorimotor, and affective domains. Across assays, Dek cKO mice of both sexes exhibited intact locomotor activity, anxiety-related behavior, sensorimotor gating, and fear-associated memory. In contrast, female Dek cKO mice displayed selective impairments in cognitive flexibility despite preserved spatial learning and memory, a phenotype not observed in males and indicative of female-specific vulnerability following DEK loss. This sex difference, observed during Morris water maze reversal learning, suggests disruption of hippocampal-prefrontal circuitry. Guided by known sex differences in hippocampal DEK expression, transcriptomic profiling of hippocampal tissue revealed shared and sex-specific consequences of Dek deficiency, including alterations in cytoskeletal organization, neuronal signaling, chromatin regulatory mechanisms, and cellular stress pathways. Collectively, these findings demonstrate sex- and cognitive-domain-specific effects of DEK loss and support further investigation of DEK in executive function and hippocampal-prefrontal cortex-mediated cognition.},
}

Animals
*Hippocampus/metabolism
Male
*Poly-ADP-Ribose Binding Proteins/deficiency/metabolism/genetics
*Chromosomal Proteins, Non-Histone/deficiency/metabolism/genetics
Female
*Oncogene Proteins/deficiency/metabolism/genetics
*Transcriptome/genetics
Mice, Knockout
*Memory/physiology
Mice, Inbred C57BL
Mice
Maze Learning
Behavior, Animal
DNA-Binding Proteins

@article {pmid42374181,
year = {2026},
author = {Gong, R and Wang, H and Cao, L and Niu, H and Rominger, A and Luo, Z and Ni, R},
title = {Targeting the crosstalk between Alzheimer's disease and gastrointestinal cancers.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {},
number = {},
pages = {},
doi = {10.1186/s10020-026-01545-x},
pmid = {42374181},
issn = {1528-3658},
abstract = {Epidemiological studies have revealed an inverse association between Alzheimer's disease and cancer. Here, we discuss the mechanisms involved in the relationship between Alzheimer's disease and gastrointestinal cancers, particularly pancreatic and gastric-colorectal cancers. The gut‒brain axis and pancreas‒brain axis connect the central nervous system with peripheral organs and form immune‒metabolic networks. We focus on bidirectional tumor-brain communication, involving cell-death pathways, apoptosis, metabolic dysregulation, microbiota, metabolic dysregulation, neuroinflammation, immune system and sensory-sympathetic circuits, and neural remodeling. Furthermore, we discuss potential integrated, multitarget therapeutic strategies, including metabolic regulation, microbiome interventions, and immune modulation. Prospective longitudinal cohorts incorporating prediagnostic exposures and molecular pathology are needed to establish temporality.},
}

@article {pmid42374285,
year = {2026},
author = {Pedersen, EK and Nielsen, A and Nicolaisdóttir, DR and Øksnebjerg, L and Tannebæk, K and Janbek, J and Waldemar, G and Nielsen, TR},
title = {Associations between a psychosocial intervention and quality of life and caregiver-related outcomes in family caregivers of people with dementia: the Danish DemTool trial.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07835-7},
pmid = {42374285},
issn = {1471-2318},
abstract = {BACKGROUND: People with dementia often need comprehensive support, depending on the stage of the disease, from both family members and healthcare professionals. Caring for a person with dementia can be stressful and impact the caregiver's health and wellbeing. Studies show that family caregivers of people with dementia frequently experience stress, depression, and reduced quality of life. We aimed to assess the association between the psychosocial intervention (DemTool) and caregiver wellbeing and quality of life among family caregivers of people with dementia.

METHOD: DemTool trial was a pragmatic, cluster-controlled trial. The intervention was delivered by primary care dementia coordinators across 30 Danish municipalities from 2020 to 2023, with 15 serving as the intervention group and 15 as treatment as usual. The primary outcome measures were the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D) and the European Quality of Life Visual Analog Scale (EQ VAS). Both measures were completed at baseline and follow-up, alongside secondary quality of life outcomes. To estimate group differences in primary and secondary outcomes, we applied analysis of variance (ANOVA) and analysis of covariance (ANCOVA).

RESULTS: A total of 245 family caregivers were included in the study (181 in the intervention group and 64 in the treatment-as-usual group). Most participants were females caring for a spouse. Baseline scores for caregiver wellbeing and quality of life were similar across groups. The DemTool intervention was associated with a significant between-group difference in change from baseline in caregiver-related quality of life as measured by the Carer Experience Scale (CES), favoring the intervention. This was evident in the analysis adjusted for baseline scores (p = 0.05) and remained significant when further adjusting for caregiver-related covariates (p = 0.02). No statistically significant between-group differences were observed for the remaining wellbeing and quality-of-life outcomes.

CONCLUSION: No effects of DemTool were found on traditional health-related quality-of-life outcomes. However, a positive association was found between the intervention and the CES, underlining the importance of selecting outcomes that are directly related to the targeted effects of the intervention.

TRIAL REGISTRATION: The study protocol was registered in the ClinicalTrials.gov system, registration number: NCT07355829.},
}

@article {pmid42374489,
year = {2026},
author = {Saul, E and Chauveau, L and Landeau, B and Lasserve, J and Montagne, B and Foyard, E and Poisnel, G and Chételat, G and de Flores, R and , },
title = {Structural and molecular determinants of medial temporal lobe network vulnerability in aging and Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02125-1},
pmid = {42374489},
issn = {1758-9193},
support = {667696//European Union's Horizon 2020 Research and Innovation Program/ ; },
abstract = {BACKGROUND: The medial temporal lobe is organized into two memory-critical networks: the anterior-temporal and posterior-medial systems. While these systems show selective vulnerability to aging and Alzheimer's disease, the underlying structural and molecular determinants of this susceptibility remain unclear. We aimed to characterize the specific white matter pathways supporting these networks, investigate how amyloid-β and neuroinflammation interact to impact their integrity, and determine if structural changes relate to functional connectivity alterations.

METHODS: In 88 cognitively unimpaired (CU) older adults (≥ 65 years) from the Age-Well cohort (NCT02977819), we combined longitudinal diffusion MRI tractography, resting-state fMRI, amyloid-β PET (Florbetapir), and plasma glial fibrillary acidic protein (GFAP). We reconstructed fiber pathways of the perirhinal (anterior-temporal system hub) and parahippocampal (posterior-medial system hub) cortices and quantified their microstructural integrity, network connectivity, and relationships to pathology.

RESULTS: The anterior-temporal and posterior-medial systems relied on partly distinct structural pathways. Both involved the inferior longitudinal and cingulum bundles, but the anterior-temporal system was specifically associated to their inferior portions, as well as thalamic radiations, and callosal fibers, whereas the posterior-medial system relied more on their superior portions and the inferior fronto-occipital fasciculus. We identified a non-linear, inverted U-shaped association between pathway integrity and amyloid-β burden, suggesting dynamic structural changes across early pathological stages. Crucially, plasma GFAP moderated this relationship for the posterior-medial pathway: the negative impact of amyloid-β on structural integrity was exacerbated in individuals with higher astroglial reactivity, highlighting a synergistic pathological effect. Finally, in high amyloid-β individuals, increased anterior-temporal functional connectivity correlated with lower anterior-temporal pathway integrity, suggesting that network higher FC may represent a maladaptive response to early amyloid-β deposition leading to white matter integrity loss.

CONCLUSIONS: Together, our findings reveal distinct mechanisms of vulnerability within medial temporal networks: while the posterior-medial system is primarily sensitive to the synergistic effects of amyloid-β and astroglial reactivity, the anterior-temporal system shows lower structural integrity linked to higher FC in the presence of amyloid. By providing a mechanistic framework for these early disruptions, this study advances the understanding of preclinical Alzheimer's disease and identifies specific structural-functional signatures that could serve as sensitive biomarkers for targeted interventions.},
}

@article {pmid42374501,
year = {2026},
author = {Bregman, N and de Barros, NP and Nathan, T and Levy, MH and Sima, D and Van Eyndhoven, S and Bar-David, A and Aizenstein, O and Niry, D and Atlan, L and Awad, AA and Ash, E and Omer, N and Shiner, T},
title = {Lecanemab in practice: AI-derived MRI predictors of benefit and Amyloid Related Imaging Abnormalities (ARIA).},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02127-z},
pmid = {42374501},
issn = {1758-9193},
abstract = {INTRODUCTION: Lecanemab, a monoclonal antibody targeting amyloid beta, has demonstrated meaningful clinical benefits in early Alzheimer's disease (AD), yet real-world data is needed to optimize patient selection and enhance safety monitoring, particularly with respect to amyloid-related imaging abnormalities (ARIA). Integration of quantitative and AI-derived MRI biomarkers may improve risk stratification and prediction of clinical trajectory.

METHODS: We conducted a retrospective real-world study of eighty-two patients with biomarker-confirmed early AD who initiated lecanemab at Tel Aviv Sourasky Medical Center between November 2023 and June 2025. Baseline MRI included volumetric T1-weighted imaging and susceptibility-weighted imaging (SWI). Automated whole-brain, regional cortical, and hippocampal volumes, and percentiles were extracted using FDA-cleared AI tools (icobrain by icometrix). Microhaemorrhage (MH) burden was assessed by both human and AI-assisted reads. Cognitive outcomes were evaluated using change in Mini-Mental State Examination (MMSE). Linear regression models assessed MRI predictors of cognitive response, and multivariable logistic regression identified predictors of ARIA.

RESULTS: Patients exhibited significantly lower cerebral volumes at treatment initiation. Mean whole brain percentile, mean gray-matter (GM) percentile, and mean white matter percentile were 11.45%, 8.6% and 38% respectively. Higher baseline GM volume predicted less MMSE decline at 12 months (β = 0.64, FDR-corrected p < 0.003). Hippocampal and white-matter volumes were not associated with cognitive outcomes. Seventeen patients (20.7%) developed ARIA. Baseline MH burden was the strongest predictor of ARIA (human rated OR=3.48 per MH, p=0.015, icobrain rated OR=3.25, p=0.01), while APOE ε4 carriage showed a strong directional trend which did not reach significance. Aspirin use and hypertension were not associated with ARIA. Agreement between icobrain and experts for MH ratings was excellent with a single-measure intraclass correlation coefficient (ICC) of 0.89 (95% CI: 0.83-0.93).

CONCLUSIONS: AI-derived MRI markers, particularly GM volume and MH burden, provide valuable predictors of cognitive response and ARIA risk in patients treated with lecanemab. Integrating quantitative neuroimaging into clinical workflows may enhance personalized treatment decisions and improve real-world implementation of Amyloid-targeting therapies.},
}

@article {pmid42374538,
year = {2026},
author = {Moon, SH and Kim, MH and Ryoo, JH},
title = {Smoking cessation duration and risk of Alzheimer's disease: a nationwide cohort study in Korea.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02132-2},
pmid = {42374538},
issn = {1758-9193},
support = {RS-2024-00509118//Ministry of Health and Welfare/ ; },
abstract = {BACKGROUND: Smoking is a modifiable risk factor for Alzheimer's disease, yet the temporal pattern of risk reduction following smoking cessation remains unclear. We investigated whether Alzheimer's disease risk declines according to the duration of sustained smoking cessation in a large nationwide cohort.

METHODS: Using the Korean National Health Insurance Service database (2002-2023), we identified 1,403,636 adults with stable longitudinal smoking patterns based on repeated biennial health examinations. Smoking status was classified as never smokers, current smokers, or sustained quitters, with cessation duration categorised into 2-year intervals (< 2, 2-3, 4-5, 6-7, ≥ 8 years). Incident Alzheimer's disease was defined as at least two separate NHIS insurance claims. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, adjusting for demographic, lifestyle, and metabolic factors.

RESULTS: During a mean follow-up of 10.5 years, 58,519 incident Alzheimer's disease cases were identified. Compared with current smokers, sustained quitters exhibited progressively lower hazards of Alzheimer's disease with increasing duration of abstinence, demonstrating a dose-response pattern. Individuals who had quit for < 2 years showed a risk reduction relative to current smokers (adjusted HR 0.899; 95% CI 0.819-0.986), while those with ≥ 8 years of abstinence had substantially lower risk (adjusted HR 0.582; 95% CI 0.423-0.801). When referenced to never smokers, those with < 2 years of abstinence retained excess risk, whereas cessation for ≥ 2 years was associated with Alzheimer's disease risk approaching that of never smokers.

CONCLUSIONS: Sustained smoking cessation was associated with a graded reduction in Alzheimer's disease risk, with approximately 2 years of abstinence needed to approach never-smoker risk.},
}

@article {pmid42374761,
year = {2026},
author = {Xing, Z and Jiang, X and Yang, W and Wang, Y and Zhang, X and Zhao, C},
title = {Corrigendum to: Lithium Chloride Improves Electrophysiological and Memory Deficits in Rats with Streptozotocin-Induced Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {23},
number = {1},
pages = {75},
doi = {10.2174/1567205023999260119152707},
pmid = {42374761},
issn = {1875-5828},
abstract = {In the published version of this article [1], the email address of the co-corresponding author, Zheng Xing, was missing from the corresponding address section. This has now been corrected. The original article can be found online at: https://www.eurekaselect.com/article/149786 Details of the error and the correction are provided below: Original: Address correspondence to this author at the Department of Pharmacy, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213004, P.R. China; E-mail: zhaochen3339@njmu.edu.cn (C.Z.); Corrected: Address correspondence to these authors at the Department of Pharmacy, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213004, P.R. China; E-mails: zhaochen3339@njmu.edu.cn (C.Z.); xingzheng@cczu.edu.cn (Z.X.).},
}

@article {pmid42374762,
year = {2026},
author = {Boudi, A and He, J and El Kader, IA and Liu, X and Mouhafid, M},
title = {Corrigendum to: Advancing Alzheimer's Disease Diagnosis Using VGG19 and XGBoost: A Neuroimaging-Based Method.},
journal = {Current Alzheimer research},
volume = {23},
number = {1},
pages = {76},
doi = {10.2174/1567205023999260119151250},
pmid = {42374762},
issn = {1875-5828},
abstract = {The publisher identified that references 42 and 43 were duplicated in the published version of this article [1]. The error has now been corrected. The original article can be found online at: https://www.benthamscience.com/article/150567 Details of the error and the correction are provided below: Original: [42] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190, 110095. [43] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190: 110095. http://dx.doi.org/10.1016/j.compbiomed.2025.110095 PMID: 40158456 Corrected: [42] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190, 110095. http://dx.doi.org/10.1016/j.compbiomed.2025.110095 PMID: 40158456 [43] Olaimat MA, Bozdag S, Saeed F. TA-RNN: An attention-based time-aware recurrent neural network architecture to predict progression of Alzheimer's disease. Alzheimer's Dement 2024; 20(S1).},
}

@article {pmid42374773,
year = {2026},
author = {Kim, H and Liu, E and Kajiyama, B and Song, J and Paun, O and Han, SG and Gallagher-Thompson, D},
title = {Development of K-iCare: a culturally adapted stress management intervention for Korean American dementia family caregivers.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13607863.2026.2693238},
pmid = {42374773},
issn = {1364-6915},
abstract = {OBJECTIVES: We developed the Korean version of iCare (K-iCare), a cognitive behavioral therapy (CBT)-based stress management intervention for Korean American family caregivers of individuals with Alzheimer's disease and related dementias (ADRD).

METHODS: Using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME), K-iCare was developed through a five-stage process: (1) initial modifications by the research team; (2) feedback from two focus groups comprising former Korean American ADRD family caregivers and Korean American community service providers; (3) refinement of K-iCare; (4) validation by focus group participants and the original iCare developers; and (5) finalization for implementation.

RESULTS: Intervention materials were translated into Korean with systematic cultural and linguistic adaptations. The number of chapters was consolidated from nine to five, and caregiving scenarios were replaced with culturally relevant examples reflecting Korean American caregiving norms. The intervention format was revised from self-paced, asynchronous modules to synchronous weekly small-group sessions delivered in a hybrid format and led by a bilingual, bicultural, doctoral-level interventionist with expertise in ADRD care. Supporting materials (e.g. fidelity monitoring checklists) were developed to promote consistent intervention delivery.

CONCLUSION: The next phase will evaluate the feasibility and acceptability of K-iCare and generate preliminary estimates of intervention-associated change and outcome variability.},
}

@article {pmid42374809,
year = {2026},
author = {Jiang, B and Yan, Y and Xu, C and Zhao, X and Qi, F and Xu, S and Yang, W and Liu, X and Feng, L},
title = {Herpes zoster as a vaccine-preventable risk factor increases the risk of dementia: A nested case-control study in Chinese population.},
journal = {Human vaccines & immunotherapeutics},
volume = {22},
number = {1},
pages = {2681253},
doi = {10.1080/21645515.2026.2681253},
pmid = {42374809},
issn = {2164-554X},
mesh = {Humans ; *Herpes Zoster/complications/prevention & control/epidemiology ; Case-Control Studies ; Female ; China/epidemiology ; Risk Factors ; *Dementia/epidemiology/etiology ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; East Asian People ; },
abstract = {Herpes zoster, a vaccine-preventable disease caused by the reactivation of varicella-zoster virus, has been linked to an increased risk of dementia in high-income countries. However, evidence from populations with low vaccination coverage remains limited. To address this gap, we conducted a nested case-control study using electronic health records from Yichang, China. A total of 51,843 incident dementia patients aged 50 y and older were matched with 338,877 controls by sex, age, and visit date. A documented clinical history of herpes zoster was significantly associated with an elevated risk of all-cause dementia (adjusted odds ratio [aOR] = 1.48; 95% confidence interval [CI]: 1.41-1.56), with the highest risk observed among individuals with herpes zoster involving the central nervous system (aOR = 1.59, 95%CI: 1.46-1.73). Among the dementia cases with prior HZ diagnosis, both Alzheimer's disease (aOR = 1.44, 95%CI: 1.14-1.79) and vascular dementia (aOR = 1.82, 95%CI: 1.49-2.21) showed increased risks following herpes zoster infection, with vascular dementia demonstrating a stronger association and more rapid progression (median time from first herpes zoster diagnosis to dementia onset: 1.5 y versus 2.2 y for Alzheimer's disease). The findings, derived from a population with minimal herpes zoster vaccination coverage, identify herpes zoster as a potentially modifiable risk factor for dementia. These also underscore the potential dual public health benefit of herpes zoster vaccination in preventing both acute infection and long-term cognitive decline.},
}

Humans
*Herpes Zoster/complications/prevention & control/epidemiology
Case-Control Studies
Female
China/epidemiology
Risk Factors
*Dementia/epidemiology/etiology
Male
Aged
Middle Aged
Aged, 80 and over
East Asian People

@article {pmid42375090,
year = {2026},
author = {Lee, HY and Hossain, MK and Jang, GH and Lee, H and Kim, YM and Chae, HJ},
title = {Behavioral and Biochemical Evaluation of a Curcumin-Loaded Nano-Liposomal Formulation in a Scopolamine-Induced Mouse Model of Cognitive Impairment.},
journal = {Biomolecules & therapeutics},
volume = {34},
number = {4},
pages = {866-881},
doi = {10.4062/biomolther.2026.062},
pmid = {42375090},
issn = {1976-9148},
abstract = {Scopolamine-induced cognitive impairment in mice models acute cholinergic dysfunction associated with early functional features of Alzheimer's disease (AD). This study evaluated the neuroprotective potential of curcumin-loaded nanoliposomes (Cur-NL), a bioavailable curcumin formulation, using behavioral, molecular, and biochemical approaches. Male mice received oral Cur-NL (250, 500, or 1000 mg/kg) for 30 days, followed by a single intraperitoneal injection of scopolamine (2 mg/kg). Cognitive performance was assessed by the open field test and Barnes maze. Acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels, hippocampal gene expression, and reactive oxygen species (ROS) accumulation were analyzed to investigate underlying mechanisms. Cur-NL significantly improved spatial learning and memory and restored cholinergic balance by normalizing AChE activity and ACh levels. Treatment also attenuated hippocampal neuroinflammation, oxidative stress, and ROS accumulation. Cur-NL modulated genes related to amyloid processing and synaptic plasticity, suppressing App and Bace1 and upregulating Adam10 and Bdnf. Network analyses supported the involvement of cholinergic, inflammatory, and synaptic signaling pathways. These findings indicate that Cur-NL confers multitarget neuroprotection in a scopolamine-induced model and may serve as a candidate for managing early cholinergic-related cognitive decline. Important limitations should be acknowledged: curcumin concentrations in plasma and brain were not quantified, and a free-curcumin comparator was not included. The findings should therefore be interpreted as evidence of efficacy of the tested Cur-NL preparation, not as a comparative demonstration of nano-liposomal superiority over free curcumin. Direct pharmacokinetic and head-to-head comparative studies are required to establish the formulation-specific contribution of nano-liposomal delivery.},
}

@article {pmid42375607,
year = {2026},
author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811183},
pmid = {42375607},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyloid-β (Aβ) accumulation is a central pathological feature of Alzheimer's disease (AD) and a major driver of disease progression. Recent evidence suggests that carbonyl stress associated with Aβ plays a critical role in AD pathology by promoting neuroinflammation and neuronal damage. In particular, methylglyoxal (MGO), a highly reactive carbonyl compound, contributes to activation of the receptor for advanced glycation end products (RAGE) and NF-κB-dependent inflammatory signaling, leading to synaptic dysfunction. The present study investigated whether fucoxanthin, a marine-derived carotenoid, attenuates Aβ-induced carbonyl stress and inflammatory responses associated with MGO/RAGE/NF-κB-related signaling.

METHODS: PC12 neuronal cells were pretreated with fucoxanthin (0.1-5 μM) and exposed to aggregated Aβ25-35 (10 μM) to assess its effects on carbonyl stress-associated inflammatory signaling. In parallel, an Aβ1-42 intracerebroventricular injection mouse model was used to validate the in vitro findings. Mice were orally administered fucoxanthin (100 or 200 mg/kg/day) for 15 days and assessed for serum MGO levels, hippocampal RAGE/NF-κB activation, microglial activation, and synaptic marker expression.

RESULTS: Fucoxanthin significantly reduced the expression of pro-inflammatory mediators, including COX-2, iNOS, IL-1β, and TNF-α in Aβ-exposed neuronal cells. This anti-inflammatory effect was associated with inhibition of NF-κB nuclear translocation and downregulation of RAGE expression. Consistent with these in vitro findings, fucoxanthin treatment in Aβ1-42-injected mice alleviated systemic and hippocampal carbonyl stress, as evidenced by decreased serum MGO levels and suppression of hippocampal RAGE/NF-κB activation. These effects were accompanied by reduced microglial activation (Iba-1) across hippocampal subregions and significant restoration of both presynaptic and postsynaptic markers, indicating preservation of synaptic integrity.

CONCLUSION: These findings demonstrate the neuroprotective role of fucoxanthin in mitigating Aβ-induced carbonyl stress by targeting the MGO/RAGE/NF-κB axis, thereby suppressing neuroinflammation and preserving synaptic integrity in Aβ-induced cellular and mouse models. Fucoxanthin emerges as a promising pharmacological candidate targeting carbonyl stress-associated mechanisms in AD.},
}

@article {pmid42375805,
year = {2025},
author = {Castro-Fuentes, R and Socas-Pérez, R},
title = {Unveiling the significance of dog domestication in cognitive dysfunction: Are wolves protected?.},
journal = {Open veterinary journal},
volume = {15},
number = {2},
pages = {6126-6145},
pmid = {42375805},
issn = {2218-6050},
mesh = {Animals ; *Wolves ; Dogs ; *Domestication ; *Cognitive Dysfunction/etiology/epidemiology ; *Dog Diseases/etiology ; Risk Factors ; Aging ; },
abstract = {Over the course of their long coexistence with humans, dogs have developed a stronger bond with humans than with any other domestic species. This close relationship has promoted notable parallels in both genetics and lifestyle, thereby facilitating the development of comparable pathological conditions, including several central nervous system disorders. Canine cognitive dysfunction (CCD) is a spontaneous model of neurodegeneration that shares clinical features, neuropathological characteristics, and risk factors with human Alzheimer's disease (AD). However, the potential role of dog domestication in increasing CCD susceptibility remains poorly explored. In this sense, the gray wolf (Canis lupus), a direct ancestor of the domestic dog (Canis lupus familiaris), represents a comparative model of great interest, as the information available on its neuropathology and behavior associated with aging is very limited. To provide a preliminary framework for assessing how domestication may have shaped vulnerability to cognitive decline in canids, this study employed a database-driven analytical approach to evaluate the degree of impact of various risk factors shared by AD and CCD-including aging, oxidative stress, inflammation, sleep disturbances, and periodontal disease-in domestic dogs and gray wolves kept in captivity or semi-captivity. Our results indicate that domestic dogs have more pronounced key risk factors for CCD than captive or semi-captive gray wolves. This finding suggests that wolves may be less vulnerable to age-related cognitive dysfunction, possibly reflecting differences in evolutionary or domestication processes. Nevertheless, given the scarcity of neuropathological and behavioral data on aged wolves, these conclusions should be interpreted with caution, and further direct investigations are warranted. Domestication may have increased susceptibility to age-related cognitive dysfunction in dogs by enhancing exposure to key risk factors, as oxidative stress, inflammation, and lifestyle-related conditions. Recognizing these domestication-linked vulnerabilities highlights the need for preventive health strategies in dogs and provides a valuable comparative framework for understanding neurodegenerative processes across species within a One Health perspective.},
}

Animals
*Wolves
Dogs
*Domestication
*Cognitive Dysfunction/etiology/epidemiology
*Dog Diseases/etiology
Risk Factors
Aging

@article {pmid42375925,
year = {2026},
author = {Sujanthi, S and Ravishankkar, AM and Ponmaniraj, S and Nanthini, S},
title = {Magnetic resonance imaging-based Alzheimer's disease detection using an EfficientNet-CMSACCN framework.},
journal = {Cytotechnology},
volume = {78},
number = {4},
pages = {146},
pmid = {42375925},
issn = {0920-9069},
abstract = {Alzheimer's Disease (AD) is a degenerative neurological condition characterized by memory loss, cognitive deterioration, and brain tissue shrinkage. Detecting it at an early stage is difficult due to variations in disease progression and the restricted scope of single-modality neuroimaging methods. Magnetic Resonance Imaging (MRI)-based Alzheimer's diagnosis, such as magnetic resonance imaging, offers complementary structural and functional insights, but existing deep learning methods often struggle with data imbalance, high computational complexity, and limited generalization. To fill these research gaps, design an MRI-based EfficientNet feature extraction framework for Alzheimer's stage classification. EfficientNet, equipped with compound scaling, depthwise-separable layers, and squeeze-and-excitation components, enables precise characterization of cortical structures and whole-brain variations while preserving computational efficiency. Extracted features are classified using a Compression-based Multi-Scale Attention Convolutional Network (C-MSACCN), which integrates attention mechanisms and compression strategies to enhance accuracy and reduce model complexity. Furthermore, the Improved Cellular Neighbours Optimiser (ICNO) fine-tunes hyperparameters, striking a balance between exploration and exploitation for optimal convergence and robustness. With 99.9% accuracy, precision, recall, and F1-score on datasets, the model outperforms prior work. Validation confirms consistency, and visualisation methods highlight disease-relevant regions to provide clinical insight.},
}

@article {pmid42376002,
year = {2026},
author = {Paitel, ER and Pettigrew, C and Moghekar, A and Miller, MI and Faria, AV and Albert, M and Na, CH and Worley, P and Soldan, A},
title = {Associations of cerebrospinal fluid measures of synaptic function with white matter microstructure and cognition in older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851829},
pmid = {42376002},
issn = {1663-4365},
abstract = {INTRODUCTION: Lower levels of several synaptic proteins in cerebrospinal fluid (CSF) have been associated with greater cognitive decline among older adults, but there is limited understanding of their associations with brain structure. This study is among the first to examine the cross-sectional relationship between levels of three synaptic proteins (VGF, NPTX2, and GluA4) with magnetic resonance imaging (MRI) measures of white matter microstructure and volumes, and with cognitive performance. We also examined whether relationships between synaptic protein levels and white matter measures are influenced by CSF Alzheimer's disease (AD) biomarker levels [ratio of p-tau181/(Aβ42/Aβ40)].

METHODS: Participants included 151 middle-aged and older adults without dementia (132 cognitively unimpaired, 19 mild cognitive impairment, M age = 69.3 years). White matter volumes and microstructure [fractional anisotropy (FA), mean diffusivity (MD)], derived from MRI scans, were assessed in three regions: global cerebral, medial temporal lobe, and cerebellar peduncles.

RESULTS: In linear regression analyses, lower levels of NPTX2, VGF, and GluA4 were associated with lower FA and higher MD, even after accounting for CSF AD biomarker levels. Synaptic proteins were not associated with white matter volumes. Additionally, lower FA, higher MD, and lower VGF levels were associated with poorer executive function performance. An exploratory mediation analysis showed that cerebral white matter MD statistically mediated the relationship between VGF and executive performance.

DISCUSSION: These findings provide preliminary, cross-sectional support that VGF may act on cognition via white matter microstructure. Together the results suggest that white matter microstructure may represent one pathway linking synaptic proteins levels to cognitive performance among older adults. Future research is needed to advance understanding of the specific mechanisms driving these relationships.},
}

@article {pmid42376437,
year = {2026},
author = {Dominguez, LJ and Veronese, N and Ragusa, FS and Seminara, F and Baio, SM and Vernuccio, L and Catanese, G and Barbagallo, M},
title = {Prevention of cognitive decline and dementia: Current evidence on lifestyle factors and dietary patterns.},
journal = {EXCLI journal},
volume = {25},
number = {},
pages = {690-724},
pmid = {42376437},
issn = {1611-2156},
abstract = {Cognitive decline and dementia represent major and growing global health challenges, driven largely by population aging and increased longevity. Currently, more than 55 million people worldwide live with dementia, a figure projected to rise to approximately 153 million by 2050. Alzheimer's disease accounts for the majority of cases, and despite extensive research, effective disease-modifying therapies remain limited. Consequently, increasing attention has shifted toward prevention strategies targeting modifiable risk factors. Accumulating evidence indicates that dementia is not an inevitable consequence of aging and that up to 45 % of cases may be attributable to potentially modifiable lifestyle and environmental factors operating across the life course. Lifestyle behaviors-including diet, physical activity, smoking, alcohol consumption, sleep, and social and cognitive engagement-have emerged as key targets for intervention. In particular, adherence to healthy dietary patterns such as the Mediterranean, DASH, and MIND diets has been associated with better cognitive outcomes, while unhealthy dietary patterns may increase risk. However, findings across studies remain heterogeneous, and uncertainties persist regarding causality, optimal exposure timing, and specific lifestyle components. Recent large prospective cohorts, meta-analyses, umbrella reviews, and multidomain intervention trials have advanced understanding of these associations but have also highlighted important gaps, including limited randomized evidence and underrepresentation of diverse populations. This narrative review critically synthesizes current evidence on lifestyle factors and dietary patterns associated with cognitive decline and dementia risk, focusing on recent high-quality studies. By integrating findings across domains, it aims to clarify areas of consensus and uncertainty, inform prevention strategies, and identify priorities for future research and public health action. See also the graphical abstract(Fig. 1).},
}

@article {pmid42376440,
year = {2026},
author = {Shet, A and Sabahuddin, S and B, P and Jami, BNSSR and Alex, JSR and Lin, CY and Lung, CW},
title = {Early Alzheimer's risk detection via diffusion tensor imaging using a few-shot multichannel attention residual learning network.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1867451},
pmid = {42376440},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is responsible for many dementia-related deaths worldwide, and Mild Cognitive Impairment (MCI) is often its earliest clinical manifestation. Early detection of MCI is essential to initiate timely interventions that can slow progression and improve the patient's quality of life. The emergence of diffusion tensor imaging (DTI) has made it a powerful neuroimaging modality for MCI detection, offering greater sensitivity to microstructural changes in white matter than basic structural imaging.

METHODS: A Multichannel Attention Residual Learning-DTI (MARL-DTI) architecture was designed with attention mechanisms and residual learning utilizing multiple DTI-derived diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AxD). To overcome the scarcity of labelled neuroimaging data, the model was supplemented with a few-shot learning framework. The dataset comprised 239 DTI scans from ADNI was used to evaluate the model. Local Interpretable Model-Agnostic Explanations (LIME) assists in analysing the model's decision-making process behaviour.

RESULTS: The proposed MARL-DTI achieved a classification accuracy of 92.76%, outperforming baseline DenseNet variants, StatFusion-FCNN, and Matching Networks. Validation on an unseen dataset of 36 ADNI subjects yielded consistent accuracy (91.67%), confirming the model's reliability. LIME analysis was used to provide instance-level explanations, enabling qualitative assessment of the model's decision-making behaviour by highlighting feature contributions for individual predictions.

DISCUSSION: These results demonstrate that the proposed MARL-DTI framework surpasses traditional deep learning architectures in the early identification of MCI using DTI data. The model consistently achieved strong performance while maintaining transparency, using LIME as a validation tool to examine its decision-making behaviour. These findings highlight the potential of combining multi-channel volumetric DTI data with explainable deep learning approaches to support reliable and clinically relevant early detection of Alzheimer's disease.},
}

@article {pmid42376442,
year = {2026},
author = {Varmaa, GD and Sekar, A and Anshul, V and Reddy, GVK and Evangelin A, P},
title = {S [3]Net: a Synthesis-Segmentation-Spiking Network for Alzheimer's disease detection and segmentation.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1845114},
pmid = {42376442},
issn = {2624-8212},
abstract = {Early and accurate detection of Alzheimer's disease (AD) from Magnetic Resonance Imaging (MRI) scans is crucial for clinical intervention. A novel S [3]Net, a Synthesis-Segmentation-Spiking Network, is proposed for this purpose. It integrates synthetic MRI generation, pathology-aware segmentation, and spike-based classification. The Synthesis Network uses a generative adversarial network framework. In this stage, original MRIs are fused with lesion-only patches from disease-relevant regions. This fusion helps preserve high-frequency pathological structures. The generator is trained with adversarial, L2, and Structural Similarity Index Measure (SSIM) losses. These losses ensure that the synthetic images remain realistic and structurally accurate. The Segmentation Network follows an encoder-bottleneck-decoder design with skip connections. It incorporates latent features from both the generator and the discriminator. A hybrid Dice-Binary Cross-Entropy loss is used to enable precise lesion delineation, even in sparsely annotated regions. For classification, a spiking network is employed. It takes fused segmentation and discriminator features and propagates them through Leaky Integrate-and-Fire neurons. This process captures temporal spike dynamics and supports low-power, event-driven computation. On the Open Access Series of Imaging Studies (OASIS) dataset, S [3]Net achieves an Accuracy of 95.1%, an F1-score of 93.0%, and an IoU of 82.6%. The proposed S [3]Net model outperforms other state-of-the-art methods, demonstrating its effectiveness and clinical viability for automated AD diagnosis.},
}

@article {pmid42376449,
year = {2026},
author = {Vukmir, RB},
title = {Alzheimer's disease and related dementia: evaluation, diagnosis and acute care management.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1743770},
pmid = {42376449},
issn = {1664-2295},
abstract = {IMPORTANCE: The patient presenting with memory loss often requires a complex, extensive multidisciplinary specialty evaluation that may begin in the primary care, emergency department, or general neurology setting. The analysis begins with a suspicion or concern regarding cognitive performance raised by the patient, family, or provider. Ideally, a better understanding will empower the primary care and general neurology communities to screen for and appropriately diagnose, treat, or refer patients with dementia.

METHODS: The thematic focus of this narrative review is diagnosis, imaging, and treatment of Alzheimer's disease and related dementia (ADRD). Information was abstracted from the National Library of Medicine MEDLINE/PubMed database. Medical Subject Headings (MeSH) heading search terms included dementia and, more specifically, Alzheimer's disease. The search targeted primary research, preferentially compared to reviews, consensus statements, or case reports if feasible.

OBSERVATIONS: Delirium typically represents an acute or subacute fluctuating change in mental status, often temporally related to acute illness. While dementia is typically associated with a more chronic progressive presentation of cognitive change without the presence of concurrent illness. However, subacute or dementia presentations may be exacerbated in that setting as well.

CONCLUSION AND RELEVANCE: The diagnosis, management, and therapy of Alzheimer's disease and related dementia is undergoing rapid change in imaging and now the utility of blood-based biomarkers. As more amyloid-modifying therapy is administered, the acute care systems should be knowledgeable of the treatment course and potential for complications.},
}

@article {pmid42376832,
year = {2026},
author = {Gorriz, JM and Segovia, F and Jimenez-Mesa, C and Arco, JE and Martinez, FJ and Ramirez, J and Abulikemu, S and Suckling, J},
title = {Latent Space Projections and Atlases, a Cautionary Tale in Deep Neuroimaging using Autoencoders.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2650053},
doi = {10.1142/S012906572650053X},
pmid = {42376832},
issn = {1793-6462},
abstract = {This study introduces a deep learning framework for the inferential exploration of latent representations in 3D brain MRI, leveraging a simple convolutional autoencoder with a hierarchical encoder and a compact latent space. Trained on segmented gray matter images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the model learns latent representations that preserve neuroanatomical structure and reflect clinical variability across cognitive status. Dimensionality reduction techniques (PCA, t-SNE, PLS, UMAP) were applied to visualize and interpret the latent space, correlating it with anatomical regions defined by the AAL atlas. As a novel contribution, the Latent-Regional Correlation Profiling (LRCP) framework, which combines statistical association and supervised discriminability to identify brain regions that encode clinically relevant latent information is proposed. Our results show that even minimal architectures capture meaningful patterns associated with progression to Alzheimer's disease. Interpretability is assessed by applying SHAP-based regression to a post-hoc model that predicts reconstruction error from atlas-based regional gray matter intensities, thereby identifying anatomically meaningful regions involved in class-specific reconstruction strategies. These findings are further validated using statistical agnostic methods, highlighting the importance of rigorous evaluation in neuroimaging. This work demonstrates the potential of autoencoders as exploratory tools for biomarker discovery and hypothesis generation in clinical neuroscience.},
}

@article {pmid42376914,
year = {2026},
author = {Nguyen, HTM and Khajehali, E and Pham, V and Scott, JW and Dite, TA and Dagley, LF and Murphy, JM and Thompson, G and Tobin, AB and Thal, DM and Christopoulos, A and van der Westhuizen, ET and Valant, C},
title = {Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator Lacking Cholinergic Adverse Effects.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00229},
pmid = {42376914},
issn = {1948-7193},
abstract = {Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) have progressed into clinical trials for cognitive disorders, such as Alzheimer's disease and schizophrenia. However, their successful translation has been limited by on-target cholinergic adverse effects. These limitations have been attributed to excessive allosteric agonism, however, the contribution of allosteric cooperativity, efficacy modulation and receptor regulatory mechanisms remains poorly defined. Here, we performed a comparative pharmacological analysis of five structurally distinct M1 PAMs (BQCA, MK-7622, PF-06767832, MIPS1780 and VU0486846) in HEK293A cells expressing the human M1 mAChR (hM1-WT) or a phosphorylation site-deficient human M1 mAChR (hM1-PD). Radioligand binding and functional assays were used to quantify binding affinity and cooperativity, as well as allosteric agonism and efficacy modulation on G protein-dependent and β-arrestin-associated pathways. Uniquely, VU0486846, previously reported to lack cholinergic adverse effects, displayed consistently low allosteric agonism, weaker binding and functional cooperativity but comparable efficacy modulation across all signaling pathways. In contrast, PAMs associated with cholinergic adverse effects had higher allosteric agonism, stronger cooperativity and preferential enhancement of β-arrestin-associated signaling. Removing the M1 mAChR phosphorylation sites uncoupled allosteric agonism from efficacy modulation for most M1 PAMs, with the loss of phosphorylation acting as a key regulator of allosteric signaling at the M1 mAChR. Together these results suggest that low allosteric agonism and balanced efficacy modulation may be essential for improved tolerability of M1 PAMs. This work provides a mechanistic framework for differentiating M1 PAM pharmacology beyond intrinsic agonism alone and may inform the design of safer M1-targeted therapeutics.},
}

@article {pmid42376965,
year = {2026},
author = {Akasaka, T and Watanabe, H and Ono, M},
title = {Bithiophene Scaffold for PET Imaging and Photosensitization as a Novel Theranostic Platform Targeting Amyloid-β Aggregates.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00047},
pmid = {42376965},
issn = {1948-7193},
abstract = {Amyloid β (Aβ) aggregates are primary targets for the diagnosis and curative treatment of Alzheimer's disease (AD). While various theranostic agents targeting Aβ aggregates have been developed, most rely on fluorescent imaging, which has limited clinical translation. In contrast, nuclear medicine imaging, particularly positron emission tomography (PET), offers high sensitivity and deep tissue permeability suitable for clinical settings. Moreover, photosensitization has emerged as a promising strategy to attenuate Aβ toxicity. In this study, we designed and synthesized novel bithiophene derivatives as PET/photosensitization theranostic agents. Western blotting analysis and MALDI-TOF MS spectrometry demonstrated that FABT-2 selectively oxidized Aβ aggregates under light irradiation, leading to a significant reduction in Aβ-induced cytotoxicity, as demonstrated by CCK8 and LDH assays. Furthermore, [18]F-labeled FABT-2 showed blood-brain barrier permeability in normal mice. These results suggest that FABT-2 may be a promising lead compound for the development of theranostic agents targeting Aβ aggregates.},
}

@article {pmid42377068,
year = {2026},
author = {Cantoni, V and Grassi, M and Premi, E and Cupidi, C and Zummo, E and Cotelli, MS and Benussi, A and Borroni, B},
title = {Long-term effects of multisession gamma transcranial alternating current stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461248},
doi = {10.1177/13872877261461248},
pmid = {42377068},
issn = {1875-8908},
abstract = {This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.},
}

@article {pmid42377071,
year = {2026},
author = {Chung, MLK and Takeda, S and Ryu, J and Murayama, S and Koshimizu, U and Kondo, T},
title = {Carboxy terminal of ECRG4 is a potential initiator for amyloid pathology in Alzheimer's disease through interacting with APP intracellular domain.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462890},
doi = {10.1177/13872877261462890},
pmid = {42377071},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) and the formation of neurofibrillary tangles. Although the amyloid cascade hypothesis underscores the centrality of Aβ accumulation, the precise initiators of this process remain unknown.ObjectiveIn this study, we investigate the potential role of Esophageal Cancer-Related Gene 4 (ECRG4) in AD. We hypothesized that ECRG4, which is associated with cognitive impairment and upregulated in AD, directly contributes to amyloid pathology.MethodsWe performed cell-based assays, co-immunoprecipitation, in vivo experiments using APP[NL-G-F/NL-G-F] knock-in mouse, and immunohistochemistry of human hippocampal sections.ResultsECRG4(133-148) associated with the amyloid precursor protein (APP) intracellular domain (AICD), leading to increased APP/Aβ accumulation. Furthermore, intracerebral injection of synthetic ECRG4(133-148) into AD model mice significantly augmented APP/Aβ deposition. Notably, the co-localization of ECRG4(133-148)-containing peptides with AICD-containing peptides increased with AD severity in human hippocampal tissue.ConclusionsOur findings establish that the carboxy-terminal fragment of ECRG4 acts as a potential initiator of amyloid pathology in AD through its interaction with AICD.},
}

@article {pmid42377087,
year = {2026},
author = {Rashid, MI and Abbas, M and Tahir, R and Alam, T and Noor, A and Ishrat, Z and Mudasir, M and Ahsan Sarfraz, M and Mehboob, U and Osman Abufatima, I},
title = {National trends and disparities in mortality among U.S. older adults, with coexisting Alzheimer's disease and hypertension, 1999-2023.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461304},
doi = {10.1177/13872877261461304},
pmid = {42377087},
issn = {1875-8908},
abstract = {BackgroundHypertension (HTN) is a major modifiable risk factor associated with cognitive decline including Alzheimer's disease (AD), which continues to be the leading cause of dementia and death in the United States (U.S.). However, the national mortality burden of coexisting AD and HTN across demographic and geographic groups remains poorly defined.ObjectiveWe aimed to study these trends to provide insights for better prevention, management, and policy planning.MethodsA retrospective analysis was conducted using the CDC WONDER Multiple Cause-of-Death database (1999-2023), focusing on adults aged ≥65 years with AD and HTN. Temporal trends were assessed using Joinpoint regression to estimate annual percent changes. Mortality patterns were examined by sex, race, region, urban-rural status, state, and place of death.ResultsBetween 1999 and 2023, 504,360 deaths among U.S. adults aged ≥65 years listed both AD and HTN on death certificates, with age-adjusted mortality rates rising from 14.5 to 60.0 per 100,000. Women consistently experienced higher mortality than men (67.5 versus 48.1 per 100,000 in 2023). Non-Hispanic African American adults had the greatest overall burden (57.1) among races. Geographically, mortality was highest in non-metropolitan areas (48.7) and the West region (52.6), More than half of all deaths occurred in nursing homes or long-term care facilities.ConclusionsMortality for coexisting AD and HTN has quadrupled in the U.S. over the past two decades with substantial variations across groups, highlighting the substantial burden of deaths where AD and HTN coexist and the importance of effective HTN control and dementia care across the lifespan.},
}

@article {pmid42377089,
year = {2026},
author = {Chen, PY and Shieh, WY and Weng, LC and Tsai, HH and Wang, WX and Liu, CY},
title = {Process-level eye-movement dynamics enhance sensitivity to early Alzheimer's disease-related cognitive vulnerability.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457344},
doi = {10.1177/13872877261457344},
pmid = {42377089},
issn = {1875-8908},
abstract = {BackgroundEarly Alzheimer's disease (AD)-related cognitive vulnerability is characterized by subtle disruptions in attentional and executive processing that may precede overt declines in global cognitive scores. Identifying process-sensitive behavioral markers capable of capturing these early alterations remains a major challenge in psychogeriatric assessment.ObjectiveTo examine whether eye-movement-derived process-level measures, particularly fixation-shift dynamics, are associated with early cognitive vulnerability in older adults and whether they provide incremental value beyond conventional cognitive screening scores in an AD-related context.MethodsThis cross-sectional study enrolled 109 adults aged ≥65 years, categorized as cognitively normal (CN, n = 33), mild cognitive impairment (MCI, n = 35), and dementia due to AD (ADD, n = 41). Participants completed a standardized online interactive cognitive task while eye movements were recorded using a non-head-fixed, desktop-based eye-tracking system. Cognitive-only, eye-movement-only, and combined multimodal models were compared using receiver operating characteristic (ROC) analysis and area under the curve (AUC).ResultsThe combined multimodal model consistently outperformed single-modality approaches. Discriminative performance was high for CN versus ADD (AUC = 0.925) and for CN versus cognitively impaired participants overall (AUC = 0.897). Fixation-shift dynamics emerged as a robust process-level marker, demonstrating particular sensitivity in distinguishing CN individuals from those with MCI.ConclusionsFixation-shift eye-movement dynamics capture early AD-related cognitive vulnerability beyond conventional total cognitive scores. This multimodal framework may support psychogeriatric screening and clinical triage by detecting subtle cognitive inefficiencies that precede measurable declines on standard cognitive tests.},
}

@article {pmid42377097,
year = {2026},
author = {Rennie, K and Tauskela, JS and Ménard, M and Aylsworth, A and Comas, R and Whitfield, J and Chakravarthy, B},
title = {The blood-brain barrier-penetrating fusion protein BBB-ABP selectively binds amyloid-β oligomers and prevents in vitro neurotoxicity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453068},
doi = {10.1177/13872877261453068},
pmid = {42377097},
issn = {1875-8908},
abstract = {BackgroundSoluble amyloid-β oligomers (Aβo) are considered the most neurotoxic species of Aβ and key drivers of Alzheimer's disease (AD) pathogenesis. Selective targeting of Aβo offers a promising therapeutic strategy. We previously identified an amyloid-binding peptide (ABP) that binds Aβo and engages Aβ deposits in AD mouse and human brain tissue. To facilitate brain penetration, ABP was fused to the blood-brain barrier (BBB) transporter FC5 and an Fc fragment, generating BBB-permeable constructs (mouse FC5-mFc2a-ABP and humanized FC5-hFc-ABP, referred to as BBB-ABP). Previous in vivo studies demonstrated the ability of BBB-enabled ABP to engage and clear Aβ from the central nervous system.ObjectiveThis study aimed to evaluate the in vitro functionality of BBB-ABP and its ability to prevent Aβo-induced neurotoxicity and synaptic dysfunction.MethodsBinding specificity was assessed using ELISA and western blot overlay assays. Functional assays were performed in SH-SY5Y cells and primary neurons to evaluate Aβo sequestration, protection against Aβo-induced toxicity, and effects on synaptic activity measured via multi-electrode arrays.ResultsBBB-ABP retained selective binding to Aβo and effectively prevented its interaction with neuronal proteins and its binding to dendritic spines in live primary neurons. BBB-ABP significantly reduced Aβo-induced toxicity in SH-SY5Y cells and primary neurons, including under conditions of NMDA-induced stress. Aβ exposure did not significantly alter spontaneous synaptic activity, precluding assessment of electrophysiological rescue by BBB-ABP.ConclusionsThese findings demonstrate that BBB-ABP maintains Aβo-selective binding and is capable of preventing the interaction of Aβo with neurons, thereby mitigating Aβo-induced toxicity in vitro, supporting its further development as a therapeutic candidate for AD.},
}

@article {pmid42377390,
year = {2026},
author = {Xu, L and Zhou, Y and Chen, H and Zhuang, J and Jiang, Y and Li, T and He, Z and Song, Z and Zhou, W},
title = {Porphyromonas gingivalis-Induced NETs Mediate Neuroinflammation via TLR4 Activation.},
journal = {Journal of dental research},
volume = {},
number = {},
pages = {220345261425925},
doi = {10.1177/00220345261425925},
pmid = {42377390},
issn = {1544-0591},
abstract = {Periodontitis, caused by periodontal pathogens such as Porphyromonas gingivalis, is a risk factor for Alzheimer's disease (AD) progression. Neutrophils, which are abundant in patients with periodontitis, release neutrophil extracellular traps (NETs) to resist microbial infection. We explored the mechanism and effects of P. gingivalis-induced NETs on the relationship between periodontitis and neuroinflammation. A murine periodontitis model was established via oral local application of P. gingivalis with or without tak242 (TLR4 inhibitor). Maxillary bones were evaluated via micro-computed tomography. The proportion of neutrophils was determined by flow cytometry. NET formation and morphology were analyzed via a cell-free DNA kit, a neutrophil elastase enzyme-linked immunosorbent assay (ELISA) and myeloperoxidase ELISA kit, reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunofluorescence. Behavior tests were used to investigate cognitive ability. Neuroinflammation was assayed by immunohistochemistry (IHC) and RT-PCR. Amyloid precursor protein (APP) processing was measured by IHC. In vitro experiments explored the functional mechanism underlying the effects of P. gingivalis-induced NETs on the neuron-glia unit. We observed significant alveolar bone resorption with elevated neutrophil count and increased NET formation in mice with periodontitis. Cognitive abilities were impaired by periodontitis. Neuroinflammation manifested as glia activation and upregulated inflammatory cytokines, and APP processing was altered by the elevated expression of APP and PSEN1. These changes were specifically reversed by tak242. In vitro, P. gingivalis-induced NETs mediated M1 polarization in BV2 cells and changed APP processing in N2a cells, along with the activation of TLR4/Myd88/NF-κB and GSK3β/Akt, which is consistent with the in vivo findings. In conclusion, P. gingivalis-induced NETs play pivotal roles in the relationship between neuroinflammation and cognitive impairment. Furthermore, the effects of P. gingivalis-induced NETs on neuron-glia unit were related to TLR4 activation.},
}

@article {pmid42377424,
year = {2026},
author = {Jian, W and Sun, H and He, Y and Lan, X and Dong, L and Wang, Z and Jiang, S and Cai, Q and Li, H and Yao, D},
title = {Depressive-cognitive interactions modulate amygdala and hippocampus functional connectivity in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462932},
doi = {10.1177/13872877261462932},
pmid = {42377424},
issn = {1875-8908},
abstract = {BackgroundDepressive symptoms frequently co-occur with cognitive impairment in older adults. Although depression and cognition interact in brain activity, the underlying functional connectivity mechanisms in mild cognitive impairment (MCI) remains unclear.ObjectiveTo investigate how depressive symptoms modulate the relationship between cognition and amygdala/hippocampus functional connectivity in MCI.MethodsThis study included 138 participants (45 healthy controls and 93 MCI patients) who underwent resting state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment using the Montreal Cognitive Assessment-Basic (MoCA-B) for cognitive function and Hamilton Depression Rating Scale (HAMD) for depressive symptoms. Seed-based functional connectivity analysis was performed using bilateral amygdala and hippocampus as seed regions to quantify the HAMD × MoCA-B non-monotonic interactions on whole-brain connectivity. Simple slopes analyses were conducted to characterize directionality changes across depression severity levels.ResultsWhole-brain analyses revealed significant HAMD × MoCA-B interaction effects (cluster p value < 0.05, voxel p value < 0.01, GRF corrected) demonstrating symptom-dependent reorganization of cognition-FC relationships. Amygdala connectivity decreased to anterior/middle cingulate and precuneus but increased to triangular part of inferior frontal gyrus (IFGtri), medial superior frontal gyrus, and cerebellar lobule IX. Hippocampal connectivity decreased to cuneus, insula, thalamus, and caudate but increased to opercular part of inferior frontal gyrus (IFGop), orbitofrontal cortex, and cerebellar lobule VIII.ConclusionDepressive symptoms alter amygdala and hippocampal FC relationships with cognition in MCI. Depression-dependent hippocampal/amygdala connectivity changes with the frontoparietal network (FPN-A)-particularly IFGop/IFGtri and cerebellum-suggest their role as critical hubs for emotional-cognitive integration, highlighting them as potential neuromodulation targets for cognitive and depressive symptoms in MCI.},
}

@article {pmid42377429,
year = {2026},
author = {Du, X and Wang, Y and Zhao, J and Liu, Y and Peng, D and , },
title = {APOE ε4-specific associations between agitation, cerebrospinal fluid biomarkers, and cognitive decline in cognitively impaired patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464188},
doi = {10.1177/13872877261464188},
pmid = {42377429},
issn = {1875-8908},
abstract = {BackgroundThe associations between agitation, cerebrospinal fluid (CSF) biomarkers, and cognitive decline, and whether these relationships vary by APOE genotype, remain unclear in Alzheimer's disease (AD) and mild cognitive impairment (MCI).ObjectiveTo investigate the association between CSF biomarkers and agitation in cognitively impaired individuals, with a focus on the potential moderating role of APOE ε4 status.MethodsWe analyzed 491 cognitively impaired individuals (359 MCI and 132 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available CSF biomarker data. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI), focusing on agitation.ResultsAmong APOE ε4 carriers, agitation was significantly associated with higher CSF GAP-43 (OR = 1.584, 95% CI: 1.159-2.195, p = 0.005) and p-tau levels (OR = 1.49, 95% CI: 1.073-2.101, p = 0.02). These associations were not observed in non-carriers. In addition, APOE ε4 carriers with agitation showed a higher risk of progression to dementia compared with other groups (HR = 4.422, 95% CI: 2.542-7.692, p < 0.001).ConclusionsCSF GAP-43 and p-tau levels are associated with agitation in APOE ε4 carriers. Agitation in this subgroup is also associated with an increased risk of progression to dementia, suggesting that it may reflect underlying disease-related processes.},
}

@article {pmid42377442,
year = {2026},
author = {Abedin, MJ and Lee, YF and Zhang, M and Russ, AN and Gerashchenko, D and Bacskai, BJ and Kastanenka, KV},
title = {Compartment-specific analysis reveals disrupted astrocytic calcium transients in anesthetized Alzheimer's disease mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464208},
doi = {10.1177/13872877261464208},
pmid = {42377442},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by presence of extracellular amyloid plaques, intracellular tau tangles, and extensive neuronal cell death. In addition to neurons, astrocytes modulate neuronal network activity through tripartite synapses. Also, astrocytes are increasingly recognized for their involvement in AD pathology. Aberrant astrocytic calcium signaling has been implicated in AD pathological processes, including disrupted synaptic transmission, dysregulated glutamate homeostasis, and impaired vascular function via astrocytic endfeet. Previous investigations have assessed compartment-specific astrocytic calcium transients, yet most employed a restricted range of metrics. Thus, comprehensive analyses of calcium dynamics within individual astrocytic compartments in mouse models of amyloidosis are lacking.ObjectiveTo analyze spontaneous calcium transients within distinct astrocytic compartments in APP/PS1 mice.MethodsUsing in vivo multiphoton imaging of Yellow Cameleon 3.6, a genetically encoded calcium indicator targeted to astrocytes in APP/PS1 mice, we analyzed spontaneous calcium transients in cortical astrocytes at 4-6 months of age. We quantified event rate, activity duration, area under the curve (AUC), and peak amplitude across four compartments: soma, processes, microdomains, and endfeet. Correlation analyses were used to assess astrocyte synchrony and distance-dependent activity relationships.ResultsIn APP/PS1 mice, somas exhibited increased activity duration and peak amplitude, while processes and microdomains showed reduced duration, AUC, and amplitude despite higher event rates. Endfeet showed reductions in all parameters. Correlation analyses revealed enhanced astrocyte synchrony in APP/PS1 mice, with distance-dependent correlation decay observed only in nontransgenic controls.ConclusionsThese findings highlight compartment-specific disruptions of astrocytic calcium activity caused by amyloidosis.},
}

@article {pmid42377581,
year = {2026},
author = {Terzioglu-Usak, S and Zaim, M and Beker, M and Isik, S and Elibol, B},
title = {Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.},
journal = {Experimental brain research},
volume = {244},
number = {8},
pages = {},
pmid = {42377581},
issn = {1432-1106},
support = {12.2016/7//Bezmialem Vakıf Üniversitesi/ ; },
mesh = {Reelin Protein ; Humans ; *Nerve Tissue Proteins/metabolism/genetics ; *Serine Endopeptidases/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; Cell Line, Tumor ; *Down-Regulation/physiology ; *Alzheimer Disease/metabolism/pathology ; *DNA Topoisomerases, Type II/metabolism/genetics ; RNA, Small Interfering/metabolism/genetics ; tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; RNA, Messenger/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Neuroblastoma/pathology ; Transfection ; Aspartic Acid Endopeptidases/metabolism ; Poly-ADP-Ribose Binding Proteins ; },
abstract = {Reelin signaling regulates multiple pathways in neurodegenerative conditions, including neuronal migration, synaptic plasticity, tau phosphorylation, and amyloidogenic processing of amyloid precursor protein (APP). This study aimed to investigate the impact of reelin downregulation on the expression of topoisomerase IIβ (topo IIβ), given its crucial role in neuronal differentiation and its established association with neurodegenerative disorders such as Alzheimer's disease (AD). Furthermore, we sought to elucidate the potential relationship between reelin downregulation and proteins implicated in the pathophysiology of AD. Firstly, the optimum concentration of small interfering RNAs (siRNA) targeting reelin was transfected into SH-SY5Y cells using Lipofectamine RNAiMAX reagent. The downregulation of reelin was confirmed at the mRNA level by real-time quantitative polymerase chain reaction (qRT-PCR). Reelin-mediated molecular alterations at both the mRNA and protein levels were analyzed by qRT-PCR and Western blotting. Reelin downregulation led to a decrease in the number of viable cells as determined by the MTT assay. Consistent with the downregulation of reelin gene expression, topo IIβ, Psen1, and BACE1 expressions were also reduced, whereas tau and APP expressions were upregulated. Although siRNA treatment effectively decreased reelin mRNA levels and the proteolytic fragment of reelin protein, no significant change was observed in total full-length reelin protein levels, suggesting the involvement of post-transcriptional regulatory mechanisms. Moreover, pTAU and APP protein expressions were increased, while Nurr1 protein was decreased in reelin-silenced cells. These findings suggest that downregulation of reelin gene expression may contribute to neurodegeneration through alterations in topo IIβ and nurr1 expression, in addition to changes in proteins associated with AD pathology.},
}

Reelin Protein
Humans
*Nerve Tissue Proteins/metabolism/genetics
*Serine Endopeptidases/metabolism/genetics
*Cell Adhesion Molecules, Neuronal/metabolism/genetics
*Extracellular Matrix Proteins/metabolism/genetics
Cell Line, Tumor
*Down-Regulation/physiology
*Alzheimer Disease/metabolism/pathology
*DNA Topoisomerases, Type II/metabolism/genetics
RNA, Small Interfering/metabolism/genetics
tau Proteins/metabolism
*DNA-Binding Proteins/metabolism/genetics
RNA, Messenger/metabolism
Amyloid beta-Protein Precursor/metabolism
Neuroblastoma/pathology
Transfection
Aspartic Acid Endopeptidases/metabolism
Poly-ADP-Ribose Binding Proteins

@article {pmid42377595,
year = {2026},
author = {Di Bari, MA and Bruno, R and Riccardi, G and Vanni, I and D'Agostino, C and Nonno, R and De Cecco, E and Burato, A and Legname, G and Cardone, F and Moda, F and Giaccone, G and Catania, M and Di Fede, G and Tagliavini, F and Agrimi, U},
title = {Prion-like transmission and propagation of human β-amyloid to the bank vole rodent model.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42377595},
issn = {1432-0533},
mesh = {Animals ; Arvicolinae ; Humans ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Brain/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism/genetics ; *Prions/metabolism ; Female ; tau Proteins/metabolism ; Male ; Aged ; *Prion Diseases/pathology/metabolism ; },
abstract = {Over the past decades, growing experimental and observational evidence has suggested that Aβ and pTau, the hallmarks of Alzheimer's disease (AD), may spread through the nervous system via a prion-like mechanism. Here, we investigated the transmissibility of Aβ and pTau by inoculating bank voles, a wild-type rodent highly susceptible to prion diseases, with brain homogenates from four sporadic and five familial AD-affected patients. We observed that (i) neo-formed Aβ deposits and pTau inclusions were induced in recipient vole brains; (ii) Aβ pathology appeared to follow a specific neurotropic distribution; (iii) Aβ proteinopathy propagated through vole-to-vole inoculation. Our findings provide the first experimental evidence that human Aβ seeds are transmissible to a wild-type rodent model, further supporting the prion-like nature of Aβ. These results strongly support recent studies suggesting iatrogenic Aβ transmission, underscoring the need to evaluate the impact of Aβ seed exposure on human health.},
}

Animals
Arvicolinae
Humans
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Brain/pathology/metabolism
*Alzheimer Disease/pathology/metabolism/genetics
*Prions/metabolism
Female
tau Proteins/metabolism
Male
Aged
*Prion Diseases/pathology/metabolism

@article {pmid42377618,
year = {2026},
author = {Saini, D and Mujeeb, M and Akhtar, M and Haque, SE and Najmi, AK},
title = {PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377618},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *PPAR gamma/metabolism ; Male ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; *Adiponectin/metabolism ; Telmisartan/pharmacology ; Disease Models, Animal ; Stress, Physiological/drug effects ; Insulin Resistance ; Neuroprotective Agents/pharmacology ; Lipopolysaccharides ; Isoflavones/pharmacology ; tau Proteins/metabolism ; },
abstract = {Background Increasing evidence links metabolic dysregulation, insulin resistance, and endotoxin-induced inflammation to sporadic AD. A disruption of the PPARγ-adiponectin-AMPK-insulin pathway leads to neuroinflammation, Aβ buildup, tau hyperphosphorylation, and cognitive impairments. This study examined the neuroprotective effects of telmisartan and formononetin alone and in combination in metabolically primed AD-like rats. Methodology A two-hit model was employed to simulate metabolic endotoxemia-related sporadic Alzheimer's disease in male wistar rats. The model utilised chronic HFD feeding and systemic administration of LPS (250 µg/kg, i.p.). The animals received telmisartan, formonoetin, their combination, or a PPARγ inhibitor/ blocker. We evaluated metabolic parameters, cognitive performance, insulin resistance, inflammatory cytokines, adiponectin concentrations, cholinergic function, histopathology, and immunohistochemical markers of Aβ, tau, IRS-1, AMPK, and AKT signalling. Results The outcomes of HFD + LPS encompass weight gain, insulin resistance, inflammation, cholinergic dysfunction, neurotoxicity, elevated Aβ and tau pathology, and cognitive impairment. The therapy with telmisartan and formononetin enhanced these alterations in a dose-dependent manner, with the combination regimen demonstrating greater efficacy. The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory. The co-administration of PPARγ inhibitor/blocker abolished these protective effects, showing mediation reliance on PPARγ. Conclusion Telmisartan and formononetin have significant metabolic and neuroprotective advantages against AD generated by HFD and LPS through the activation of the PPARγ-adiponectin-AMPK-IRS-1-AKT signalling pathway. Targeting metabolic-inflammatory pathways using natural PPARγ modulators may aid in delaying or preventing sporadic AD associated with obesity, insulin resistance, and endotoxemia.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*PPAR gamma/metabolism
Male
Rats
Proto-Oncogene Proteins c-akt/metabolism
Rats, Wistar
*AMP-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
*Adiponectin/metabolism
Telmisartan/pharmacology
Disease Models, Animal
Stress, Physiological/drug effects
Insulin Resistance
Neuroprotective Agents/pharmacology
Lipopolysaccharides
Isoflavones/pharmacology
tau Proteins/metabolism

@article {pmid42377628,
year = {2026},
author = {Nasybullina, E and Akhmetzyanova, E and Rizvanov, A and Mukhamedshina, Y},
title = {Advances in neural organoids: structural organization, disease modeling, and applications in gene therapy.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377628},
issn = {1573-4978},
support = {Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030)//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Organoids/metabolism/pathology/cytology ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics/pathology ; Animals ; Genetic Vectors/genetics ; Neurons/metabolism ; Dependovirus/genetics ; Brain/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; Gene Transfer Techniques ; },
abstract = {Neural organoids and assembloids have emerged as advanced in vitro models that reproduce the cytoarchitecture and functional complexity of the human brain. This review focuses on recent applications of these three-dimensional systems for modeling neurodegenerative diseases and assessing the efficacy of gene therapy, particularly using adeno-associated viral vectors. The development of induced pluripotent stem cell technology enables the creation of patient-specific organoids that reflect individual genetic backgrounds and disease phenotypes. Neural organoids have been used to model Alzheimer's, Parkinson's, and Huntington's diseases, reproducing hallmark features such as protein aggregation, neuroinflammation, and synaptic dysfunction. They have also served as test systems for evaluating AAV-mediated gene delivery, revealing serotype-specific tropism and supporting optimization of vector design and gene expression. Further advances include integration of immune and vascular components and the construction of multi-regional assembloids that replicate inter-regional neuronal communication and complex network dynamics. Ongoing standardization and scalability of neural organoid systems, combined with bioengineering and analytical innovations, are expected to enhance reproducibility and translational relevance. The convergence of organoid models with gene therapy testing frameworks may accelerate preclinical validation and contribute to the development of precision approaches in neurology.},
}

Humans
*Organoids/metabolism/pathology/cytology
*Genetic Therapy/methods
*Neurodegenerative Diseases/therapy/genetics/pathology
Animals
Genetic Vectors/genetics
Neurons/metabolism
Dependovirus/genetics
Brain/metabolism
Induced Pluripotent Stem Cells/metabolism/cytology
Gene Transfer Techniques

@article {pmid42377668,
year = {2026},
author = {Zhang, J and Zhang, Q and Jordan, JD and Zong, X},
title = {Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42377668},
issn = {1559-1174},
support = {R01AG082207 and R01AG081874//National Institute on Aging of the National Institutes of Health under/ ; 149251504A//U.S. Department of Defense/ ; 24CDA1269588//American Heart Association Career Development/ ; },
mesh = {Humans ; *Microglia/radiation effects/physiology ; Animals ; *Low-Level Light Therapy/methods ; *Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology ; *White Matter/radiation effects/injuries ; *Infrared Rays/therapeutic use ; Oligodendroglia/radiation effects ; Oxidative Stress ; Astrocytes/radiation effects ; Remyelination/radiation effects ; Axons/radiation effects ; },
abstract = {White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.},
}

Humans
*Microglia/radiation effects/physiology
Animals
*Low-Level Light Therapy/methods
*Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology
*White Matter/radiation effects/injuries
*Infrared Rays/therapeutic use
Oligodendroglia/radiation effects
Oxidative Stress
Astrocytes/radiation effects
Remyelination/radiation effects
Axons/radiation effects

@article {pmid42377735,
year = {2026},
author = {Das, K and Khatun, R and Begum, S and Bhattacharyya, K and Datta, M and Saha, D and Sarma, A and Mehta, P and Das, BK},
title = {The interplay between gut microbiota and Alzheimer's disease: mechanistic insights from dysbiosis to disease modulation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42377735},
issn = {1573-7365},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/metabolism/microbiology ; Animals ; Brain/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative condition marked by memory loss and cognitive decline. It is characterized by neuropathological features such as amyloid plaque accumulation, neurofibrillary tangles of tau protein, and inflammatory changes in the brain. Recent research emphasizes how gut microbes influence the onset and progression of AD primarily through the gut-brain connection, a bidirectional communication system. The human gastrointestinal tract (GI) contains trillions of bacteria, primarily Bacteroidetes, Firmicutes, and Actinobacteria, which play vital roles in digestion, metabolic regulation, and immune modulation. However, factors such as diet, lifestyle, and environmental exposure can disrupt microbial balance, weaken intestinal barrier function, and initiate systemic inflammation. Such dysbiosis has been linked to defective regulation of the amyloid precursor protein (APP), leading to increased deposition of amyloidogenic peptides (Aβ). Moreover, the enteric nervous system, which expresses APP, may serve as an initial site of amyloid deposition, affecting gastrointestinal motility and inflammatory susceptibility. The gut microbiota also produces key bioactive compounds, including neurotransmitters such as serotonin, dopamine, acetylcholine, histamine, and gamma-aminobutyric acid (GABA), which influence the central nervous system (CNS) through neural, immune, and endocrine pathways. An imbalance in these neuroactive molecules may disrupt synaptic signaling and contribute to Alzheimer's-related cognitive dysfunction. Therefore, improving our understanding of gut-brain communication may advance knowledge of AD development and support the creation of new therapies. This review highlights the strong association between intestinal microbes and Alzheimer's pathogenesis, emphasizing microbiota modulation through probiotics, prebiotics, postbiotics, synbiotics, and antibiotics as potential therapeutic approaches, supported by emerging clinical trial evidence.},
}

Humans
*Alzheimer Disease/metabolism/microbiology
*Gastrointestinal Microbiome/physiology
*Dysbiosis/metabolism/microbiology
Animals
Brain/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42377771,
year = {2026},
author = {Kuznetsov, AV},
title = {Investigating a relation between amyloid beta plaque burden and accumulated neurotoxicity caused by amyloid beta oligomers.},
journal = {Medical & biological engineering & computing},
volume = {},
number = {},
pages = {},
pmid = {42377771},
issn = {1741-0444},
support = {DMS-2451660//Division of Mathematical Sciences/ ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ), yet the specific link between plaque burden and cognitive decline remains a subject of intense investigation. This paper presents a mathematical model that simulates the coupled dynamics of Aβ monomers, soluble oligomers, and fibrillar species in the brain tissue. By modifying existing governing equations to include a dedicated conservation equation for Aβ monomers, the model explores how various microscopic processes, such as primary nucleation, surface-catalyzed secondary nucleation, fibril elongation, and fragmentation, contribute to macroscopic disease progression. Central to this study is the concept of "accumulated neurotoxicity" as a surrogate marker of biological age, defined as the time-integrated concentration of soluble Aβ oligomers. Unlike plaque burden, accumulated neurotoxicity cannot be reversed, and the harm it causes depends critically on the sequence of events that produced it. Numerical results demonstrate that while plaque burden and neurotoxicity both increase over time, their relationship is non-linear and highly sensitive to the efficiency of protein degradation machinery. Specifically, impaired degradation causes biological age, defined in terms of accumulated neurotoxicity, to advance considerably faster than calendar age. The model further identifies oligomer dissociation and fibril fragmentation as potential protective mechanisms that can counterintuitively reduce neurotoxic burden by diverting monomers away from the soluble oligomer pool. These findings provide a quantitative basis for understanding why individuals with similar plaque burdens may experience vastly different cognitive outcomes, underscoring the importance of targeting soluble oligomers early in therapeutic interventions.},
}

@article {pmid42377782,
year = {2026},
author = {Zeenny, MN and Salame, I and Maatouk, L and Akoury, E},
title = {Neuroinflammation and Tauopathies.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377782},
issn = {1573-4978},
mesh = {Humans ; *Tauopathies/metabolism/pathology ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; tau Proteins/metabolism ; Signal Transduction ; Microglia/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Inflammation/metabolism/pathology ; Phosphorylation ; Inflammasomes/metabolism ; Oxidative Stress ; Astrocytes/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) and related Tauopathies are neurodegenerative disorders characterized by the accumulation of hyperphosphorylated Tau protein in neurofibrillary tangles and frequently accompanied by amyloid-β (Aβ) pathology.[1] While Tau aggregation has long been considered a primary driver of neurodegeneration, growing evidence highlights neuroinflammation as a central and early contributor to disease onset and progression. This review combines current knowledge on the molecular and cellular mechanisms linking Tau pathology to chronic neuroinflammatory signaling, with a particular focus on microglia- and astrocyte-mediated responses. We discuss how dysregulated kinase-phosphatase balance, impaired proteostasis, and oxidative stress promote Tau hyperphosphorylation and aggregation, and how these processes are amplified by innate immune pathways, including TREM2-DAP12, toll-like receptors, GPCR signaling, the PI3K-Akt/PTEN axis, Wnt/β-catenin signaling, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Special emphasis is placed on the transition from early protective glial responses to chronic inflammation, which fosters prion-like propagation of Tau and accelerates synaptic dysfunction and neuronal loss. Finally, we evaluate emerging therapeutic strategies aimed at modulating neuroinflammatory pathways and restoring signaling homeostasis, highlighting their potential to slow or halt disease progression. Collectively, this review positions neuroinflammation as a critical mechanistic link between Tau pathology and neurodegeneration, underscoring its relevance as a therapeutic target in AD and other Tauopathies.},
}

Humans
*Tauopathies/metabolism/pathology
Animals
*Neuroinflammatory Diseases/metabolism/pathology
tau Proteins/metabolism
Signal Transduction
Microglia/metabolism/pathology
Alzheimer Disease/metabolism/pathology
Inflammation/metabolism/pathology
Phosphorylation
Inflammasomes/metabolism
Oxidative Stress
Astrocytes/metabolism/pathology

@article {pmid42377826,
year = {2026},
author = {Lachhab, S and Elmoussaoui, S and Rafya, M and El Mansouri, AE and Mehdi, A and Ramalhosa, RR and Costa, AR and Carreiro, EP and Andrei, G and Snoeck, R and Benkhalti, F and Sanghvi, YS and Ali, MA and Lazrek, HB},
title = {Discovery of novel perillyl and myrtenyl nucleobase conjugates as dual anti-Alzheimer and antimicrobial agents.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42377826},
issn = {1573-501X},
abstract = {Recent studies suggest that Alzheimer's disease may be influenced by microbial infections and may involve multiple microbial pathogens contributing to its development and progression. Based on this hypothesis, dual antimicrobial and anti-Alzheimer's agents may provide advantages such as improved therapeutic effectiveness, treatment of infection-related Alzheimer disease, and reduced toxicity compared with single-target drugs. To discover novel therapeutic agents, a series of terpene-substituted pyrimidine derivatives were synthesized and evaluated for their antiviral, antibacterial, antifungal and anti-Alzheimer's activities. All compounds were characterized by spectroscopic methods to support their structures. Among all compounds screened for their biological activity, compounds 11 and 32 displayed excellent IC50 values of 10.1 and 9.9 µM, respectively, against eqBChE in comparison with Food and Drug Administration (FDA)-approved drugs galantamine (IC50 = 20.6 µM) and donepezil (IC50 = 4.1 µM) for the treatment of Alzheimer's disease (AD). Additionally, compound 32 exhibited promising antifungal activity against C. tropicalis (MIC = 0.83 µmol/ml and MFC = 1.69 µmol/ml), showing two-fold greater potency than fluconazole and three-fold greater potency than 5-fluorocytosine. Moreover, terpene derivative 32 showed moderate antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis, with MIC and MBC values ranging from 3.35 to 6.71 µmol/ml. The docking studies of 32 with eqBChE supported the observed in vitro results. This study provides a promising lead compound with dual antimicrobial and anti-Alzheimer activity that may be further developed as a potential therapeutic agent for the treatment of Alzheimer's disease.},
}

@article {pmid42261768,
year = {2026},
author = {Deng, R and Shargorodsky, A and Teopiz, K and Dri, CE and Wong, S and Le, GH and Zheng, YJ and McIntyre, RS},
title = {Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e18},
doi = {10.1017/S1092852926100996},
pmid = {42261768},
issn = {2165-6509},
mesh = {Humans ; *Bipolar Disorder/drug therapy/psychology ; *Lithium Compounds/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Antimanic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy/psychology ; Cognitive Enhancement ; },
abstract = {Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.},
}

Humans
*Bipolar Disorder/drug therapy/psychology
*Lithium Compounds/therapeutic use
*Cognitive Dysfunction/drug therapy
*Antimanic Agents/therapeutic use
*Dementia/drug therapy/psychology
Randomized Controlled Trials as Topic
*Alzheimer Disease/drug therapy/psychology
Cognitive Enhancement

@article {pmid42364284,
year = {2026},
author = {Ramabharathi, TG and Subramaniam, K},
title = {Ternary pattern-driven feature extraction and self-attending GRU for clinical score prediction in Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {362},
number = {},
pages = {112269},
doi = {10.1016/j.pscychresns.2026.112269},
pmid = {42364284},
issn = {1872-7506},
abstract = {This article presents a unique deep learning technique to identify AD using data from magnetic resonance imaging (MRI). However, deep learning models' lack of interpretability prevents them from being used in clinical settings, where explainability is crucial for winning over medical personnel. In order to diagnose AD, this work proposes a self-attending bidirectional gated recurrent unit (SA-Bi-GRU) method based on explainable AI (XAI) that makes use of a deep learning model. Before the diagnosis process, an integrated Ternary pattern and Fourier-Bessel series expansion based empirical wavelet transform (TP-FBSE-EWT) method is used to extract features. Then, a hybrid binary teaching learning and Horse herd optimization (H-BTL-HHO) algorithm is presented to minimize the dimensions and screen properties of brain regions associated with AD. Additionally, by using the Gradient-weighted Class Activation Mapping (Grad-CAM) technique, the proposed structure seeks to improve the interpretability of deep learning models, giving clinicians important insights into disease diagnosis and an understanding of the decision-making process. The process is implemented using the MATLAB tool. The simulation findings reveal that the proposed CAD system for clinical score prediction outperforms prevailing systems by boosting accuracy, sensitivity, and specificity to 99.97%, 99.34%, and 98.89% for multi-class problems, respectively.},
}

@article {pmid42364425,
year = {2026},
author = {Rodrigues, EA and Dionizio, A and Rosa, CM and Campos, DHS and Damatto, FC and Reyes, DRA and Souza, LM and Santos, PP and Gatto, M and Borim, PA and Pagan, LU and Araújo, TT and Buzalaf, MAR and Cunha, TM and Okoshi, K and Okoshi, MP},
title = {Effects of SGLT2 inhibitor dapagliflozin on the heart of rats with long-standing Type 1 diabetes mellitus: Protein profile.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119719},
doi = {10.1016/j.biopha.2026.119719},
pmid = {42364425},
issn = {1950-6007},
abstract = {UNLABELLED: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified.

OBJECTIVE: To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model.

METHODS: Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40 mg/kg); dapagliflozin was added to chow (5 mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO.

STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn.

RESULTS: Dapagliflozin attenuated body weight loss (C 574 ± 43; DM 339 ± 31*; DM+DAPA 413 ± 30*# g; p < 0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM + DAPA 343 (237-416)*# mg/dL; p < 0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM + DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM + DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM + DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism.

CONCLUSION: Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.},
}

@article {pmid42364498,
year = {2026},
author = {Hu, H and Zhao, S and Xu, L and Ma, Z and Ma, R and Huang, F and Shi, L},
title = {Sequential targeting nanochaperone disrupts positive feedback loop of mitochondrial dysfunction for Alzheimer's disease therapy.},
journal = {Biomaterials},
volume = {335},
number = {},
pages = {124408},
doi = {10.1016/j.biomaterials.2026.124408},
pmid = {42364498},
issn = {1878-5905},
abstract = {Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca[2+]) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca[2+] dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca[2+] homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca[2+]-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.},
}

@article {pmid42364649,
year = {2026},
author = {Lamichhane, B and Niraula, A and Merindol, N and Gélinas, SE and Lagüe, P and Ricard, S and Germain, H and Desgagné-Penix, I},
title = {A Golgi-localized N-methyltransferase and reversible aldo-keto reductases coordinate dual terminal routes in galanthamine biosynthesis.},
journal = {The Plant journal : for cell and molecular biology},
volume = {126},
number = {6},
pages = {e70910},
pmid = {42364649},
issn = {1365-313X},
support = {CRC-2023-00353//Canada Research Chairs/ ; },
mesh = {*Galantamine/biosynthesis/metabolism ; *Methyltransferases/metabolism/genetics ; *Golgi Apparatus/metabolism/enzymology ; *Plant Proteins/metabolism/genetics ; *Alcohol Oxidoreductases/metabolism/genetics ; *Liliaceae/enzymology/metabolism/genetics ; *Amaryllidaceae/enzymology/metabolism/genetics ; },
abstract = {Galanthamine, a therapeutic Amaryllidaceae alkaloid produced exclusively by species within the Amaryllidoideae subfamily, is a key treatment for early-stage symptoms of Alzheimer's disease. Elucidating its biosynthetic pathway is essential for strategies aimed at enhancing production through metabolic engineering. Galanthamine derives from the metabolic precursor 4'-O-methylnorbelladine, which undergoes cytochrome P450-mediated para-ortho' C-C phenol coupling to yield nornarwedine. Two competing terminal routes have been proposed: (i) reduction of nornarwedine to norgalanthamine, followed by N-methylation, or (ii) N-methylation of nornarwedine to narwedine prior to reduction. Here, we identify three aldo-keto reductase (AKR) candidates (LaAKR1, LaAKR2, and LaAKR3) and three N-methyltransferase (NMT) candidates from Leucojum aestivum: LaNMT, homologous to coclaurine N-methyltransferase-like (NMT-like), and two γ-tocopherol methyltransferases (TMT) homologs, LaTMT1 and LaTMT2. Subcellular localization studies revealed distinct compartmentalization, with LaNMT targeted to the ER-cytosol, LaTMT1 to plastids, and LaTMT2 to the Golgi apparatus. In vitro, LaTMT2 methylated both nornarwedine and norgalanthamine, with a kinetic preference for nornarwedine. LaTMT1 methylated γ-tocopherol to α-tocopherol (vitamin E). All three AKRs catalyzed reversible interconversions between nornarwedine and norgalanthamine, and between narwedine and galanthamine, with LaAKR3 favoring the reduction reaction whereas LaAKR1 the oxidation reaction. These findings identify LaTMT2 and LaAKRs as key branch-enabling enzymes, reconcile long-standing models of galanthamine biosynthesis, and provide a strategic target for metabolic engineering strategies to enhance galanthamine production.},
}

*Galantamine/biosynthesis/metabolism
*Methyltransferases/metabolism/genetics
*Golgi Apparatus/metabolism/enzymology
*Plant Proteins/metabolism/genetics
*Alcohol Oxidoreductases/metabolism/genetics
*Liliaceae/enzymology/metabolism/genetics
*Amaryllidaceae/enzymology/metabolism/genetics

@article {pmid42364669,
year = {2026},
author = {Qiu, X and Liu, Z and Wang, L and Yuan, Y and Tan, J and Han, Y and Li, Z and Meng, Y and Wang, W and Tan, Y},
title = {Time-dependent circulating metabolic changes and key regulatory pathways in Alzheimer's disease: A combined animal model and public database study.},
journal = {Experimental gerontology},
volume = {222},
number = {},
pages = {113216},
doi = {10.1016/j.exger.2026.113216},
pmid = {42364669},
issn = {1873-6815},
abstract = {Early diagnosis remains a major challenge in Alzheimer's disease (AD), as clinical symptoms often appear after irreversible pathological progression. This study aimed to identify early diagnostic biomarkers and clarify metabolic regulatory mechanisms in AD by integrating metabolomic profiling from a mouse model with validation using public human datasets. AD models were established in 42 C57BL/6J mice by intraperitoneal injection of D-galactose (120 mg/kg) combined with intragastric administration of aluminum chloride (20 mg/kg) for 8 weeks. Plasma samples were collected at weeks 0, 3, 6, and 8 for untargeted metabolomic profiling. Public plasma/cerebrospinal fluid metabolomic datasets and brain transcriptomic datasets from AD patients were further analyzed for validation. Time-dependent metabolic alterations were observed in AD mice, characterized by predominant metabolite depletion at weeks 3-6 and compensatory accumulation at week 8. The metabolic profile of AD mice was clearly separated from that of controls at week 8. Nicotinamide metabolism and sphingosine-related pathways showed dynamic dysregulation during AD progression. Notably, nicotinamide and sphingosine were persistently increased in AD mice and were also elevated in plasma samples from AD patients, whereas metabolites such as N,N-diethyl-m-toluamide were decreased. Transcriptomic analysis revealed abnormal expression of key genes involved in nicotinamide metabolism (NMNAT1 and SIRT1) and sphingosine metabolism (SPTSSA and SPHK1) in brain tissues from AD patients. In conclusion, AD is characterized by stage-dependent metabolic dysregulation, featuring early depletion followed by late compensation. Dysregulated nicotinamide and sphingosine metabolism may contribute to AD pathogenesis, and related metabolites and regulatory genes may serve as potential diagnostic biomarkers and therapeutic targets.},
}

@article {pmid42365084,
year = {2026},
author = {Kumar, D and Martin, AJ},
title = {Integrated machine learning, molecular docking, and molecular dynamics simulations for in silico identification of GSK3β inhibitors for Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59744-9},
pmid = {42365084},
issn = {2045-2322},
abstract = {Glycogen Synthase Kinase-3 Beta is a multifunctional serine/threonine kinase, involved in regulating multiple cellular processes. Its dysregulation plays a key role in progression of Alzheimer's disease and no FDA-approved GSK3β inhibitors for AD therapy are available, due to challenges in isoform selectivity, safety and pharmacokinetic limitations. Here, an OECD guideline-compliant, two-stage machine learning-based virtual screening framework is developed for GSK3β inhibitors. A chemically diverse dataset from different databases were pre-processed and used for model development and validation. A comparative study confirmed the superiority of this two-stage approach over standard multiclass models, by yielding significantly higher balanced accuracy on the internal test set (0.86 against 0.74) and specificity. The best predictive models were deployed as an open-access web tool and were used for screening ASINEX Synergy Library. In the structure-based approach, molecular docking with a validated docking protocol was performed and the best molecules were subjected to molecular dynamics simulation, binding free energy and per-residue decomposition analysis. Principal component analysis of trajectories confirmed global stability and consistent binding modes. Cross-screening against the homologous GSK3α isoform and the structurally distinct Cyclin-dependent kinase 2 (CDK2) by molecular docking revealed distinct mechanistic interaction profiles. Rather than exhibiting strict single-target exclusivity, the top hits showed binding affinity profiles consistent with potential CMGC family Multi-Target Directed Ligands (MTDLs), warranting experimental kinome validation. This presumed polypharmacological profile is advantageous for Alzheimer's therapeutics, positioning these compounds as robust candidates for simultaneously mitigating multiple kinase pathways that drive Tau hyperphosphorylation. Overall, this integrated ML model development, validation, screening, protein selection, molecular docking and molecular dynamics workflow provides a reproducible, interpretable, and high-confidence method for identification of GSK3β inhibitors for Alzheimer's disease.},
}

@article {pmid42365183,
year = {2026},
author = {Park, DK and Constant, AB and Honig, LS and Marder, KS and Provenzano, FA and , },
title = {Machine learning classification and regional differentiation of neuropathologically-confirmed Alzheimer's disease and comorbid Lewy body disease.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01652-0},
pmid = {42365183},
issn = {2730-664X},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging.

METHODS: We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses.

RESULTS: Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe.

CONCLUSIONS: This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired.},
}

@article {pmid42365239,
year = {2026},
author = {Novak, P and Katina, S and Brandoburova, P and Jezberova, M and Reznakova, V and Hanes, J and Jurcaga, F and Koson, P and Novak, M and Jönsson, L and Zilka, N},
title = {Which assessment tools best distinguish between mild cognitive impairment and dementia? Lessons from a Slovak memory clinic cohort.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07801-3},
pmid = {42365239},
issn = {1471-2318},
support = {20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; 20-0447//Agentúra na Podporu Výskumu a Vývoja/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; ADDITION: Alzheimer's disease data-driven insights on individual outcomes of importance//EU Joint Programme - Neurodegenerative Disease Research/ ; },
abstract = {BACKGROUND: The utility of various cognitive assessment tools for distinguishing between mild impairment and dementia, as well as for determining cutoff values for specific populations, continues to be the subject of extensive research. Here, we assessed the utility and feasibility of these tools in the first Slovak memory clinic cohort.

METHODS: We enrolled a Slovak memory clinic cohort of patients with MCI and dementia (MCI, n = 84; dementia, n = 55). The participants were characterized using a range of cognitive assessment tools-Auditory Verbal Learning (AVLT), Category and Letter Fluency (CFT, LFT), Digit Span (DSF, DSB), Digit-Symbol Coding (DS-C), Frontal Assessment Battery (FAB), MMSE, MoCA, Rey Osterrieth Complex Figure (ROCF), and Trail Making Test (TMTA, TMTB); clinical assessments-Amsterdam Instrumental Activities of Daily Living (A-IADL) and 5-level EuroQol questionnaire with 5 dimensions (EQ-5D-5 L); and scales for anxiety, dependency, depression, dignity, and MRI volumetry. The ability of the various assessments to distinguish between MCI and dementia was evaluated.

RESULTS: Over the course of three years, at a single memory clinic, it was feasible to enrol and evaluate a total of 150 participants, 139 of whom fulfilled the definition of either MCI or nonvascular dementia. Of the employed cognitive and clinical assessment tools, the best differentiation between MCI and dementia was observed for the AVLT and A-IADL. The DSF and DSB tests did not reveal differences between the populations. No differences were observed in education, vital signs, or anthropometric measurements. Participants with dementia had greater degrees of brain atrophy in the hippocampi and frontal, parietal, and temporal cortex; lower total brain volumes; and greater ventricular dilation.

CONCLUSIONS: This study confirms the utility of a range of cognitive assessment tools and scales for differentiating between MCI and dementia but reveals that some commonly employed tools, such as the DSF and DSB, may not be sensitive to these differences. This study highlights the importance of accurate assessment of the ability to perform activities of daily living and supports the development of objective, ecologically valid assessments of IADL.},
}

@article {pmid42365511,
year = {2026},
author = {Song, A and Zhao, Y and Wu, S and Xu, X},
title = {Frequency-specific effects of pulsed magnetic field on BV2 microglial cell function.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/15368378.2026.2694326},
pmid = {42365511},
issn = {1536-8386},
abstract = {The objective of this study was to investigate the effects of pulsed magnetic field (PMF) at different frequencies on phagocytosis, migration, and the expression of inflammatory factors in microglia. BV2 microglia were subjected to PMF at different frequencies for 3 d, twice daily. The changes of cell viability, phagocytosis and migration after magnetic stimulation were detected. The mRNA and protein levels of TNF-α and IL-1β were determined using RT-PCR and ELISA. The nuclear translocation of NF-κB P65 and intracellular Ca2+ level was detected through immunofluorescence. PMF at different frequencies did not affect microglial viability. Stimulation at all frequencies enhanced the ability of microglia to phagocytosis and migration. The mRNA expression level of IL-1β and TNF-α was significantly decreased by magnetic stimulation at 20 Hz and 40 Hz. However, only the protein level of IL-1β was significantly reduced by magnetic stimulation at 20 Hz, while TNF-α remained unaffected. Magnetic stimulation at 20 Hz and 40 Hz inhibited the nuclear translocation of NF-κB P65 and increased the intracellular Ca2+ level. Repetitive magnetic stimulation can modulate the secretion of inflammatory cytokines and enhance the phagocytosis and migration capacity of microglia in a frequency-dependent manner. This variation may be linked to differences in the activation of NF-κB and calcium in microglia.},
}

@article {pmid42366122,
year = {2026},
author = {Amado-Riveros, P and Riveros-Perez, E},
title = {Hormone Therapy is Associated with Better Cognitive Performance in Postmenopausal Women: Insights from the National Health and Nutrition Examination Survey (NHANES).},
journal = {Annals of geriatric medicine and research},
volume = {30},
number = {2},
pages = {236-245},
doi = {10.4235/agmr.25.0180},
pmid = {42366122},
issn = {2508-4909},
mesh = {Humans ; Female ; *Postmenopause/psychology/drug effects ; Cross-Sectional Studies ; *Cognition/drug effects ; Nutrition Surveys ; Aged ; Middle Aged ; *Estrogen Replacement Therapy ; United States/epidemiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Alzheimer's disease is more prevalent among females. Estrogens influence brain metabolism and function, and low blood levels before, during, and after menopause may be associated with cognitive decline in later years. Here, we investigate the association between hormone therapy and reproductive lifespan with cognitive performance using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database.

METHODS: This cross-sectional study included 1,374 eligible women aged 60 years or older from the NHANES database. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning subtest, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Univariate analysis and multivariate logistic regression were employed to evaluate the association between hormone therapy, reproductive span, and cognitive performance. Restricted cubic spline curves were used to assess the relationship between age as a continuous variable and cognitive performance.

RESULTS: After adjusting for age, race, and educational level, hormone therapy was significantly associated with word recall, digit symbol, and animal fluency cognitive performance (p < 0.05). The reproductive span was associated with word recall performance (p = 0.027) but not with digit symbol or animal fluency. The age-related cognitive decline is attenuated by hormone therapy with maximum effect between 65 and 70 years for all dimensions.

CONCLUSION: There is a positive association between hormone therapy and cognitive performance in postmenopausal women, particularly in age groups with the steeper decline. In addition, there is no significant association between reproductive span and cognitive function.},
}

Humans
Female
*Postmenopause/psychology/drug effects
Cross-Sectional Studies
*Cognition/drug effects
Nutrition Surveys
Aged
Middle Aged
*Estrogen Replacement Therapy
United States/epidemiology
Neuropsychological Tests

@article {pmid42366179,
year = {2026},
author = {Sim, SY and Kim, S and Kim, YS and Han, JS},
title = {Age-dependent Upregulation of Selenbp1 in 5XFAD Mice.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26013},
pmid = {42366179},
issn = {1226-2560},
abstract = {Selenium-binding protein 1 (SELENBP1), previously implicated in several neurological and psychiatric disorders, was recently reported to be altered in the brains of individuals with Alzheimer's disease (AD). However, the cellular specificity of SELENBP1 in AD pathogenesis, including its role in amyloid-beta, remains unclear. Given the prominent role of microglia in amyloid-driven neuroinflammation and the hippocampal regional vulnerability in early AD, clarifying how SELENBP1 is regulated at both regional and cell-type-specific levels is essential. In this study, we examined age- and genotype-dependent changes in Selenbp1 expression in the hippocampus and prefrontal cortex of non-transgenic and 5XFAD mice at 1.5, 3, and 6 months of age by using western blot and immunofluorescence analyses. Western blot analyses revealed robust age-dependent increases in Selenbp1 expression in both regions, with no statistically significant genotype-dependent differences. However, immunofluorescence analyses showed that Selenbp1 levels were selectively increased in amyloid-vulnerable hippocampal subregions, including the dentate gyrus, dorsal subiculum, and retrosplenial cortex. Selenbp1 expression was expressed in microglia and was largely absent from neurons or astrocytes. These findings indicate that Selenbp1 elevation under AD-like conditions is region- and cell-type-specific, reflecting microglial responses detectable only through spatially resolved analysis. Therefore, Selenbp1 may represent a microglial molecular signature associated with early amyloid pathology.},
}

@article {pmid42366201,
year = {2026},
author = {Chen, Y and Gui, H and Ma, K and Zhang, Z and Zhao, T and Wang, M},
title = {Lifestyle-associated blood metabolic pathways and functional performance in cognitive aging.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58782-7},
pmid = {42366201},
issn = {2045-2322},
abstract = {Functional decline is a major clinical feature of Alzheimer's disease (AD), yet the blood metabolic pathways associated with lifestyle factors and multidimensional functional performance across cognitive stages remain incompletely characterized. We applied a pathway-level blood metabolomics framework to harmonized, de-identified data from aging and dementia-related cohort resources spanning cognitively normal aging (CN), mild cognitive impairment (MCI), and AD. Metabolites were mapped to curated pathways and summarized into pathway activity scores across five domains: energy metabolism, amino acid metabolism, lipid metabolism, inflammation/oxidative stress, and microbiome-linked metabolism. We evaluated associations among physical activity, diet quality, pathway activity scores, and functional outcomes, including activities of daily living, gait speed, grip strength, global cognition, composite function, and frailty. To summarize pathway patterns jointly associated with physical activity and diet quality, we derived a lifestyle-modulated metabolic pathway score (LMPS) using elastic net regression with cross-validation, out-of-fold score estimation, and bootstrap stability assessment. Lifestyle-associated pathway activity showed coordinated patterns across metabolic domains and was associated with functional performance across cognitive groups. Higher LMPS values were associated with better physical and cognitive function and lower frailty, with graded differences observed across CN, MCI, and AD. Internal robustness analyses indicated greater stability at the pathway-domain level than at the individual-pathway coefficient level. Sensitivity analyses adjusting for cognitive group attenuated but did not eliminate the directionally consistent associations between LMPS and major functional outcomes. Convergent pathway patterns involved mitochondrial energy metabolism, lipid remodeling, inflammatory regulation, and microbiome-related metabolism. Pathway-level blood metabolomics identified lifestyle-associated metabolic patterns related to multidimensional functional outcomes across the cognitive aging spectrum. LMPS provides a data-driven summary of lifestyle-associated pathway variation in this cohort and may help generate hypotheses about metabolic correlates of functional performance. Independent and longitudinal validation will be required to determine its reproducibility, temporal relevance, and translational utility.},
}

@article {pmid42366234,
year = {2026},
author = {Rong, W and Xu, J and Li, B and Li, Y and Xu, Y},
title = {Correction: Single-cell atlas reveals the key role of pro-inflammatory IREB2[+] microglia subsets in the microenvironment of Alzheimer's disease.},
journal = {Clinical and experimental medicine},
volume = {26},
number = {1},
pages = {},
doi = {10.1007/s10238-026-02238-9},
pmid = {42366234},
issn = {1591-9528},
}

@article {pmid42366246,
year = {2026},
author = {Liao, K and Li, J and Jiao, F and Zhang, Z and Xu, L and Wang, Z and Li, W and Pang, H},
title = {Impact of reduced [18]F-MK6240 PET/MR acquisition duration on image quality and tau pathology assessment in patients with cognitive impairment.},
journal = {EJNMMI physics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40658-026-00914-z},
pmid = {42366246},
issn = {2197-7364},
support = {82472019//National Natural Science Foundation of China/ ; 82502406//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: [18]F-MK6240 tau positron emission tomography (PET) is critical in Alzheimer's disease diagnosis and therapeutic monitoring. However, the standard 20-minute static acquisition poses challenges for cognitively impaired patients with limited tolerance for prolonged scans. This study evaluates the feasibility of reducing scan time while maintaining diagnostic accuracy through image quality and quantitative comparisons.

METHODS: 69 memory clinic patients (27 males and 42 females) who underwent [18]F-MK6240 PET examinations were retrospectively analyzed. All 20-minutes scans were acquired 90 min post-injection of ~ 3.7 MBq/kg ¹⁸F-MK6240 and reconstructed mainly into 5-, 10-, 15-, and 20-minute datasets. Images were rated on a 5-point scale for overall quality, noise, and diagnostic confidence. Tau status (positive/negative) was the visually defined, and standardized uptake value ratios (SUVr) of Braak regions were calculated using cerebellar gray matter as reference. Agreement across durations was assessed via Bland-Altman analysis.

RESULTS: Among the 69 patients, 50 were classified as tau-positive and 19 as tau-negative. Diagnostic efficacy remained consistent across acquisition times compared to the 20-minute reference. The slight reduction in image quality for the 5-minute images relative to the other groups, but none of the images across any of the four durations were rated as poor (score < 3). For 16 predefined regions used for visual assessment of regional tau involvement, both readers showed near-perfect agreement in scoring the extent of involvement (0%, 1-25%, 26-75%, or > 75%) across the four scan durations, as evidenced by Kendall's W coefficients ranging from 0.984 to 1.000 (all p < 0.001). Negative scans showed lower SUVr spread over Braak stages of four different time duration. Bland-Altman analysis demonstrated high agreement in Braak-stage SUVr values between the 20-minute images and the shortened acquisitions with mean differences close to zero across all comparisons.

CONCLUSION: Shortening ¹⁸F-MK6240 PET acquisition to 5 min on a modern high-sensitivity PET/MR system results in a small, clinically acceptable decline in image quality. It does not compromise the reliability of visual reads or the stability of semi-quantitative measures compared to the standard 20-minute scan. These findings support the feasibility of 5-minute protocols, which offer practical benefits like reduced motion artifacts and improved patient throughput, as an operationally efficient alternative in clinical tau imaging.},
}

@article {pmid42366338,
year = {2026},
author = {Dey, AK and Al-Amin, MY and Ferdous, R and Alam, AHMK and Rahman, AA and Hossen, MB and Mollah, MNH and Sadik, MG},
title = {Isolation and identification of hasubanan alkaloids having anti-cholinesterase and antioxidant activity from the stem Stephania japonica.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05447-7},
pmid = {42366338},
issn = {2662-7671},
support = {37-01-0000-073-04-012/2019//University Grants Commission of Bangladesh/ ; },
abstract = {BACKGROUND: A recent report showed that Stephania japonica chloroform fraction has potential anticholinesterase and antioxidant activities and is able to improve learning and memory in mice. Therefore, the aim of the present study was to isolate and identify compounds from the chloroform fraction with cholinesterase inhibitory and antioxidant activity that may be useful as new candidates for the treatment of AD.

METHODS: Chromatographic methods were used for isolation of compounds and the isolated compounds were analyzed by spectroscopic methods for structure elucidation. Acetyl- and butyryl-cholinesterase inhibitory activity were evaluated for by Ellman's method and the antioxidant activity by several in vitro models such as DPPH and hydroxyl radicals scavenging, reducing power, total antioxidant activity, and inhibition of brain lipid peroxidation. The interaction of cholinesterase enzymes and isolated compounds were examined by molecular docking studies.

RESULTS: Bioactivity guided approach led to the isolation of four compounds from the chloroform fraction and identified as aknadinine, aknadilactam, aknadicine and stephisoferuline on the basis of their [1]H-NMR and [13]C-NMR spectral data. All the compounds were of hasubanan type. They showed significant inhibition against acetylcholinesterase and butyrylcholinesterase, with at least two fold increased affinity for butyrylcholinesterase than acetylcholinesterase. The IC50 values of the alkaloids were in the range of 9.36-14.89 µg/mL against acetylcholinesterase and 3.97-6.66 µg/mL against butyrylcholinesterase. Kinetic analysis revealed that all the four compounds exhibited mixed type of inhibition against both acetylcholinesterase and butyrylcholinesterase. The interaction of compounds with several amino acids of enzymes was supported by molecular docking studies. All the hasubanan alkaloids showed antioxidant activity in all in vitro assays and inhibited peroxidation of brain lipid. The IC50 values of the compounds for scavenging of DPPH and hydroxyl radicals, and lipid peroxidation inhibition were found to be in the range of 5.1-40.91, 10.44-19.41, and 20.60-31.72 µg/mL, respectively.

CONCLUSION: The hasubabanan alkaloids isolated from S. japonica may represent a new class of anti-cholinesterase compounds. The multitargeted activity of hasubanan alkaloids may lead to new candidates for the treatment of AD.},
}

@article {pmid42366401,
year = {2026},
author = {Sun, W and Xing, R and Zhou, J and Li, Y and Xu, G},
title = {Facial phenotypes in Alzheimer's disease: from neurobiology to artificial intelligence.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02129-x},
pmid = {42366401},
issn = {1758-9193},
support = {KYCX25_0823 to RX//Major Project of Philosophy and Social Science Research for Universities of Jiangsu Province/ ; 82171330//National Natural Science Foundation of China/ ; 4004013//Shenzhen Talent Introduction Fund/ ; 2023ZD0504800, 2023ZD0504801, 2023ZD0504802, 2023ZD0504803, 2023ZD0504804//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; },
abstract = {Facial analysis is increasingly being explored as a source of scalable behavioral signals relevant to Alzheimer's disease (AD) and AD-related cognitive impairment. In this narrative review, informed by a structured literature search, we summarize current evidence on the biological and behavioral basis of facial alterations in AD, with particular emphasis on affective expressivity, neuropsychiatric manifestations, and dynamic facial behavior. We also review representative artificial intelligence-based facial analysis methods, including commonly used datasets, feature representations, and modeling strategies, ranging from facial landmarks and texture descriptors to spatiotemporal video models, multimodal fusion, and language-enhanced frameworks. Current evidence remains limited by small and largely single-center cohorts, heterogeneity in acquisition settings and outcome definitions, inadequate control of confounding factors, limited external validation, poor calibration reporting, and persistent concerns regarding interpretability and clinical specificity. Within the evolving biomarker-based diagnostic framework of AD, facial analysis is better viewed as a candidate, non-specific, and context-dependent tool for auxiliary risk stratification, triage support, and longitudinal monitoring rather than as stand-alone diagnostic tests. Future progress will depend on standardized data acquisition, integration with clinical and biomarker data, improved explainability, and prospective real-world validation.},
}

@article {pmid42366433,
year = {2026},
author = {Chen, Y and Yao, C and Yan, F and Xiao, P and Lu, X},
title = {[Finite-element simulation and experimental investigation of nanosecond transcranial pulsed electric field propagation and distribution in a three-dimensional brain model].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {43},
number = {3},
pages = {504-512},
pmid = {42366433},
issn = {1001-5515},
mesh = {Humans ; *Finite Element Analysis ; *Brain/physiology ; Computer Simulation ; Alzheimer Disease/therapy ; *Transcranial Direct Current Stimulation/methods ; Electromagnetic Fields ; Amyloid beta-Peptides/metabolism ; },
abstract = {Nanosecond pulsed electric field (nsPEF) exposure can disrupt and disaggregate amyloid-β, indicating its potential to improve symptoms of Alzheimer's disease. However, the propagation and distribution patterns of nsPEF within brain tissue remain insufficiently understood, making related simulation analysis necessary. In this study, a high-resolution three-dimensional human head model incorporating the scalp, skull, cerebrospinal fluid, gray matter, white matter, and hippocampus was constructed. Based on the spectral characteristics of nsPEF, the dielectric properties of human tissues at different frequency ranges were assigned, and a transient finite-element model of nsPEF exposure in the human brain was established. The simulation analysis identified two optimal electrode-pair positions and characterized the spatial distributions of intracranial electric field strength as well as current density. It further elucidated the dependence of the hippocampal electric field response and current density on pulse parameters. In addition, a physical human brain model was constructed to experimentally validate the finite-element simulation results. The results showed that transcranial nsPEF can reach deep brain regions with extremely narrow pulse widths, and pulsed electric fields with kilovolt-level amplitudes and nanosecond-scale pulse widths can generate electric field strengths of approximately 10 [3] V/m in the hippocampus. In summary, this work provides a theoretical basis and experimental support for optimizing the electrode configuration and stimulation parameters of transcranial nsPEF, thereby laying a foundation for future research on its application in non-invasive physical interventions for Alzheimer's disease.},
}

Humans
*Finite Element Analysis
*Brain/physiology
Computer Simulation
Alzheimer Disease/therapy
*Transcranial Direct Current Stimulation/methods
Electromagnetic Fields
Amyloid beta-Peptides/metabolism

@article {pmid42366543,
year = {2026},
author = {Sui, Z and Feng, A and Gong, Y and Zha, S and Lv, Y and Zheng, Q and Li, L and Wang, Y},
title = {Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70665},
pmid = {42366543},
issn = {1365-2125},
support = {2025ZHYL037//Shanghai Municipal Health Commission Smart Healthcare Special Project/ ; 2024YFC3506600//National Key R&D Program of China/ ; LSLSKL20240203//Open Research Program of the State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; },
abstract = {OBJECTIVES: This study investigates the association between amyloid-β (Aβ) biomarkers and clinical cognitive outcomes and quantitatively elucidates their relationship, providing robust evidence supporting the amyloid hypothesis and advancing the development of novel anti-amyloid therapeutics, such as aducanumab, lecanemab and donanemab.

METHODS: Placebo-controlled randomized clinical trials reporting Aβ-related biomarkers and cognitive function clinical outcomes were retrieved from PubMed, EMBASE and Cochrane Library. Pearson correlation analysis was first used to screen indices, and then a model-based meta-analysis (MBMA) using non-linear mixed-effect modelling was established to predict cognitive function based on biomarkers while examining relevant factors affecting the relationship.

RESULTS: Primary outcomes included changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG-11). The analysis included 57 articles representing 93 417 subjects, with a modelling subset of 18 246 patients providing paired biomarker-endpoint data for Alzheimer's disease or mild cognitive impairment. Results showed significant correlations between the standard uptake value ratio (SUVR) of β-amyloid plaques and CDR-SB, centiloid and CDR-SB, and SUVR and ADAS-COG-11. Three prediction models of cognitive function scales based on imaging index of β-amyloid plaques were established and found to be significantly impacted by factors such as baseline CDR-SB, treatment duration and the proportion of patients receiving basic treatment.

CONCLUSIONS: This study clarified the correlation and established predictive models for CDR-SB and ADAS-COG-11 based on amyloid imaging. This research identifies potential biomarkers and model-derived benchmarks for future dose selection and decision-making in Alzheimer's drug development, potentially accelerating the development of new treatments.},
}

@article {pmid42366747,
year = {2026},
author = {Abed, H},
title = {Postoperative Experiences After Dental Treatment Under General Anesthesia in People Living With Alzheimer's Disease: A Descriptive Study With Caregiver and Staff Reports.},
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 = {4},
pages = {e70201},
doi = {10.1111/scd.70201},
pmid = {42366747},
issn = {1754-4505},
mesh = {Humans ; *Anesthesia, General ; *Alzheimer Disease/complications ; Female ; Aged ; *Caregivers/psychology ; Male ; Aged, 80 and over ; *Anesthesia, Dental ; Postoperative Complications/epidemiology ; Middle Aged ; *Dental Care for Chronically Ill ; Anesthesia Recovery Period ; },
abstract = {AIMS: To describe the demographic and clinical characteristics of people living with Alzheimer's disease (AD) undergoing dental treatment under general anesthesia, to summarize peri-recovery challenges reported by healthcare staff, and to describe caregiver-reported postoperative experiences at three time points. The occurrence of postoperative delirium or hallucinations was also descriptively examined.

METHODS: In this single-center descriptive study, postoperative information was obtained through structured telephone contacts with caregivers and relevant clinical staff at three time points (immediate recovery, 2 days, and 2 weeks). Responses were analyzed using inductive content analysis and summarized descriptively.

RESULTS: Participants (n = 14) were elderly and predominantly in the moderate to late stages of AD, with substantial dependence on caregivers. Staff-reported observations indicated that agitation and behavioral disturbance during emergence and early recovery were the most prominent challenges. Resistance to care with monitoring devices was also noted. Caregivers reported increased pain, agitation, and care demands within the first 48 h following general anesthesia. By one week, most caregivers reported physical recovery and behavioral improvement. No documented cases of postoperative delirium or hallucinations were identified.

CONCLUSIONS: In this exploratory descriptive study, dental treatment under general anesthesia in people living with AD was followed by short-term postoperative behavioral and physical challenges that generally improved within one week. Given the small sample size and descriptive design, findings should be interpreted cautiously.},
}

Humans
*Anesthesia, General
*Alzheimer Disease/complications
Female
Aged
*Caregivers/psychology
Male
Aged, 80 and over
*Anesthesia, Dental
Postoperative Complications/epidemiology
Middle Aged
*Dental Care for Chronically Ill
Anesthesia Recovery Period

@article {pmid42366768,
year = {2026},
author = {},
title = {Corrigendum to "Electromagnetic field induced activation of amyloid-β degrading enzyme, neprilysin, for accelerated Alzheimer's disease therapy".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261463830},
doi = {10.1177/13872877261463830},
pmid = {42366768},
issn = {1875-8908},
}

@article {pmid42366949,
year = {2026},
author = {González, EG and Dicu, M and Villar, JR and Chira, C},
title = {Transformer-Based Anomaly Detection for Neurodegenerative Screening in MRI Images.},
journal = {International journal of neural systems},
volume = {},
number = {},
pages = {2650052},
doi = {10.1142/S0129065726500528},
pmid = {42366949},
issn = {1793-6462},
abstract = {The automatic detection of anomalies in medical images is a significant challenge in the assisted diagnosis of neurodegenerative diseases such as Alzheimer's. This paper presents an anomaly detection model based on Transformers for the analysis of brain magnetic resonance images. The proposed architecture combines a Vision Transformer as an encoder with a memory bank module that allows modeling the distribution of healthy brains and detecting deviations through reconstruction error. The model is trained using a one-class learning approach, using only images considered normal, with the aim of learning the representation of normality and automatically flagging atypical structural patterns. To adapt volumetric studies to the architecture, a preprocessing procedure is designed that transforms three-dimensional information into a two-dimensional representation compatible with the model. The results obtained demonstrate a solid ability to characterize normality and generate reliable predictions, confirming the viability of Transformer-based architectures for unsupervised anomaly detection in neuroimaging. This approach lays the foundation for future extensions in clinical settings and other medical imaging applications.},
}

@article {pmid42367034,
year = {2026},
author = {West, NR and Lindberg, MF and Dairou, J and MacGregor, S and Puthireddy, S and Meijer, L and Bhattacharyya, A},
title = {Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 induced pluripotent stem cell-derived neural cells.},
journal = {Disease models & mechanisms},
volume = {19},
number = {6},
pages = {},
doi = {10.1242/dmm.052740},
pmid = {42367034},
issn = {1754-8411},
support = {//School of Medicine and Public Health, University of Wisconsin-Madison/ ; //Wisconsin Alumni Research Foundation/ ; P50HD105353//National Institute of Child Health and Human Development/ ; //Fondation Jérôme Lejeune/ ; //Agence Nationale de la Recherche/ ; //France 2030/ ; //Bpifrance/ ; 848077//HORIZON EUROPE Innovative Europe/ ; 190138295//HORIZON EUROPE European Innovation Council/ ; //University of Wisconsin-Madison/ ; },
mesh = {Humans ; Dyrk Kinases ; *Protein Serine-Threonine Kinases/metabolism/genetics/antagonists & inhibitors ; *Protein-Tyrosine Kinases/metabolism/genetics ; *Down Syndrome/pathology/enzymology/genetics ; *Induced Pluripotent Stem Cells/drug effects/pathology/metabolism/enzymology ; *Neural Stem Cells/drug effects/pathology/metabolism/enzymology ; *Neurons/drug effects/pathology/metabolism/enzymology ; *Gene Dosage/drug effects ; Protein Kinase Inhibitors/pharmacology ; Cell Differentiation/drug effects ; Dioxoles ; Imidazoles ; },
abstract = {Dosage imbalance of dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimer's disease and Parkinson's disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer's disease, for example, but the ability of these inhibitors to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell (iPSC)-derived neural progenitor cells and neurons, in which DYRK1A expression and activity are increased. Our results demonstrated that Leucettinib-21, a potent and selective low-molecular-mass pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 iPSC-derived neural progenitor cells and cortical neurons. Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.},
}

Humans
Dyrk Kinases
*Protein Serine-Threonine Kinases/metabolism/genetics/antagonists & inhibitors
*Protein-Tyrosine Kinases/metabolism/genetics
*Down Syndrome/pathology/enzymology/genetics
*Induced Pluripotent Stem Cells/drug effects/pathology/metabolism/enzymology
*Neural Stem Cells/drug effects/pathology/metabolism/enzymology
*Neurons/drug effects/pathology/metabolism/enzymology
*Gene Dosage/drug effects
Protein Kinase Inhibitors/pharmacology
Cell Differentiation/drug effects
Dioxoles
Imidazoles

@article {pmid42367320,
year = {2026},
author = {Csikos, V and Thyfault, JP and Wilkins, HM},
title = {The impact of exercise on brain mitochondrial health and its relevance to Alzheimer's disease.},
journal = {Brain and environment},
volume = {5},
number = {},
pages = {},
pmid = {42367320},
issn = {3050-5917},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Mounting evidence implicates mitochondrial dysfunction as an upstream driver of AD pathogenesis, contributing to bioenergetic deficits, oxidative stress, impaired calcium homeostasis, and chronic neuroinflammation. Given the high energy demand of the brain, the preservation of mitochondrial function is critical for neuronal health. Physical exercise is recognized for its neuroprotective effects, with growing support that it may attenuate AD progression through enhancing mitochondrial quality control. This review explores how exercise influences key mitochondrial quality control processes in the brain-including mitochondrial-biogenesis, -dynamics, and mitophagy-and how these adaptations counteract AD-related pathologies. We further examine the dual role of reactive oxygen species, the impact of exercise-induced signaling molecules such as brain-derived neurotropic factor, irisin, and insulin-like growth factor 1, and the importance of cardiorespiratory fitness in fostering mitochondrial resilience. Finally, we highlight critical gaps in our understanding of how different exercise modalities uniquely affect brain mitochondria and AD pathology. Collectively, this underscores the potential of exercise as a non-pharmacological strategy to enhance brain mitochondrial health and promote cognitive resilience in aging and AD.},
}

@article {pmid42367372,
year = {2026},
author = {Cabán, M and Brown-Bradley, C and Wetmore, JB and Ottman, R and Siegel, K},
title = {Latinos' beliefs regarding the role played by nonmedical factors in the quality of Alzheimer's disease care: Findings from a NYC community-based sample.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42367372},
issn = {2667-3215},
abstract = {Latinos represent the fastest-growing subpopulation in the United States and are expected to experience the steepest increase in the coming decades in adults 65 and older living with Alzheimer's disease (AD). However, they also have a higher likelihood of delayed diagnosis, greater difficulty in accessing specialist referrals, treatments and support services and have fewer long-term and nursing care options than non-Latino Whites. A New York City community-based sample of Latinos completed qualitative interviews in English (63%) or Spanish (37%). We investigated participants' beliefs regarding Latinos' access to quality AD-related care. Data were coded by three team members using ATLAS.ti and thematic analysis was conducted by the senior qualitative team members. The results are organized along the care continuum from diagnosis through medical, supportive, and long-term care. The data revealed that participants (n = 155) believed a combination of nonmedical factors contributed to Latinos being diagnosed at a more advanced stage of AD and receiving poorer quality of care once diagnosed than non-Latino Whites. These included: limited financial assets, restricted health insurance coverage, cultural values and tendencies, limited availability of providers who understood their background and experiences or spoke Spanish, and to a lesser extent prejudice or discrimination. These findings are important because expectations of poor care may deter care seeking or once diagnosed may influence patients' level of engagement in care and treatment adherence. They have implications for enhancing patient-centered care for Latinos with AD as it emphasizes the incorporation of their perspectives when assessing the quality of care being delivered.},
}

@article {pmid42367689,
year = {2026},
author = {Liu, Y and Zhao, J and Shi, Z},
title = {Anti-Metabotropic Glutamate Receptor 5 Autoimmune Encephalitis with a Typical Alzheimer's Disease Biomarker Profile: A Case of Rapidly Progressive Dementia Unresponsive to Cholinesterase Inhibitors.},
journal = {Case reports in neurology},
volume = {18},
number = {1},
pages = {280-284},
pmid = {42367689},
issn = {1662-680X},
abstract = {INTRODUCTION: The distinction between neurodegenerative and autoimmune causes of rapidly progressive dementia can be challenging, particularly when atypical Alzheimer's disease (AD) biomarkers are present. We present a case of anti-metabotropic glutamate receptor 5 (mGluR5) autoimmune encephalitis (AE) initially misdiagnosed as AD due to concordant clinical, imaging, and biomarker findings.

CASE PRESENTATION: A 51-year-old woman developed progressive memory decline, apathy, and stereotyped paper-folding behavior over 2 years. She was diagnosed with rapidly progressive AD and treated with donepezil and memantine without improvement. Initial workup showed hippocampal neurodegeneration on magnetic resonance imaging/MRS and elevated plasma phosphorylated tau181, tau217, and GFAP - consistent with an AD biomarker profile. Neurological examination later revealed bilateral pyramidal signs. Re-evaluation identified serum anti-mGluR5 antibodies. Treatment with intravenous methylprednisolone and immunoglobulin led to marked improvement in cognition and behavior within 2 weeks.

CONCLUSION: This case demonstrates that anti-mGluR5 AE can manifest with a biomarker profile highly suggestive of AD, leading to prolonged misdiagnosis. It underscores the importance of considering AE in treatment-refractory or atypical dementia, even in the presence of supportive AD biomarkers, and highlights the potential for significant recovery with timely immunotherapy.},
}

@article {pmid42367849,
year = {2026},
author = {Gabal, E and Nguyen, TKO and Kovalenko, T and Gao, H and Rappaport, N and Funk, C and Baloni, P and Trushina, E},
title = {Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.14.732179},
pmid = {42367849},
issn = {2692-8205},
abstract = {Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid42367894,
year = {2026},
author = {Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Fan, F},
title = {Anatomical Identification and Pressure Myography of the Rat Middle Cerebral Artery: A Comprehensive Protocol for Diverse Genetic Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.12.718520},
pmid = {42367894},
issn = {2692-8205},
abstract = {The middle cerebral artery (MCA) is critical for cerebral blood flow autoregulation and a primary site of cerebrovascular pathology in stroke, Alzheimer's disease, and vascular dementia. Pressure myography enables precise ex vivo quantification of MCA structure and function, but requires accurate anatomical identification and careful vessel handling to ensure reproducibility across diverse rat genetic models. This chapter provides a comprehensive, step-by-step protocol for isolating and cannulating the rat MCA M2 segment for pressure myography. We detail precise anatomical landmarks to ensure consistent vessel selection across strains. The protocol includes optimized solutions, cannulation techniques, and pressure protocols validated across multiple rat models, including transgenic (TgF344-AD), diabetic (T2DN), consomic (SS.5 [BN] , FHH.1 [BN]), and genome-edited strains. Extensive troubleshooting notes address common technical challenges, including vessel viability assessment, pressure integrity, and strain-specific autoregulatory ranges. This methodology bridges molecular genetic findings with fundamental cerebrovascular physiology, enabling researchers to characterize myogenic reactivity, passive mechanical properties, and structural remodeling in rat models of cerebrovascular disease.},
}

@article {pmid42367902,
year = {2026},
author = {Huang, Y and Xie, X and Fernaine, M and Li, Z and Wang, X and Wang, J},
title = {Subregion-Specific Input Organization of Prefrontal-Projecting Basal Forebrain Cholinergic Neurons and Weakened Striatal-NBM Inhibitory Transmission in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731708},
pmid = {42367902},
issn = {2692-8205},
abstract = {UNLABELLED: Basal forebrain cholinergic neurons regulate cortical activity and cognition and are vulnerable in Alzheimer's disease (AD). However, the upstream circuits controlling projection-defined basal forebrain cholinergic populations remain incompletely understood. Here, we used projection-specific rabies-mediated monosynaptic tracing to map whole-brain inputs to medial prefrontal cortex (mPFC)-projecting cholinergic neurons in the nucleus basalis of Meynert (NBM) and horizontal limb of the diagonal band of Broca (HDB). mPFC-projecting NBM and HDB cholinergic neurons received broad but distinct input patterns. NBM cholinergic neurons received prominent striatal input, including input from D1-expressing medium spiny neurons, whereas HDB cholinergic neurons showed proportionally weaker striatal input and broader non-striatal contributions. Optogenetic electrophysiology confirmed that striatal inputs formed monosynaptic GABAergic inhibitory synapses onto NBM cholinergic neurons. This inhibitory transmission was weakened in 5xFAD mice, indicating impairment of a striatal-NBM inhibitory circuit in an AD mouse model. Together, these findings reveal subregion-specific input organization of mPFC-projecting basal forebrain cholinergic neurons and identify a vulnerable striatal-NBM circuit in AD.

HIGHLIGHTS: Whole-brain rabies tracing reveals input organization of mPFC-projecting BF cholinergic neurons.NBM and HDB cholinergic neurons projecting to mPFC show distinct monosynaptic input profiles.Striatal D1-MSNs are a major input source to mPFC-projecting NBM cholinergic neurons.Striatal-NBM inhibitory transmission is functionally impaired in 5xFAD mice.},
}

@article {pmid42367939,
year = {2026},
author = {Montenegro, P and Kim, R and Zedek, M and Chicas, M and Yeh, P and Yeh, H},
title = {Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731622},
pmid = {42367939},
issn = {2692-8205},
abstract = {Although prenatal alcohol exposure (PAE) has been proposed as an early-life risk factor for Alzheimer's disease and related dementias (AD/ADRD), the mechanistic underpinnings are underexplored. Mutations in the Presenilin genes contribute to AD/ADRD, with Presenilin 1 acting as the catalytic subunit of the γ-secretase complex responsible for cleaving Notch and amyloid precursor protein (APP). We hypothesized that PAE disrupts γ-secretase activity during brain development, which persists and is associated with behavioral deficits later in life. Pregnant wild-type B6129 and 3xTg-AD mice were fed an ethanol-containing liquid diet during gestational days 13-15. From birth to adulthood, PAE increased APP C-terminal fragments and Notch intracellular domain (NICD) levels in cortical lysates. These changes were associated with impaired hippocampal-dependent learning and memory in wild-type mice at 3 and 6 months of age and exacerbated behavioral deficits in 4-month-old 3xTg-AD mice. Our findings provide the first mechanistic insight linking PAE to AD/ADRD vulnerability.},
}

@article {pmid42367943,
year = {2026},
author = {Ee, R and Amouzgar, M and Afaghani, J and Vijayaragavan, K and Cannon, BJ and Mrdjen, D and Tebaykin, D and Spence, A and Sant, C and Aley, D and Guo, Z and Sedov, K and Zafar, F and Montine, KS and Perna, A and Serrano, GE and Beach, TG and Angelo, M and Schüle, B and Corces, MR and Montine, TJ and Bendall, SC},
title = {APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.18.733295},
pmid = {42367943},
issn = {2692-8205},
abstract = {UNLABELLED: Variation in APOE, notably the ε4 allele, profoundly shapes risk and severity of late-onset Alzheimer's disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain.

GRAPHICAL ABSTRACT: APOE4/4 in Alzheimer's disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence.},
}

@article {pmid42367992,
year = {2026},
author = {Haynes, KA and Pandey, RS and Doud, EH and Cope, ZA and Little, GJ and Williams, SP and Nepali, U and Quinney, SK and Nagar, A and Charbe, NB and da Silva, L and Dage, JL and Duong, DM and Seyfried, NT and Sasner, M and Lamb, BT and Oblak, AL and Territo, PR and Carter, GW and Sukoff Rizzo, SJ},
title = {Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.16.731973},
pmid = {42367992},
issn = {2692-8205},
abstract = {INTRODUCTION: Improving the predictive validity of preclinical studies for Alzheimer's disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects.

METHODS: Male and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2aκ isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (Aβ), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment.

RESULTS: chAdu produced sex-dependent changes in Aβ, including increased plasma Aβ42:40 and reductions in brain Aβ which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of Aβ-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment.

DISCUSSION: These findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.},
}

@article {pmid42368021,
year = {2026},
author = {Wang, R and Maloney, B and Nho, K and Beck, JS and Counts, SE and Lahiri, DK},
title = {MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.11.731747},
pmid = {42368021},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide plaques and neurofibrillary tangles from hyperphosphorylated tau, though factors linking amyloid and tau pathology remain unclear. We investigated whether microRNA-181d-5p (miR-181d) associates with AD-related brain changes and regulates neprilysin and tau. Modeling miR-181d across individuals with no cognitive impairment, mild cognitive impairment, and AD revealed region- and sex-specific associations. Higher miR-181d levels associated with greater AD probability in the temporal lobe and cerebellum, and lower probability in the posterior cingulate cortex of males; miR-181c attenuated these probabilities. SNPs near MIR181 associated with altered entorhinal cortical thickness. In cellular models, miR-181 reduced neprilysin 3'-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs Aβ clearance and elevates tau, contributing to AD. RNA sequencing identified miR-181d-responsive neurodegenerative pathways. These findings identify miR-181 as a regulator of AD-relevant amyloid and tau pathways, providing novel targets.

TEASER: MiRNA-181 is a key regulator of Alzheimer's risk through its effects on neprilysin and tau proteins, a novel potential target.},
}

@article {pmid42368109,
year = {2026},
author = {Dorogan, M and Namballa, HK and Patra, S and Harding, WW},
title = {Recent Advances in Dopamine Receptor Ligands as Chemical Biology Tools.},
journal = {ACS omega},
volume = {11},
number = {24},
pages = {34870-34884},
pmid = {42368109},
issn = {2470-1343},
abstract = {Dopamine receptors (DRs) have been implicated in numerous disorders and diseases (e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, and substance use disorders) and have served as attractive drug targets for these ailments. Despite their potential clinical utility, the development of selective DR ligands has been challenging due to difficulties in selectivity among the DR subtypes as well as other biogenic amine receptors and poor pharmacokinetic properties. The realization of their full potential necessitates continued advancements in DR ligands as investigative tools. This review aims to highlight the recent developments made in the chemical biology of DR ligands (e.g., bivalent ligands, photoactivatable ligands, photoswitchable probes, and fluorescent probes).},
}

@article {pmid42368154,
year = {2026},
author = {Sha, J and Geng, Z and Qi, S and Du, L and Hu, Q and Cai, M and Chen, D and Chen, Y and Liu, S and Song, H and Ling, T and Chang, C and Bai, B},
title = {Characterization of the Anti-Alzheimer Drug Lecanemab by Mass Spectrometry.},
journal = {ACS omega},
volume = {11},
number = {24},
pages = {35903-35912},
pmid = {42368154},
issn = {2470-1343},
abstract = {Lecanemab is a humanized mouse monoclonal antibody that is clinically approved for treating Alzheimer's disease by binding to amyloid oligomers, protofibrils, and insoluble fibrils to clear Aβ aggregates in the brain. Although therapeutically effective, lecanemab is also associated with side effects, and its quality might vary among different batches due to impurities and modifications. Herein, we provide proteomics, intact protein, and N-glycoproteomics analyses of lecanemab by liquid chromatography coupled with mass spectrometry. We found that the lecanemab drug is highly pure but displays two major peaks in the chromatography and contains many species with close molecular weights around 150 kDa under mass spectrometric scanning. There were 40 N-glycans found at the N304 site of lecanemab of the heavy chain. Further analysis by MSFragger identified other modifications and additional glycosites. These results provide data as resource for the identification of critical quality attributes of lecanemab in studying its therapeutic effectiveness, side effects, and possible batch-to-batch qualities.},
}

@article {pmid42368190,
year = {2026},
author = {Meng, J and Deng, ZJ and Zhang, J and Yu, W and Wu, X and Lei, P},
title = {Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.},
journal = {Life medicine},
volume = {5},
number = {3},
pages = {lnag016},
pmid = {42368190},
issn = {2755-1733},
abstract = {Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed "tauopathy", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the "atypical" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.},
}

@article {pmid42368192,
year = {2026},
author = {Lei, S and Huang, Z and Wang, W and Meng, Y},
title = {Depletion of microglial compensation in glial network: Disease-associated response dynamics in the revised amyloid hypothesis.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {131-142},
pmid = {42368192},
issn = {2770-730X},
abstract = {Microglia mount coordinated, stage-dependent compensatory programs in response to early amyloid β (Aβ) accumulation that preserve proteostasis and neuronal integrity during preclinical Alzheimer's disease. We propose the "microglial compensation-depletion" framework that describes a distributed compensatory network whose failure constitutes a mechanistic tipping point. Once compensatory capacity falls below a critical threshold, positive-feedback loops amplify irreversible pathology, eventually leading to cognitive decline. Integrating single-cell transcriptomics, chromatin accessibility, and genetic evidence from human cohorts and animal models, we synthesize evidence for stage-dependent microglial transitions and for glial interactions that shape resilience or vulnerability. The microglial compensation-depletion framework in the revised amyloid hypothesis is a multiscale, dynamical perspective and highlights potential strategies for modeling and clinical intervention. Intercellular ligand-receptor networks may provide quantitative substrates for defining glial-state patterns and even identifying key communication axes that delineate transitions. For example, microglial triggering receptor expressed on myeloid cells 2 (TREM2)-apolipoprotein E (APOE) signaling exemplifies an intercellular axis that modulates microglial phenotype and Aβ handling. Clinically, in vivo imaging and biofluid biomarkers may offer potential means to track glial functional reserve and to detect approaching tipping points.},
}

@article {pmid42368193,
year = {2026},
author = {Li, S and Ji, X and Walczak, P and Boltze, J},
title = {Novel approaches for neuroprotection: Focus on neurodegenerative and ischemic central nervous system diseases.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {95-98},
pmid = {42368193},
issn = {2770-730X},
}

@article {pmid42368196,
year = {2026},
author = {Liu, Y and Luo, S and Zhang, H and Lin, J and Xiao, H and Ma, Y and Ye, D and Cong, L and Li, Y},
title = {Research status and trends of Piezo1 and brain: A bibliometric analysis.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {178-187},
pmid = {42368196},
issn = {2770-730X},
abstract = {AIM: As a key mechanosensitive ion channel, Piezo1 plays a critical role in various brain functions, including the regulation of cerebral blood flow and neuronal excitability, by converting mechanical stimuli into biochemical signals. This study conducted a quantitative and visual analysis of the global research landscape, evolving trends, and knowledge structure of Piezo1 in brain research from 2014 to 2025.

METHODS: A comprehensive bibliometric analysis was conducted. We conducted a comprehensive literature search in the Web of Science and Scopus databases for publications focusing on Piezo1 in the brain from January 1, 2014, to October 1, 2025. After rigorous screening and deduplication, 173 studies were finally included in the analysis. Scientometric indicators and visualization tools were employed to examine publication trends, core journals, productive authors and countries, and keyword co-occurrence networks.

RESULTS: Annual publication output in this field increased rapidly, with an average growth rate of 34.48%. Research publications are concentrated in a limited number of high-impact journals, reflecting a strong academic focus. Keyword analysis identified core research hotspots, including "mechanotransduction," "ion channels," and "neuroinflammation," highlighting the pivotal role of Piezo1 in cerebral hemodynamics and neuropathology. Intellectual structure analysis revealed that foundational mechanistic studies dominate the current literature.

DISCUSSION: Although basic research on Piezo1 in the brain has advanced significantly, studies directly targeting its clinical translation are limited. These findings highlight a clear knowledge gap between mechanistic understanding and therapeutic applications. Future research should prioritize bridging this gap by fostering interdisciplinary collaborations that translate fundamental insights into clinical validation, thereby accelerating the development of Piezo1 as a novel therapeutic target for neurological disorders.},
}

@article {pmid42368200,
year = {2026},
author = {Chong, AEY and Sasmita, AO and Koh, RY and Ling, APK},
title = {Neuroprotective effects of ursodeoxycholic acid in Parkinson's disease and Alzheimer's disease.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {2},
pages = {111-130},
pmid = {42368200},
issn = {2770-730X},
abstract = {Neurodegenerative diseases (NDDs) including Parkinson's disease (PD) and Alzheimer's disease (AD), are progressive disorders characterised by shared pathological features, including mitochondrial dysfunction, oxidative stress, apoptosis, neuroinflammation, neurotoxic protein buildup, and impaired protein clearance. Current treatments can only relieve disease symptoms but cannot delay the disease progression. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid traditionally used in hepatology, has recently gained attention for its neuroprotective properties. This review critically evaluates UDCA's mechanisms of action, including the restoration of mitochondrial function, inhibition of apoptosis, reduction of oxidative stress and neuroinflammation, and enhancement of autophagy in both PD and AD models. In vitro and in vivo studies demonstrate UDCA's ability to preserve neuronal integrity, improve motor and cognitive outcomes, and reduce toxic protein aggregates. Although early-phase clinical trials, such as the UDCA for Parkinson's (UP) study in PD, show promising mitochondrial benefits and safety, clinical evidence in AD remains limited. Future directions emphasise the need for large-scale trials, personalised medicine, improved central nervous system (CNS) delivery strategies, or dietary interventions to modulate UDCA production from the gut microbiome. While not a first-line treatment, UDCA represents a compelling mitochondrial stabiliser with disease-modifying potential in NDDs.},
}

@article {pmid42368255,
year = {2026},
author = {Zhang, J and Nie, X and Yue, J and Shi, Y},
title = {Feynman Kac Reweighted Schrödinger Bridge Matching for Surface-Based Tau PET Harmonization.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42368255},
issn = {2331-8422},
abstract = {Tau PET imaging is central to tracking Alzheimer's disease progression, but systematic differences between scanners, protocols, and radiotracers across sites introduce nonbiological variability that inflates biomarker variance, reduces sensitivity to disease effects, and can bias downstream clinical assessments. Harmonization methods aim to remove these site-induced shifts while preserving biologically meaningful signal, yet existing approaches struggle when source and target cohorts differ in subgroup composition, risking conflation of site effects with biological variation such as tau-positivity status. We propose the Feynman Kac Reweighted Schröodinger Bridge Matching (FKRSBM) model to address this problem. Rather than routing data through a Gaussian noise prior as in diffusion-based methods, FKRSBM learns a direct stochastic transport process between source and target distributions via entropy-regularized optimal transport. To enforce biologically consistent transport, FKRSBM incorporates a subgroup-aware endpoint proposal derived from a Feynman Kac reweighting of the reference bridge measure, implemented entirely through stratified importance sampling at the data level and requiring no changes to the underlying bridge-matching solver or network architecture. For surface-based neuroimaging, FKRSBM employs a spherical convolutional backbone operating on cortical meshes to perform vertex-level harmonization. We evaluate the method on tau PET SUVR maps, harmonizing PI-2620 data from the HABS-HD cohort into the AV-1451 domain of ADNI. Compared against ComBat, CycleGAN, a diffusion-based method (DF), and unregularized Diffusion Schröodinger Bridge Matching (DSBM), FKRSBM achieves superior distributional alignment, reduced tau-positivity sign mismatch, stronger APOE subgroup alignment, and improved downstream disease classification performance.},
}

@article {pmid42368463,
year = {2026},
author = {Shi, M},
title = {Next-generation TREM2-targeted therapies for Alzheimer's disease: insights and directions from the INVOKE-2 trial.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1837720},
pmid = {42368463},
issn = {1663-4365},
}

@article {pmid42368467,
year = {2026},
author = {Ji, T and Wang, L and Weng, X and Lu, C and Gao, Y and Yu, K and He, J and Shen, X and Gao, X},
title = {Protective effect of baicalein from Pinellia ternate on Alzheimer's disease cell injury: a network pharmacology, molecular docking, and molecular dynamics study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848282},
pmid = {42368467},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) constitutes the primary leading cause of dementia. Pinellia ternata (Thunb.) Breit. is a traditional Chinese herb with unclarified potential therapeutic effects against AD. This study aimed to explore the therapeutic potential and underlying mechanism of Pinellia ternata (Thunb.) Breit. in the treatment of AD.

METHODS: The bioactive components and corresponding targets of Pinellia ternata (Thunb.) Breit. were screened from TCMSP, Herb, and SymMap databases. AD-related targets were retrieved from OMIM, GeneCards, and TTD databases, and key targets were obtained via target intersection analysis. Functional enrichment analyses were performed to identify the main signaling pathways involved in the targets. Core targets and major bioactive components were further screened, and molecular docking as well as dynamics simulations were conducted to verify the binding affinity between key components and core targets. In vitro cell experiments using BV2 cells were implemented to validate the therapeutic effect of the core bioactive component.

RESULTS: A total of 13 bioactive components and 99 corresponding targets of Pinellia ternata (Thunb.) Breit. were identified, and 29 key AD-related targets were screened out through target intersection. Enrichment analysis results showed that these key targets were mainly enriched in neuroactive ligand-receptor interaction and calcium signaling pathways. PTGS2, CASP2, and AKT1 were determined as core therapeutic targets, with β-sitosterol and baicalein identified as the principal bioactive components of Pinellia ternata (Thunb.) Breit. against AD. Molecular docking and dynamics simulations verified the strong binding affinity between baicalein and PTGS2. In vitro experimental results further demonstrated that baicalein pretreatment could relieve the inhibitory effect of Aβ1-42 on BV2 cell proliferation.

DISCUSSION: Pinellia ternata (Thunb.) Breit. exerts therapeutic effects on AD via a synergistic mechanism characterized by multi-component, multi-target, and multi-pathway regulation. The active ingredient baicalein targeting PTGS2 is a crucial material basis for its anti-AD effect. The findings of this study elucidate the potential mechanism of Pinellia ternata (Thunb.) Breit. in AD treatment and provide a reliable theoretical foundation for subsequent in-depth research and clinical exploration of the herb as a therapeutic agent for AD.},
}

@article {pmid42368586,
year = {2026},
author = {Han, M and Wang, N and Song, M and Liu, C and Wu, Y and Yin, J and Jin, L and Jin, W and Gao, Z},
title = {The mechanisms and strategies for Alzheimer's disease prevention: An update.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {6},
pages = {3582-3602},
pmid = {42368586},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses growing global health and socioeconomic challenges due to aging populations and limited therapeutic efficacy. Current treatments, including cholinesterase inhibitors and anti-amyloid monoclonal antibodies, can only delay disease progression without reversing pathology. Emphasizing on prevention, this review provides key updates on advancements in the pathogenesis, diagnosis, and intervention of AD highlighting preventive strategies that can target modifiable risk factors. Key findings underscore the role of managing hypertension and diabetes, optimizing trace elements, vitamins, and regular physical exercise in mitigating the risk of AD. Biomarker-based early diagnosis and emerging therapies provide further support for proactive intervention. Future challenges include the long-term validation of preventive measures and policy-driven funding for large-scale cohort studies. Prioritizing prevention through lifestyle modifications, nutritional balance, and precision medicine is pivotal to reduce the burden of AD in aging societies.},
}

@article {pmid42368893,
year = {2026},
author = {Xie, J and Li, Y and Lu, J and Wang, W and Hou, Y and Huang, Y and Wu, H and Zhou, Y and Li, J},
title = {Mechanisms of electroacupuncture for the treatment of Alzheimer's disease by activating Wnt/β-catenin pathway to improve blood-brain barrier function.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {106-113},
pmid = {42368893},
issn = {2667-2421},
abstract = {AIMS: In this study, we used APP/PS1 mice as a research vehicle to illustrate that electroacupuncture can improve the blood-brain barrier function by activating the Wnt/β-catenin pathway for the treatment of Alzheimer's disease (AD).

METHODS: 18 7-month-old SPF APP/PS1 male double-transgenic mice were selected as AD model mice and randomly divided into model group, electroacupuncture group and donepezil hydrochloride group, with 6 mice in each group, and 6 C57BL/6 J male mice as normal group. After the end of the intervention, the mice in each group were subjected to Morris water maze behavioural test. After the behavioural test, the pathological morphology of hippocampal tissue was observed by HE staining method, Aβ was detected in the hippocampal region of mice by IHC method, the mRNA expression of Axin2 and Dkk1 was detected in hippocampal tissue by Real-time PCR method, and the tight junction protein, Claudin-5, was detected in hippocampal region of mice by Western Blot method. Claudin-5, Occludin protein with active β-catenin, p-GSK3β protein expression in mouse hippocampus by Western Blot.

RESULTS: EA can improve the learning ability of APP/PS1 mice, restore the morphology and structure of the hippocampus, reduce the positive expression of Aβ in the hippocampus, down-regulate the expression of Axin2 and Dkk1 mRNA, and elevate the expression of the tight junction-related proteins, Claudin-5, Occludin with active β-catenin, and p-GSK3β.

CONCLUSION: EA can improve the expression of blood-brain barrier-related molecules in AD mice by regulating the expression of molecules related to the Wnt/β-catenin pathway, which is beneficial to the early treatment of AD.},
}

@article {pmid42368914,
year = {2026},
author = {Zhang, Z and Hu, M and Teng, Z and Mu, Y and Yin, P},
title = {Joint association of a healthy low-carbohydrate diet and frailty with the risk of incident Alzheimer's disease and vascular dementia: a prospective cohort study.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1853648},
pmid = {42368914},
issn = {2296-2565},
mesh = {Humans ; *Dementia, Vascular/epidemiology ; Female ; *Diet, Carbohydrate-Restricted/statistics & numerical data ; *Frailty/epidemiology ; Male ; Aged ; *Alzheimer Disease/epidemiology ; Prospective Studies ; Risk Factors ; United Kingdom/epidemiology ; Middle Aged ; Incidence ; },
abstract = {BACKGROUND: We aimed to investigate the associations between a healthy low-carbohydrate diet (HLCD) score, frailty and their combined effects with the risk of Alzheimer's disease (AD) and vascular dementia (VD).

METHODS: This cohort study analyzed 157,465 participants from the UK Biobank. The HLCD score was calculated based on the intake of total carbohydrates, vegetable proteins, and unsaturated fats, while frailty was assessed using a frailty index incorporating a wide range of biological systems and physical capacities, including sensory functions, mental health, and systemic comorbidities, which was developed and validated by the UK Biobank. Cox proportional hazards models and restricted cubic splines were employed for analysis.

RESULTS: Higher HLCD scores were significantly associated with a lower risk of AD (Q4 vs. Q1: HR = 0.66; 95% CI: 0.52-0.84) and VD (Q4 vs. Q1: HR = 0.54; 95% CI: 0.39-0.75). Frailty was identified as a risk factor for both dementia subtypes. Compared with the nonfrail group, the adjusted HRs for AD were 1.33 (1.08-1.65) for prefrail and 1.62 (1.33-1.98) for frail groups, while the adjusted HRs for VD were 1.61 (1.20-2.17) for prefrail and 2.46 (1.89-3.20) for frail groups. In the joint association analysis, adherence to a high-quality HLCD effectively mitigates the increased risk of AD attributed to frailty. Frail individuals with high HLCD scores exhibited a significantly lower risk of AD compared to those with low HLCD scores (HR = 0.63, 95% CI: 0.47-0.85). For VD, the protective benefit was more pronounced in the prefrailty stage (HR = 0.52, 0.35-0.79) than in the frail stage (HR = 0.83, 0.59-1.17).

CONCLUSIONS: High adherence to the HLCD was associated with a lower risk of AD and VD, whereas frailty independently was associated with an increased the risk of AD and VD. Adherence to a high-quality HLCD effectively mitigates the increased risk associated with frailty. Promoting healthy low-carbohydrate diets may serve as a robust strategy to enhance cognitive resilience in older populations.},
}

Humans
*Dementia, Vascular/epidemiology
Female
*Diet, Carbohydrate-Restricted/statistics & numerical data
*Frailty/epidemiology
Male
Aged
*Alzheimer Disease/epidemiology
Prospective Studies
Risk Factors
United Kingdom/epidemiology
Middle Aged
Incidence

@article {pmid42368974,
year = {2026},
author = {Murden, RJ and Tian, G and Qiu, D and Risk, BB},
title = {Probabilistic Joint and Individual Variation Explained (ProJIVE) for Data Integration.},
journal = {Journal of computational and graphical statistics : a joint publication of American Statistical Association, Institute of Mathematical Statistics, Interface Foundation of North America},
volume = {},
number = {},
pages = {},
pmid = {42368974},
issn = {1061-8600},
abstract = {Collecting multiple types of data on the same set of subjects is common in modern scientific applications including genomics, metabolomics, and neuroimaging. Joint and Individual Variation Explained (JIVE) seeks a low-rank approximation of the joint variation between two or more sets of features captured on common subjects and isolates this variation from that unique to each set of features. We develop an expectation-maximization (EM) algorithm to estimate a probabilistic model for the JIVE framework. The model extends probabilistic PCA to multiple datasets. Our maximum likelihood approach simultaneously estimates joint and individual components, which can lead to greater accuracy compared to other methods. We apply ProJIVE to measures of brain morphometry and cognition in Alzheimer's disease. ProJIVE learns biologically meaningful sources of variation, and the joint morphometry and cognition subject scores are strongly related to more expensive existing biomarkers. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Code to reproduce the analysis is available at https://github.com/thebrisklab/ProJIVE.},
}