@article {pmid42308717,
year = {2026},
author = {Srimaharaj, W},
title = {Synaptic regulatory flux dynamics: Stiffness and homeostatic failure in Alzheimer's disease.},
journal = {Computer methods and programs in biomedicine},
volume = {285},
number = {},
pages = {109509},
doi = {10.1016/j.cmpb.2026.109509},
pmid = {42308717},
issn = {1872-7565},
abstract = {BACKGROUND: Traditional electroencephalographic analysis in Alzheimer Disease focuses on spectral slowing, a terminal phenotype that overlooks the preceding functional failure of homeostasis. This study introduces Synaptic Regulatory Flux Dynamics (SRFD), a computational framework that models the EEG signal as a physical trajectory governed by the interplay between Excitatory Drive (E) and Regulatory Flux (R).

METHODS: Resting state EEG recordings from 88 participants (36 CE, 23 Frontotemporal Dementia [FTD], and 29 Cognitively Normal [CN]) were analyzed. The study derived novel biophysical metrics, including Instantaneous Homeostatic Error (IHE) and the Synaptic Stiffness Index (SSI), to assess the integrity of the excitation inhibition (E/I) balance.

RESULTS: It found that the AD cohort exhibited a statistically significant elevation in Mean IHE compared to controls (0.557vs0.535; p=0.0115), indicating a systemic failure of inhibitory interneurons to clamp excitatory transients. This flux decoupling was accompanied by a reduced Synaptic Stiffness Index (p=0.011), predominantly affecting posterior beta band networks. Furthermore, the framework successfully differentiated the metabolic silence of AD from the high energy, disorganized hyperexcitability of FTD.

CONCLUSION: Synaptic Regulatory Flux Dynamics provides a noninvasive, mechanistic biomarker of synaptic fragility that precedes gross atrophy. By evaluating the loss of regulatory stiffness, this framework offers a functional window into the early pathophysiology of neurodegeneration, potentially enhancing early detection and therapeutic monitoring.},
}

@article {pmid42308766,
year = {2026},
author = {Kam, MK and Kim, JW and Choi, JY and Koh, YH and Jo, C},
title = {HSP90 is involved in curcumin-mediated inhibition of tau aggregation.},
journal = {Biochemical and biophysical research communications},
volume = {829},
number = {},
pages = {154140},
doi = {10.1016/j.bbrc.2026.154140},
pmid = {42308766},
issn = {1090-2104},
abstract = {Tau aggregation in neurons is a pathological hallmark of Alzheimer's disease (AD). The development of therapeutic drugs that inhibit tau aggregation in tauopathies, including AD, remains challenging. Herein, we developed a tau self-interaction reporter system using split Nanoluciferase (Tau-NLuc) in which luciferase activity is restored by the self-assembly of split Nanoluciferases following self-interaction between tau proteins. Curcumin (CCM), a phenolic organic compound, significantly reduced luciferase activity in the Tau-NLuc system, including mutant tau forms such as S396/404E and P301L, which are known aggregation-prone tau forms, suggesting that CCM may act as a potential inhibitor of tau aggregation. CCM did not alter the protein levels of phosphorylated tau as well as total tau, indicating that the reduction in luciferase activity by CCM did not originate from tau degradation, but rather from tau aggregation inhibition. Of note, CCM significantly increased heat shock protein (HSP) 90 dimer. The reduced luciferase activity in the Tau-NLuc system by CCM was recovered by knockdown of the HSP90 gene using a siRNA specific for HSP90 or treatment of an inhibitor of HSP90 NCT-58, supporting the involvement of HSP90. Intriguingly, hexahydrocurcumin (HHC), a derivative of CCM, did not reduce luciferase activity, nor did it induce the formation of the HSP90 dimer, suggesting that HSP90 dimer formation may contribute to the CCM-mediated inhibition of tau aggregation. Taken together, the results demonstrate that CCM inhibits tau aggregation with the involvement of HSP90, providing novel insights into the development of therapeutic strategies for AD.},
}

@article {pmid42308924,
year = {2026},
author = {Pacheco-Sánchez, B and López-Gambero, AJ and Gavito, AL and Rivera, P and Suárez, J and Sanjuan, C and Nilsson, P and Tambaro, S and de Fonseca, FR},
title = {D-chiro-inositol modulates brain insulin-related signaling and reduces amyloid burden, neuroinflammation and cognitive decline in preclinical models of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119629},
doi = {10.1016/j.biopha.2026.119629},
pmid = {42308924},
issn = {1950-6007},
abstract = {Brain metabolic dysregulation and insulin-related signaling are increasingly recognized as contributing factors in Alzheimer's disease (AD) pathogenesis, disrupting amyloid-beta (Aβ) proteostasis and exacerbating neuroinflammation, and synaptic failure. However, current therapies yield inconsistent results due to a singular focus on specific targets, bioavailability and safety risks. D-chiro-inositol (DCI) is a natural compound with insulin-mimetic properties that has previously shown promising anti-inflammatory and neuroprotective results. This study investigated the neuroprotective efficacy of DCI using a tripartite approach: physiologically relevant primary neurons derived from App[NL-G-F] knock-in mice, human hAPPswe SH-SY5Y cells, and the aggressive 5xFAD mouse model of AD. Toxicity, pharmacokinetic and pharmacodynamic profiling established DCI's safety and its ability to acutely improve systemic glucose handling. In vitro, DCI enhanced basal AKT and insulin receptor activation and modulated glycogen synthase kinase-3 beta (GSK-3β) activation, a kinase linked to amyloid precursor protein (APP) processing. This modulation was accompanied by reduced secretion of toxic Aβ42 species, preservation of neuronal integrity as determined by MAP2 immunostaining, and decreased overall APP protein levels. In vivo, chronic oral DCI administration significantly reduced hippocampal amyloid burden and promoted a shift in microglia from a reactive to a surveilling phenotype, with stronger effects in females. Notably, while DCI resolved microglial reactivity, astrogliosis remained largely unaffected, suggesting a cell-specific immunometabolic mechanism. These improvements translated into rescued recognition memory and normalized disinhibited risk-assessment behavior, indicative of restored hippocampal function. Collectively, DCI acts as a multi-modal agent by modulating insulin-related signaling, downregulating amyloid burden and attenuating neuroinflammation, making it an orally bioavailable candidate for AD therapy.},
}

@article {pmid42309020,
year = {2026},
author = {Milà-Alomà, M and Hausle, I and Petersen, KK and Thropp, P and Schindler, SE and Tosun, D and , },
title = {The time interval from amyloid to tau PET positivity varies by age, sex and APOE-ε4 status.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100622},
doi = {10.1016/j.tjpad.2026.100622},
pmid = {42309020},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials.

OBJECTIVES: To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events ("amyloid-tau time interval"), relate to symptom onset and clinical progression, and to assess the effects of APOE-ε4 status and sex on these associations.

DESIGN: This analysis used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS).

SETTING: The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center observational cohort.

PARTICIPANTS: This study included participants with at least one positive amyloid PET scan (ADNI n = 792; HABS n = 104) or at least one positive tau PET scan (ADNI n = 212; HABS n = 48). All participants had information on sex, APOE-ε4 status, and longitudinal cognitive assessments.

MEASUREMENTS: We examined the influence of APOE-ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline, as measured by CDR-SB, over five years following symptom onset according to estimated biomarker positivity age and amyloid-tau time interval. Additional models included interaction terms with sex or APOE-ε4 status.

RESULTS: The amyloid-tau time interval varied markedly between individuals and was shorter in APOE-ε4 carriers, women, and those with older age at amyloid PET positivity. APOE-ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time to symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset, were not influenced by the amyloid-tau time interval.

CONCLUSIONS: After becoming amyloid PET positive, APOE-ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.},
}

@article {pmid42309126,
year = {2026},
author = {Mehmood, A and Shah, AZ and Martinez Juarez, JA and Liu, X and Jiang, H and Wang, X},
title = {Novel aptamers targeting heparan sulfate for delivery of RNA therapeutics in Alzheimer's disease.},
journal = {Progress in biomedical engineering (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/2516-1091/ae7eb9},
pmid = {42309126},
issn = {2516-1091},
abstract = {Heparan sulfate (HS) proteoglycans are abundant, sulfation-patterned glycosaminoglycans on brain cells and the neurovascular unit that interact with amyloid-β (Aβ) and tau, aggregate and propagate proteopathic species, and modulate cellular uptake pathways. Aptamers are short, chemically synthesized single-stranded nucleic acids that fold to form high-affinity ligands. Novel aptamers bind specific HS motifs for targeting ligands to deliver RNA therapeutics (siRNA, antisense oligonucleotides, mRNA, RNA aptamer-cargo hybrids) into the brain and diseased cells in Alzheimer's disease (AD). We cover diagnostic aptamers, SELEX approaches adapted for glycans and HS, chemistry, optimization (AI/machine-learning-enabled design), novel therapeutic applications, delivery vehicles and conjugation strategies, catalytic aptamers/ribozymes, and challenges for clinical translation. We propose a workflow-in-silico HS motif mapping and machine learning (ML)-guided sequence design through microfluidic/in-vivo SELEX, site-specific chemical modification for nuclease resistance and blood-brain barrier (BBB) transcytosis, to scalable GMP manufacture. Aptamer-HS technology could enable the precision delivery of RNA therapeutics in AD.},
}

@article {pmid42309176,
year = {2026},
author = {Ferreira, HG and Losada-Baltar, A and Márquez-González, M and Vieira da Silva Falcão, D and Cavalcante da Silva, IK and Dos Santos Oliveira Marques Dantas, J},
title = {Cultural Adaptation and Psychometric Properties of the Caregiving Ambivalence Scale for Brazilian Family Caregivers.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/07317115.2026.2689613},
pmid = {42309176},
issn = {1545-2301},
abstract = {OBJECTIVES: Culturally adapt and validate the Caregiving Ambivalence Scale (CAS) for Brazil.

METHODS: Two independent translations and back-translations were conducted. Conceptual, cultural, and idiomatic equivalence were evaluated (Fleiss' Kappa = 1.0). The Brazilian CAS, a sociodemographic questionnaire, the Depression Anxiety and Stress Scale -21 were administered online to 111 family caregivers of people with Alzheimer's across Brazil.

RESULTS: Parallel Analysis and an Exploratory Factor Analysis indicated a single empirical dimension with excellent fit indices (χ[2] = 4.921; df = 5, p = .430; CFI = 0.999; TLI = 1.000; RMSEA = 0.000). The CAS was significantly associated with depression (β = 0.589), stress (β = 0.653), and anxiety (β = 0.455) when controlling for sociodemographic variables.

CONCLUSIONS: The Brazilian version of CAS is still in the early stages of validation, but demonstrated good psychometric properties and equivalence to the original instrument.

CLINICAL IMPLICATIONS: The Brazilian version of CAS has the potential to support interventions to promote caregivers' mental health.},
}

@article {pmid42309243,
year = {2026},
author = {Muralidhara, M and Vismaya, and Lalith Kumar, V},
title = {Ayurvedic Herbs as neurogenesis modulators: Current understanding on their potential therapeutic relevance in enhancing neuroplasticity and cognition in aging and neurodegeneration.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106204},
doi = {10.1016/j.neuint.2026.106204},
pmid = {42309243},
issn = {1872-9754},
abstract = {Ayurvedic medicine, an ancient Indian health system, promotes a category of Ayurvedic herbs (AH) known as Medhya Rasayanas (nootropic rejuvenators) for cognitive enhancement and neuroprotection. Currently, AH are increasingly being studied for their potential to boost neuroplasticity and neurogenesis, as they can stimulate the growth of new neurons, improve the complexity of existing ones, and support cognitive resilience. Recent evidence-based research suggests the potential to use these AH and their formulations to develop new therapies for addressing cognitive decline during aging and neurodegenerative disorders (NDD). Neurogenesis is known to be compromised in mild cognitive impairment (MCI) and is impaired early in animal models of Alzheimer's disease (AD), suggesting that rescuing neurogenesis may restore hippocampal plasticity and attenuate neuronal vulnerability and memory loss. Several AH, including Brahmi (Bacopa monnieri), Gotu Kola (Centella asiatica), Ashwagandha (Withania somnifera), Shankhapushpi (Convolvulus pluricaulis), Guduchi (Tinospora cordifolia), and Yashtimadhu (Glycyrrhiza glabra), are well recognized for their cognitive-enhancing and neuroprotective properties. Further, in chronic stress models, the neurogenic effects of AH are proposed to be mediated by mechanisms including antioxidant and anti-inflammatory effects, modulation of neurotransmitters, and effects on the gut microbiota. Neurotrophins (particularly brain-derived neurotrophic factor -BDNF) are important mediators of neuroplasticity as they modulate multiple processes, including synaptic plasticity, axonal and dendritic growth, spine morphogenesis, and neurogenesis. BDNF is compromised in depression and recovered by conventional antidepressants. The antidepressant-like effects of AH are associated with the reversal of chronic stress-induced impairment in neuroplasticity, most notably through up-regulation of BDNF, activation of downstream signaling pathways, and increased neurogenesis in the hippocampus and/or prefrontal cortex. This review summarizes current developments regarding AH's propensity to enhance neuronal plasticity and its therapeutic role as a modulator of neurogenesis. It also emphasizes the importance of using them as adjuvant therapy to attenuate cognitive deficits associated with aging and neurodegeneration.},
}

@article {pmid42309369,
year = {2026},
author = {Zhang, H and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {P1642-1, a novel pancreatic polypeptide analogue, ameliorates cognitive impairment in 5×FAD mice and is associated with enhanced PINK1/Parkin-related mitophagy.},
journal = {Peptides},
volume = {},
number = {},
pages = {171501},
doi = {10.1016/j.peptides.2026.171501},
pmid = {42309369},
issn = {1873-5169},
abstract = {Currently, few pharmacological treatments are available for Alzheimer's disease (AD). However, gut-brain peptides, especially pancreatic polypeptide (PP) analogues, have shown promise. PP analogues have been reported to cross the blood-brain barrier and activate neuropeptide Y4 receptor (NPY4R) in the brain, thereby ameliorating AD-related cognitive deficits. P1642-1 is a novel PP analogue, but its role and mechanism in AD remain unexplored. This study utilized 5×FAD mice as a model to assess the effects of P1642-1 on cognitive dysfunction and its underlying mechanisms, while an Aβ25-35-induced cellular model was used to provide complementary mechanistic support. The findings revealed that administration of P1642-1 significantly ameliorated cognitive deficits, alleviated neuronal injury, decreased β-amyloid (Aβ) accumulation, and attenuated mitochondrial damage in the hippocampus of 5×FAD mice. These improvements were accompanied by enhanced mitophagy, as evidenced by upregulation of the PINK1/Parkin axis, increased LC3-II, and decreased p62 levels. In the Aβ25-35-induced cellular AD model, P1642-1 also exerted neuroprotective effects and was associated with the regulation of PINK1/Parkin-related mitophagy. Molecular dynamics simulation suggested that P1642-1 may interact with NPY4R, although receptor expression in hippocampal neurons was not directly verified in the present study. In conclusion, our study suggests that the novel PP analogue P1642-1 ameliorates cognitive impairment in 5×FAD mice and is associated with enhanced PINK1/Parkin-related mitophagy. These findings provide experimental support for further investigation of P1642-1 as a potential therapeutic candidate for AD.},
}

@article {pmid42309609,
year = {2026},
author = {Mia, M and Dutta, A and Hossain, MM and Adhikari, J and Rahman, MM and Shibly, AZ},
title = {Exploring the neuroprotective, antioxidant, and anti-amyloid effects of Ganoderma lucidum compounds in Alzheimer's disease: insights from experimental and computational approaches.},
journal = {Journal, genetic engineering & biotechnology},
volume = {24},
number = {2},
pages = {100706},
pmid = {42309609},
issn = {2090-5920},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation and oxidative stress, with limited effective therapeutic options. This study evaluated the antioxidant, neuroprotective, and anti-amyloidogenic potential of Ganoderma lucidum, medicinal mushroom rich in bioactive compounds, including triterpenoids and sterols. Antioxidant activity was assessed using the DPPH assay, and neuroprotective effects were examined in Caenorhabditis elegans models (N2 and CL4176). The anti-Aβ potential of selected bioactive compounds was investigated through molecular docking, molecular dynamics simulations, and MM/GBSA analysis, along with ADMET predictions. The extract exhibited strong antioxidant effects, achieving 96.3% scavenging at 0.25 mg/mL. In C. elegans, treatment enhanced survival under oxidative stress by 25% at 0.5 mg/mL (p < 0.01) and delayed Aβ-induced paralysis, with 17.82% of worms remaining active at 68 h. Docking studies identified Epoxyganoderiol C (-7.8 kcal/mol), 5,6-Dihydroergosterol (-7.9 kcal/mol), and Ganoderiol A (-7.7 kcal/mol) as potent Aβ inhibitors, stabilized in molecular dynamics simulations with favorable RMSD, RMSF, Rg, and SASA profiles. MM/GBSA analysis confirmed strong binding affinities for 5,6-Dihydroergosterol, Epoxyganoderiol C, and Ganoderiol A against Aβ, with ΔG_bind values of - 71.66, -56.42, and - 45.45 kcal/mol, respectively. ADMET predictions indicated good drug-likeness, high gastrointestinal absorption, and no toxicity risks. In conclusion, G. lucidum extract demonstrated potent antioxidant and neuroprotective effects, while its bioactive key compounds-Epoxyganoderiol C, 5,6-Dihydroergosterol, and Ganoderiol A-showed favorable binding affinity and stability with Aβ, along with acceptable pharmacokinetic profiles. These findings suggest that G. lucidum and its bioactive constituents may serve as promising natural candidates for AD therapy.},
}

@article {pmid42309984,
year = {2026},
author = {Mundada, NS and Sadeghpour, N and McGrew, E and Tucker, HL and Nasrallah, IM and Das, SR and Wolk, DA and Yushkevich, PA and Brown, CA and Wisse, LEM},
title = {Vulnerability of anterior medial temporal lobe subregions to early tau-related neurodegeneration in Alzheimer's disease: Converging evidence from tau-PET and plasma p-tau217.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71571},
doi = {10.1002/alz.71571},
pmid = {42309984},
issn = {1552-5279},
support = {AF-1010833//Alzheimerfonden/ ; R01-AG072796//National Science Foundation/ ; R01-AG056014//Foundation for the National Institutes of Health/ ; AACSF-23-1152241/ALZ/Alzheimer's Association/United States ; R01-AG070952/AG/NIA NIH HHS/United States ; 20210690//Crafoordska Stiftelsen/ ; //MultiPark/ ; //Greta and Johan Kockska Foundation/ ; 2022-00900//Swedish Research Council/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; *tau Proteins/blood/metabolism ; Positron-Emission Tomography ; Female ; Male ; *Temporal Lobe/diagnostic imaging/pathology/metabolism ; Aged ; Magnetic Resonance Imaging ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; Phosphorylation ; },
abstract = {INTRODUCTION: The anterior medial temporal lobe (MTL), including the entorhinal cortex (ERC) and Brodmann area 35 (BA35), is among the earliest cortical sites of tau pathology in Alzheimer's disease (AD), yet conventional image segmentation methods poorly capture these regions.

METHODS: We applied an automated segmentation approach using an extended Automatic Segmentation of Hippocampal Subfields (ASHS) atlas, including anterior MTL subregions, in 448 Pennsylvania Alzheimer's Disease Research Center participants with magnetic resonance imaging, tau positron emission tomography (PET) (n = 199), and/or plasma phosphorylated tau 217 (p-tau217) (n = 377). Amyloid beta (Aβ) positivity was defined using PET or plasma.

RESULTS: Tau-PET showed an anterior-posterior gradient, with highest uptake in BA35, ERC, and anterior hippocampus. Increased MTL tau-PET uptake and plasma p-tau217 were associated with cortical thinning localized to BA35 and ERC, even in cognitively unimpaired Aβ-positive individuals.

CONCLUSIONS: Anterior MTL subregions, especially BA35, show early vulnerability to tau-related neurodegeneration. Extended anterior MTL parcellation improves localization of early tau-associated structural changes and may facilitate biological staging in preclinical AD.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
*tau Proteins/blood/metabolism
Positron-Emission Tomography
Female
Male
*Temporal Lobe/diagnostic imaging/pathology/metabolism
Aged
Magnetic Resonance Imaging
Aged, 80 and over
Amyloid beta-Peptides/metabolism
Phosphorylation

@article {pmid42309986,
year = {2026},
author = {Vidal, V and Farías, G and Delgado, C and Delano, PH and Vergara, RC and Orellana, P and Ossandón, T and Crossley, NA and Gonzalez-Campo, C and Naismith, SL and Gonzalez-Gomez, R and Coronel-Oliveros, C and Ibáñez, A and Wainstein, G and Sanders, RD and Shine, JM and Medel, V},
title = {White matter hyperintensities are associated with locus coeruleus atrophy and astrocytic β2-adrenergic receptor expression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71583},
doi = {10.1002/alz.71583},
pmid = {42309986},
issn = {1552-5279},
support = {AARG-25-1490306/ALZ/Alzheimer's Association/United States ; //Multi-partner consortium to expand dementia research in Latin America [ReDLat/ ; //Fogarty International Center (FIC)/ ; /NH/NIH HHS/United States ; R01s AG075775//National Institutes of Aging/ ; AG057234//National Institutes of Aging/ ; AG082056//National Institutes of Aging/ ; AG083799//National Institutes of Aging/ ; 75N95022C00031/DA/NIDA NIH HHS/United States ; //Rainwater Charitable Foundation-The Bluefield project to cure FTD/ ; //Global Brain Health Institute/ ; 1250091//ANID/FONDECYT/ ; 1210195//ANID/FONDECYT/ ; 1210176//ANID/FONDECYT/ ; 1220995//ANID/FONDECYT/ ; 13240170//ANID/FONDECYT/ ; 11251578//ANID/FONDECYT/ ; ACT210096//ANID/PIA/ANILLOS/ ; ID20I10152//FONDEF/ ; 15150012//ANID/FONDAP/ ; FB210017//Centro Nacional de Inteligencia Artificial CENIA/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology/metabolism/diagnostic imaging ; *White Matter/pathology/diagnostic imaging/metabolism ; *Receptors, Adrenergic, beta-2/metabolism ; Male ; Atrophy/pathology ; Female ; *Astrocytes/metabolism/pathology ; Magnetic Resonance Imaging ; Aging/pathology ; Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: White matter hyperintensities (WMHs) are a robust marker of brain aging and dementia risk, typically attributed to vascular pathology. However, impaired astrocytic support may also contribute. The locus coeruleus (LC), which degenerates early in aging and Alzheimer's disease, provides widespread noradrenergic projections that regulate astrocytic metabolism via β2-adrenergic signaling.

METHODS: In a healthy aging cohort (N = 106), we quantified LC volume, WMHs, and voxel-wise (q-WMHs). Associations were tested, controlling for age, cardiovascular risk, and other subcortical nuclei. Spatial partial least squares regression related q-WMH patterns to LC volume, age, and cortical adrenergic receptor expression.

RESULTS: LC volume was independently associated with WMH burden and mediated age-related WMH increases. A latent q-WMH pattern aligned with cortical β2-adrenergic receptor expression and mediated its association with WMH burden.

DISCUSSION: LC degeneration may contribute to regional WMH vulnerability through noradrenergic mechanisms consistent with astrocytic β2-adrenergic signaling, highlighting a potential nonvascular pathway influencing white matter integrity.},
}

Humans
*Locus Coeruleus/pathology/metabolism/diagnostic imaging
*White Matter/pathology/diagnostic imaging/metabolism
*Receptors, Adrenergic, beta-2/metabolism
Male
Atrophy/pathology
Female
*Astrocytes/metabolism/pathology
Magnetic Resonance Imaging
Aging/pathology
Aged
Aged, 80 and over

@article {pmid42309987,
year = {2026},
author = {Veitch, DP and Miller, MJ and Kanoria, S and Aisen, PS and Beckett, LA and Green, RC and Harvey, DJ and Jack, CR and Jagust, W and Lee, EB and Nho, K and Nosheny, R and Okonkwo, OC and Perrin, RJ and Petersen, RC and Mindt, MR and Saykin, AJ and Shaw, LM and Toga, AW and Tosun, D and Landau, SM and Weiner, MW and , },
title = {Contributions of the Alzheimer's Disease Neuroimaging Initiative to advancing AD research: a targeted review of recent publications.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71566},
doi = {10.1002/alz.71566},
pmid = {42309987},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/diagnostic imaging/pathology ; Humans ; *Neuroimaging/methods ; Disease Progression ; Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging/pathology ; Biomarkers ; },
abstract = {The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high-impact studies using ADNI data or biospecimens from 2023 to mid-2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co-pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.},
}

*Alzheimer Disease/diagnostic imaging/pathology
Humans
*Neuroimaging/methods
Disease Progression
Amyloid beta-Peptides/metabolism
Brain/diagnostic imaging/pathology
Biomarkers

@article {pmid42309988,
year = {2026},
author = {Agrawal, S and Yu, L and Leurgans, SE and Li, J and Kapasi, A and Agarwal, P and Dage, JL and Barnes, LL and Bennett, DA and Boyle, P and Schneider, JA},
title = {Hippocampal GFAP in aging: Associations with AD and LATE-NC pathologies and cognitive decline in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71613},
doi = {10.1002/alz.71613},
pmid = {42309988},
issn = {1552-5279},
support = {R01AG017917//National Institute on Aging Grants/ ; R01AG067482//National Institute on Aging Grants/ ; P30AG072975//National Institute on Aging Grants/ ; R01AG022018//National Institute on Aging Grants/ ; R01AG015819//National Institute on Aging Grants/ ; R01AG034374//National Institute on Aging Grants/ ; R01AG085483//National Institute on Aging Grants/ ; },
mesh = {Humans ; *Glial Fibrillary Acidic Protein/metabolism ; *Alzheimer Disease/pathology/metabolism ; Female ; *Hippocampus/pathology/metabolism ; *Aging/pathology/metabolism ; Male ; *Cognitive Dysfunction/pathology/metabolism ; Aged ; Aged, 80 and over ; Neurofibrillary Tangles/pathology ; Hippocampal Sclerosis ; Biomarkers/metabolism ; Dementia ; TDP-43 Proteinopathies ; },
abstract = {INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker for Alzheimer's disease (AD) progression in clinical studies, yet the role of brain GFAP in AD/AD-related dementias (ADRD) pathologies and cognitive decline remains unclear.

METHODS: GFAP burden from CA1-subiculum of the hippocampus were quantified. Regression and mixed-effect models, adjusting for demographics and other brain pathologies examined associations between hippocampal GFAP and AD/ADRD pathologies and separately with Alzheimer's dementia and cognitive decline.

RESULTS: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis of aging (HS-A), and neurofibrillary tangle density (but not amyloid-beta) were associated with GFAP burden. Hippocampal GFAP was associated with increased odds of Alzheimer's dementia and faster decline in global cognition, episodic memory, semantic memory, and perceptual speed. LATE-NC and tangles explained some but not all the association between hippocampal GFAP and cognitive decline.

DISCUSSION: GFAP burden in the hippocampus is related to LATE-NC and tangles but may also be an independent contributor to cognitive decline.},
}

Humans
*Glial Fibrillary Acidic Protein/metabolism
*Alzheimer Disease/pathology/metabolism
Female
*Hippocampus/pathology/metabolism
*Aging/pathology/metabolism
Male
*Cognitive Dysfunction/pathology/metabolism
Aged
Aged, 80 and over
Neurofibrillary Tangles/pathology
Hippocampal Sclerosis
Biomarkers/metabolism
Dementia
TDP-43 Proteinopathies

@article {pmid42310147,
year = {2026},
author = {Ning, Y and Gao, Y},
title = {Focused Ultrasound Modulation of PGC-1α Pathways in Neurological Disease: Mechanistic Rationale and Translational Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42310147},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Signal Transduction ; *Nervous System Diseases/metabolism/therapy ; *Translational Research, Biomedical ; *Ultrasonic Waves ; Mitochondria/metabolism ; },
abstract = {The brain's disproportionate energy demand creates an enduring bioenergetic imperative where mitochondrial performance directly determines synaptic resilience and neuronal survival. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) has emerged as a master transcriptional regulator orchestrating mitochondrial biogenesis, antioxidant defenses, proteostasis, and neuroplasticity, with dysregulation of this axis representing a convergent pathogenic mechanism across Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and neuropsychiatric disorders. Despite compelling preclinical evidence, conventional pharmacological PGC-1α activators confront fundamental translational barriers including poor blood-brain barrier penetration, inadequate bioavailability, and off-target metabolic effects. This review synthesizes mechanistic evidence suggesting that focused ultrasound may provide a noninvasive platform for regionally precise modulation of PGC-1α pathways. In this review, focused ultrasound is presented as a proposed upstream modulator of the PGC-1α axis. Existing studies support its ability to induce membrane tension, engage mechanosensitive channels such as Piezo1 and TRAAK, and trigger downstream kinase signaling, but the full ultrasound → PPARGC1A → neuroprotection chain in brain tissue remains a working hypothesis rather than a demonstrated therapeutic mechanism. Indirect priming through reversible blood-brain barrier opening, hemodynamic augmentation, and glial immunomodulation may further facilitate this model. We integrate emerging concepts including the mitochondrial synapse, PGC-1α isoform diversity, and theranostic architectures combining functional ultrasound mapping with targeted sonication. By defining mechanistic opportunities, disease-specific therapeutic strategies, and the sonogenetics frontier, this review proposes a hypothesis-generating roadmap for ultrasonic modulation of PGC-1α-dependent neuroprotection, a drug-free, focal approach that converts acoustic energy into a testable mitonuclear rescue framework requiring direct experimental validation.},
}

Humans
Animals
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
*Signal Transduction
*Nervous System Diseases/metabolism/therapy
*Translational Research, Biomedical
*Ultrasonic Waves
Mitochondria/metabolism

@article {pmid42310191,
year = {2026},
author = {Xu, S and Mu, J and Wang, Z and Yang, J and Tian, D and Shi, T and Lan, J and He, P and Hao, Z and Fu, Y and Xing, L and Ye, J and Wang, J},
title = {Unveiling the pathogenesis and therapeutic strategies of Alzheimer's disease through cuproptosis.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {42310191},
issn = {1572-8773},
support = {ZTNB404, ZTNB212//Yunnan province innovation team of prevention and treatment for brain diseases with acupuncture and Tuina-202405AS350007/ ; 82460974//National Natural Science Foundation of China/ ; 202201AT070214//General Project of Yunnan Applied Basic Research Program/ ; 202001AZ070001-020, 202301AZ070001-016//Joint Special Fund for Applied Basic Research on Traditional Chinese Medicine of Yunnan Provincial Department of Science and Technology/ ; 202205AD160024//Two Types of Talent Program of Yunnan Province/ ; },
abstract = {Alzheimer's disease (AD), a leading cause of dementia, remains incurable, necessitating novel insights into its pathogenesis and therapeutic strategies. Recent studies highlight cuproptosis-a copper (Cu)-dependent mitochondrial cell death pathway-as a critical player in AD progression. Cuproptosis is triggered by Cu overload, which disrupts mitochondrial tricarboxylic acid cycle enzymes, resulting in toxic aggregation of lipoylated proteins and iron-sulfur cluster destabilization. This process exacerbates mitochondrial dysfunction, oxidative stress, and neuronal loss, synergizing with hallmark AD pathologies like Aβ deposition and Tau hyperphosphorylation. Unlike ferroptosis or apoptosis, cuproptosis uniquely involves mitochondrial protein lipoylation and Cu homeostasis imbalance. Therapeutic strategies targeting cuproptosis include Cu chelators, inhibitors of Cu transporters, antioxidants, and gene editing approaches to restore Cu homeostasis or mitigate protein aggregation. Immunotherapy and neuroprotective agents further show promise in alleviating cuproptosis-driven neuroinflammation. Despite preclinical advancements, challenges remain in balancing Cu's essential roles with therapeutic interventions. This review underscores cuproptosis as a pivotal mechanism in AD and outlines emerging therapeutic avenues, emphasizing the ncessity for precision in targeting Cu dysregulation to halt neurodegeneration.},
}

@article {pmid42310298,
year = {2026},
author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS},
title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08971-z},
pmid = {42310298},
issn = {2041-4889},
support = {4R01AG068292//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; },
abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.},
}

@article {pmid42310327,
year = {2026},
author = {Varga, BT and Ernyey, AJ and Tajti, BT and Gáspár, A and Demeter, Z and Kollár, L and Kovács, P and Albert, M and Alpár, A and Gyertyán, I},
title = {Translational difficulties in establishing a pharmacologically induced neurovascular uncoupling model in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58244-0},
pmid = {42310327},
issn = {2045-2322},
abstract = {Neurovascular uncoupling (NVU) contributes to neurological disorders like Alzheimer's disease. While a mouse NVU model exists, a reliable rat model critical for cognitive research remains underdeveloped. To address this methodological gap, we investigated a pharmacological approach in rats using the same drugs (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH), L-NG-nitroarginine methyl ester (L-NAME), indomethacin) that proved to be efficacious in mice. The compounds were formulated as a cocktail solution and administered intraperitoneally for 13 days to aged, cognitively experienced Long-Evans rats. Our goal was to induce NVU while minimizing adverse systemic effects seen previously (e.g., hypertension, intestinal ulceration). The treatment induced only a modest (28%, non-significant) reduction in cerebral hyperaemia, with decreased prostaglandin E2 levels but unchanged 11,12-epoxyeicosatrienoic acid concentration in the brain. Cognitive effects were limited-transient impairment in the 5-choice task but no changes in spontaneous alternation, visual discrimination, cooperation, or motor learning. Significant adverse effects emerged: reduced food intake, weight loss, gastrointestinal malaise, and moderate renal toxicity. Our findings specifically highlight the challenges of achieving sufficient and symptomatically apparent NVU while minimizing systemic toxicity. While partial NVU occurred, this polypharmacy approach had major limitations. A reliable, industrially applicable rat NVU model remains urgently needed to accelerate antidementia drug development.},
}

@article {pmid42310520,
year = {2026},
author = {Zhang, Y and Chen, J and Jiang, J and Yang, N and Guo, S and Gao, F and Zhang, C and Weng, Q and Xiao, H and Luo, J and Chen, J and Shen, Q and Shen, G and Ji, L},
title = {Plasmalogens in Alzheimer's Disease: A Narrative Review of Dietary Sources, Metabolism, and Neuroprotective Mechanisms.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.6c05250},
pmid = {42310520},
issn = {1520-5118},
abstract = {Plasmalogens are ether phospholipids. They have a vinyl ether bond at sn-1 and polyunsaturated fatty acids at sn-2, and are abundant in marine- and animal-derived foods. Their unique structures may help maintain membrane organization, redox balance, and signaling. Human studies show that plasmalogen levels decline with age, and the drop is even sharper in Alzheimer's disease (AD), suggesting a link between dietary lipids and neurodegeneration. This narrative review summarizes dietary sources, molecular composition, and metabolism of plasmalogens, focusing on how structural diversity affects stability, bioavailability, and function. Based on cell and animal studies, we discuss potential mechanisms linking plasmalogens to AD pathology, including amyloid-β metabolism, oxidative stress, neuroinflammation, synaptic dysfunction, and myelin integrity. Unlike previous reviews, this work integrates structure-function relationships across food composition, lipid metabolism, and disease mechanisms. Finally, we discuss emerging uses in functional foods and precision nutrition, offering a fresh framework for dietary plasmalogens as part of neuroprotective strategies.},
}

@article {pmid42311340,
year = {2026},
author = {Li, G and Jiao, S and Zhou, Y and Cheng, X},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: theoretical foundations, regulatory suspension, and translational challenges.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1849207},
pmid = {42311340},
issn = {2673-6217},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological changes in β-amyloid protein deposition, abnormal tau protein phosphorylation neurofibrillary tangles, and chronic neuroinflammation. Recent studies have shown that the glymphatic-meningeal-cervical lymphatic system pathway plays a crucial role in the clearance of intracranial metabolic waste. Dysfunction of this system may lead to a decrease in the clearance efficiency of Aβ and tau proteins. Deep cervical lymphaticovenous anastomosis (DCLVA) has been proposed as a novel surgical approach to enhance cervical lymphatic drainage, reduce Aβ/tau accumulation, and improve cognitive function in patients with AD. However, on 8 July 2025, the National Health Commission of China issued a notice prohibiting the clinical application of "deep cervical lymphaticovenous anastomosis" for the treatment of AD. This article provides a narrative review with critical appraisal of the theoretical basis, surgical mechanisms, and clinical evidence of DCLVA for AD. We objectively evaluate the strengths and limitations of current clinical studies, critically appraise the uncertainty of underlying physiology, and comprehensively analyze the potential risks, safety concerns, and translational obstacles that led to regulatory suspension. We further clarify unresolved scientific questions including pressure gradients, lymphatic contractility, reflux risk, anastomotic patency, and biomarker validation. By framing DCLVA within the context of its clinical prohibition, we provide clinicians and researchers with a balanced appraisal that acknowledges both the procedure's potential and the substantial gaps that must be addressed before widespread application can be justified.},
}

@article {pmid42311341,
year = {2026},
author = {Boland, SW and Coyner, GN and Risen, SJ and Alsulami, A and McGrath, S and Moreno, JA},
title = {Increased neurotoxic gliosis and blood-brain barrier dysregulation in canine cognitive dysfunction syndrome (CCD).},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1829442},
pmid = {42311341},
issn = {2673-6217},
abstract = {BACKGROUND: As Alzheimer's Disease (AD) and related dementias (ADRD) prevalence is projected to double by 2050, the urgency for relevant models to study its pathology intensifies. Aging is the primary risk factor for AD development and influenced by a myriad of factors including neurotoxic glial activation and BBB degradation; however, historically AD models consist of transgenic mouse in-vivo and in-vitro methods. While this offers many strengths, it is limited in their ability to mimic aging induced AD pathology. Currently, canine cognitive dysfunction (CCD) syndrome is being investigated as it is a natural and spontaneous disease with similar pathologies to AD and other dementias. Our lab and many others have worked extensively to characterize CCD pathology. However, the role of microglial and astrocytic activation and the interplay between the blood-brain barrier (BBB) have not been investigated. This study aims to fill this gap in knowledge in CCD and in turn its relation to human AD. We hypothesize that CCD-afflicted canines will exhibit increased neurotoxic glial activation and BBB degradation.

METHODS/RESULTS: We utilized immunohistochemistry (IHC), morphological analyses, and immunofluorescence to investigate CCD pathology comparing CCD negative and CCD positive dogs. In this study we see glial morphology consistent with those seen in neurotoxic glia in neurodegenerative disease, increased S100β/C3 astrocyte activation, decreased claudin-5 expression, and region-dependent perivascular AQP4 expression modulation in dogs with CCD, compared to those without CCD.

CONCLUSION: Our results further characterize glial and BBB roles in CCD pathogenesis and reinforces the strengths of modeling AD/ADRD in aging dogs.},
}

@article {pmid42311453,
year = {2026},
author = {Stephens-Sarlós, E and Szabo, A},
title = {Primitive reflexes as candidate quantitative readouts of hierarchical inhibitory control across the lifespan.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1860053},
pmid = {42311453},
issn = {1662-5161},
abstract = {Primitive reflexes are typically inhibited during normal neurodevelopment as cortical and subcortical inhibitory systems mature. However, persistent or incompletely integrated primitive reflexes have been observed in neurodevelopmental conditions including attention-deficit/hyperactivity disorder (ADHD), dyslexia, developmental coordination difficulties, sensory-processing-related presentations, and delayed speech and language development. Re-emergence of primitive reflexes has also been reported in aging and neurological disorders such as Alzheimer's disease and Parkinson's disease. Based on these observations, this paper explores the hypothesis that primitive reflex expression may reflect distributed hierarchical inhibitory systems spanning spinal, brainstem, and cortical levels. We propose that persistence or reappearance of early stereotyped reflex patterns may indicate altered inhibitory regulation and sensorimotor integration associated with changes in GABAergic function and activity-dependent neural plasticity. We further propose that quantitative reflex profiling may represent a candidate behavioral framework for studying distributed inhibitory regulation across the lifespan. Reflex integration patterns may relate to motor control, sensory processing, attentional regulation, and broader neurocognitive functioning. However, clinical applicability depends on standardized measurement procedures, validated protocols, multimodal neurophysiological correlations, and replication. The proposed model should currently be interpreted as a theoretical and hypothesis-generating framework rather than a validated mechanistic or clinical account. Primitive reflex profiling is not yet part of standard clinical or neurophysiological assessment. Future research should prioritize longitudinal, multimodal, and interventional studies testing relationships between primitive reflex expression, inhibitory network organization, cortical dynamics, and sensorimotor function. Primitive reflexes may therefore represent developmentally informative behavioral phenomena associated with distributed inhibitory systems across the lifespan.},
}

@article {pmid42311464,
year = {2026},
author = {Li, P and Gao, Y and Liu, W},
title = {GLP-1 Receptor Agonists in Neurological Disorders: From Mechanisms to Clinical Translation.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {613616},
pmid = {42311464},
issn = {1177-8881},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Glucagon-Like Peptide-1 Receptor/metabolism ; },
abstract = {Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, have been used for years to treat type 2 diabetes and obesity. More recently, it has become clear that these receptors are widely distributed throughout the central nervous system (CNS), which has raised the possibility of repurposing these drugs for neurological disorders. In this review we go through the evidence across a range of neurological conditions, discuss the main mechanisms thought to explain their neuroprotective effects, and point out the hurdles that still need to be cleared before they can be used in the clinic. Preclinical work has been fairly consistent. These drugs activate the cAMP/PKA/CREB pathway to boost BDNF expression. They also turn on the PI3K/Akt pathway, which reins in GSK-3β and cuts down tau hyperphosphorylation. At the same time, they put the brakes on NLRP3 inflammasome activation in microglia and get AMPK dependent mitochondrial biogenesis and autophagy going. In animal models of Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, intracerebral hemorrhage (ICH), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression, epilepsy, and spinal cord injury (SCI), these cellular changes add up to less protein aggregation, less neuron loss, and better functional outcomes. Clinical data are harder to interpret. Some trials have shown modest improvements in cognition or motor function, but others have found no meaningful effect on disease progression. One thing that does not get enough attention is that different GLP-1 receptor agonists cross the blood-brain barrier at widely varying rates, and these differences could well explain why trial results have been so mixed. Looking ahead, getting these drugs into the clinic will depend on choosing the ones that actually reach the CNS, developing biomarkers that can predict who will respond, and designing trials that take disease heterogeneity into account. Seen this way, this review offers a practical framework for turning mechanistic insights into real patient benefit.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
*Nervous System Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Glucagon-Like Peptide-1 Receptor/metabolism

@article {pmid42311495,
year = {2026},
author = {Jin, S and Yu, J and Liu, HL and Wang, C and Zheng, FM},
title = {Serum BP180 and BP230 autoantibodies in Alzheimer's disease: diagnostic and cognitive associations in a retrospective study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1757497},
pmid = {42311495},
issn = {1663-4365},
abstract = {BACKGROUND: To assess the prevalence and diagnostic value of serum anti-BP180 and anti-BP230 antibodies in Alzheimer's Disease (AD) and their relationship with cognitive function.

METHODS: We conducted a retrospective case-control study comprising 279 participants, including patients with clinically diagnosed AD and neurologically healthy controls, who were consecutively enrolled at the Third People's Hospital, Hangzhou, China, between 2022 and 2024. Serum levels of anti-BP180 and anti-BP230 antibodies were quantified using enzyme-linked immunosorbent assays (ELISAs). Among patients with AD, the relationship between cognitive function, assessed by the Mini-Mental State Examination (MMSE), and serum antibody concentrations was further evaluated.

RESULTS: After adjustment for age and sex, serum BP180 levels were significantly higher in AD patients compared with healthy controls (β = 2.257, 95% CI: 1.102-3.412, p < 0.001). Similarly, BP230 levels were also significantly elevated in AD patients (β = 3.432, 95% CI: 0.395-6.468, p = 0.027). Multivariable logistic regression analysis identified BP180 (odds ratio [OR] = 1.149, 95% CI: 1.056-1.275, p = 0.004), age (OR = 1.176, 95% CI: 1.110-1.254, p < 0.001), and female sex (OR = 5.318, 95% CI: 2.853-10.272, p < 0.001) as independent predictors of AD. A predictive model incorporating BP180, age, and sex was subsequently developed, demonstrating good diagnostic performance with an area under the curve (AUC) of 0.798 (95% CI: 0.734-0.862). Compared with BP180 alone (AUC = 0.591) or BP230 alone (AUC = 0.598), the multivariable model showed significantly improved discriminative ability. In addition, both BP180 (p < 0.001) and BP230 (p = 0.003) levels were significantly and negatively correlated with MMSE scores.

CONCLUSION: The multivariable model incorporating BP180, age, and sex demonstrated good discriminative performance in distinguishing AD patients from controls and outperformed individual biomarkers. Integrating clinical and serological markers may improve the diagnostic performance for AD.},
}

@article {pmid42311497,
year = {2026},
author = {Wang, T and Shang, Y and McLean, JW and Yin, F and Brinton, RD},
title = {APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1796680},
pmid = {42311497},
issn = {1663-4365},
abstract = {INTRODUCTION: Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at increased AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further exacerbated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.

METHODS: To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages from pre- to postmenopause.

RESULTS: APOE3/3 mice exhibited dynamic regulation of metabolic systems that supported postmenopausal brain bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice exhibited accelerated and compromised metabolic adaptation, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and compromised brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.

DISCUSSION: Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.},
}

@article {pmid42311499,
year = {2026},
author = {Mitrovic Tartanoglu, D and Tartanoglu, CH and Sonnenberg, C and Sabariego, M and Haberl, MG and Viana da Silva, S},
title = {Age-dependent vulnerability to spatial memory interference in APP/PS1 mice.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1794153},
pmid = {42311499},
issn = {1663-4365},
abstract = {BACKGROUND: While Alzheimer's disease (AD) is well known for progressive memory impairment, less is understood about how amyloid pathology affects flexible updating of competing spatial representations. Here, we used the Objects in Updated Locations (OUL) paradigm to investigate how amyloidosis influences spatial memory updating and the handling of competing mnemonic information in APP/PS1 mice.

METHODS: APP/PS1 and wild-type control mice were tested in the OUL paradigm, which probes memory for object displacement and subsequent updating of overlapping spatial representations. Exploration behavior was quantified using an automated behavioral tracking pipeline based on object proximity and gaze orientation criteria and validated against blinded manual scoring. Object discrimination performance was assessed during the object displacement session and during the subsequent updating performance session involving competing spatial information. cFos immunohistochemistry following novelty exposure was used to assess neuronal recruitment associated with memory performance.

RESULTS: During the object displacement session, control mice reliably discriminated the displaced object location, whereas APP/PS1 mice showed weaker and more variable performance, with a greater proportion failing to reach discrimination criterion levels. During the subsequent updating performance session, control mice demonstrated more flexible adaptation across overlapping spatial representations, while APP/PS1 mice exhibited weaker performance under conditions involving competing spatial traces. In APP/PS1 mice, longer exploration latencies were negatively associated with discrimination performance specifically under competing-memory conditions. Age-stratified analyses revealed a significant genotype effect in older animals, driven primarily by the condition involving overlapping spatial representations. In control mice, cFos expression in hippocampal regions associated with spatial memory processing correlated with behavioral performance, whereas these relationships were absent in APP/PS1 mice.

CONCLUSION: These findings indicate that amyloidosis is associated with reduced reliability of spatial memory performance and impaired handling of competing spatial information, particularly under conditions requiring flexible updating of overlapping mnemonic representations. The results further suggest increased vulnerability to interference-related spatial memory deficits with age. Together, these findings support the utility of the OUL paradigm for studying memory updating impairments in AD-related pathology and identify flexible spatial updating under interference as a sensitive behavioral domain affected by amyloidosis.},
}

@article {pmid42311688,
year = {2026},
author = {Shen, X and Zheng, C and Lin, R and Wang, J and Chen, Z},
title = {Mechanisms and therapeutic advances of gut metabolites in the regulation of neuroimmune inflammatory diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1795042},
pmid = {42311688},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology/therapy/etiology ; *Gastrointestinal Microbiome/immunology ; Bile Acids and Salts/metabolism ; Fatty Acids, Volatile/metabolism ; Dysbiosis/immunology ; },
abstract = {Gut-derived metabolites function as critical signaling intermediaries that translate environmental cues into central nervous system (CNS) responses, playing an indispensable role in the pathogenesis and trajectory of neuroimmune inflammatory disorders. Key metabolites, including short-chain fatty acids (SCFAs) and bile acids, either traverse the blood-brain barrier directly or orchestrate immune modulation peripherally, thereby fine-tuning the dynamic crosstalk between systemic immunity and neural homeostasis. SCFAs exert potent anti-inflammatory effects by promoting regulatory T-cell (Treg) differentiation through activation of G protein-coupled receptors (GPCRs) on immune cells and inhibition of histone deacetylases (HDACs). Within the CNS, they further confer neuroprotection by suppressing the pro-inflammatory activation of microglia and astrocytes. In contrast, bile acids display a context-dependent, "double-edged sword" effect: while certain subtypes activate the anti-inflammatory TGR5 receptor, neurotoxic metabolites (e.g., taurolithocholic acid) can accumulate and directly provoke pro-inflammatory polarization of microglia, thereby fueling neuroinflammation. Dysbiosis of the gut microbiota and consequent metabolite profile alterations are strongly implicated in neuroimmune inflammatory diseases-such as multiple sclerosis (MS), Alzheimer's disease (AD), and neuromyelitis optica spectrum disorders (NMOSD) -which are characterized by both a distinct metabolite imbalance and a pervasive pro-inflammatory immune milieu. Building on this framework, novel therapeutic strategies targeting the "gut-immune-brain axis" are evolving along two complementary avenues: (1) Immune-centric approaches that directly modulate neuroimmune pathways (e.g., by tempering microglial activation or expanding Treg populations); and (2) Microbiota-centric interventions that employ specific probiotics, prebiotics, or metabolite supplements to restore gut ecological balance, systemically recalibrate immunity, and mitigate neuroinflammation. Future research must prioritize elucidating the precise molecular dialogues between metabolites and immune cell subsets, conducting large-scale clinical validation, and advancing personalized, precision-medicine strategies. Such efforts will solidify a novel systemic perspective and strategic paradigm for preventing and treating neuroimmune inflammatory diseases.},
}

Humans
Animals
*Neuroinflammatory Diseases/metabolism/immunology/therapy/etiology
*Gastrointestinal Microbiome/immunology
Bile Acids and Salts/metabolism
Fatty Acids, Volatile/metabolism
Dysbiosis/immunology

@article {pmid42311699,
year = {2026},
author = {Büyükgök, D and Karabulut, SN and Kepenek, AO and Direk, N and Baral-Kulaksızoğlu, I},
title = {Community-based survey of perceived stigma in dementia: Insights from a collectivist culture.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70357},
pmid = {42311699},
issn = {2352-8729},
abstract = {INTRODUCTION: In collectivist cultures, internalization of negative beliefs fosters stigma. This study aimed to assess the relationship between Alzheimer's disease (AD) knowledge and perceived stigma, focusing on sociodemographic variables; gender, marital status, occupation, and caregiving.

METHODS: In this cross-sectional study, 529 participants without psychiatric or neurological disorders completed the AD knowledge scale, Affiliated Stigma Scale (ASS), and stigma survey.

RESULTS: Age showed no significant association with dementia knowledge or stigma. Higher education, living with family/spouse, and being dementia caregiver predicted perceived stigma. Caregivers demonstrated higher knowledge; but similar stigma levels compared to non-caregivers which was significantly related to the ASS-affective component. Healthcare workers also had greater knowledge but did not differ in terms of stigma.

DISCUSSION: Knowledge improved by education and caregiving, but stigma persisted, shaped by emotional and cultural dynamics. These findings suggest that future interventions may benefit from integrating empathy-focused and attitude-based modules, as knowledge alone is insufficient to reduce stigma.},
}

@article {pmid42311700,
year = {2026},
author = {Owora, AH and Summanwar, D and Kulshreshtha, A and Miled, ZB and Dexter, PR and Jiang, B and Shah, Y and Puster, E and Coppedge, K and Disla, S and Galvin, JE and Fowler, NR and Boustani, M},
title = {Optimizing scalable approaches for early detection of cognitive impairment in primary care.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70393},
pmid = {42311700},
issn = {2352-8729},
abstract = {INTRODUCTION: Unrecognized cognitive impairment remains common in primary care, delaying access to care.

METHODS: We conducted a prospective cross-sectional study to evaluate a multimodal screening approach combining a passive digital marker (PDM) from electronic health records with the Quick Dementia Rating System (QDRS).

RESULTS: Individually, each method showed limited discrimination (area under the curve [AUC] 0.61-0.62). The combined model, incorporating PDM, QDRS, and comorbidity context, improved performance (AUC 0.79; sensitivity 0.75; specificity 0.71). Decision curve analysis showed a net benefit of 0.5 at a 50% risk threshold, corresponding to a modest increase in correctly identified cases relative to alternative screening strategies.

DISCUSSION: This low-burden, scalable multimodal approach improves detection of cognitive impairment, including mild cognitive impairment and Alzheimer's disease and related dementias, and may support improved risk stratification and referral prioritization in primary care.},
}

@article {pmid42311701,
year = {2026},
author = {Lahoud, E and Moynier, F and Mahan, B and Luu, TH and Rigoussen, D and Le Borgne, M and Paquet, C and Fowler, C and Bush, AI},
title = {Copper isotope shifts in biofluids track Alzheimer's pathology.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70316},
pmid = {42311701},
issn = {2352-8729},
abstract = {INTRODUCTION: Altered copper metabolism has been reported in Alzheimer's disease (AD), with post mortem brain tissue showing depletion of [65]Cu compared with [63]Cu. Whether such isotopic shifts can be detected in biofluids remains unknown.

METHODS: We analyzed copper isotope composition in human cerebrospinal fluid (CSF) and serum from AD patients and controls using multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) and single quadrupole inductively coupled plasma mass spectrometry (SQ-ICP-MS). Samples included 22 CSFs (10 AD, 12 controls), 54 sera (28 AD, 26 controls).

RESULTS: AD CSF was enriched in [65]Cu (+0.32‰, p = 0.02), correlating inversely with CSF amyloid beta (Aβ)42/40 ratios. Serum from AD patients was depleted in [65]Cu (-0.23‰, p = 0.013), trending inversely with amyloid positron emission tomography burden. Serum and CSF δ [65]Cu diagnostically discriminate between AD and controls (area under the curve = 0.8, Youden's J ≈ 0.5 SD, p ≤ 0.0002).

DISCUSSION: Copper isotope excursions in brain parenchyma are mirrored in CSF and serum. These shifts reflect amyloid pathology and highlight isotopic copper analysis as a potential minimally invasive biomarker for AD.},
}

@article {pmid42311702,
year = {2026},
author = {Baiardi, S and Caldera, S and Capellari, S and Magliocchetti, F and Mammana, A and Zenesini, C and Cappa, S and Caraglia, N and Cotelli, M and Marra, C and Miraglia, F and Perani, D and Redolfi, A and Spadin, P and Tagliavini, F and Vanacore, N and Vecchio, F and Rossini, PM and Parchi, P},
title = {Prevalence of Lewy body pathology and phenotypic associations in patients with mild cognitive impairment: Evidence from the Interceptor study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70382},
pmid = {42311702},
issn = {2352-8729},
abstract = {INTRODUCTION: Clinical effects and prevalence of Lewy body (LB) pathology in patients with mild cognitive impairment (MCI) remain poorly understood.

METHODS: We assessed LB pathology in 339 patients with MCI from the Italian multicenter Interceptor cohort using the cerebrospinal fluid α-synuclein seed amplification assay. Baseline assessment was followed by serial cognitive evaluations over 3 years.

RESULTS: LB+ participants (n = 50, 15%) were older and showed a higher frequency of parkinsonism, falls, and delirium episodes than those LB-, although these differences were not statistically significant. At follow-up, patients with biomarker evidence of Alzheimer's disease (AD), either isolated (AD+/LB-) or with concomitant LB pathology (AD+/LB+), showed the fastest cognitive decline and progression to dementia.

DISCUSSION: In a multicenter MCI cohort, LB pathology was associated with older age and an increased frequency of motor/psychiatric symptoms. Larger studies are needed to clarify the independent contribution of AD and LB pathologies to the MCI phenotype and clinical progression.},
}

@article {pmid42311735,
year = {2026},
author = {Harikumar, N and Gupta, M and Al Janabi, T and Mand, KK},
title = {A Severe Symptomatic Case of Amyloid-Related Imaging Abnormalities After Donanemab Infusion.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109045},
pmid = {42311735},
issn = {2168-8184},
abstract = {Amyloid-related imaging abnormalities (ARIA) are known complications of anti-amyloid monoclonal antibody therapy for Alzheimer's disease. Although many cases are asymptomatic, severe presentations can mimic stroke or toxic encephalopathy. This case highlights a rare presentation of ARIA with myoclonic movements and acute encephalopathy following donanemab infusion. We report a 75-year-old woman with Alzheimer's disease who developed acute confusion, hallucinations, and involuntary movements one day after her sixth donanemab infusion. Stroke workup was negative. MRI demonstrated findings consistent with both ARIA-E and ARIA-H. She was treated with high-dose intravenous methylprednisolone, followed by an oral prednisone taper, which resulted in gradual neurological improvement. Clinicians must maintain a high suspicion for ARIA in patients receiving anti-amyloid therapy who present with acute neurologic decline. Early MRI evaluation and prompt corticosteroid treatment may improve outcomes.},
}

@article {pmid42311824,
year = {2026},
author = {Angarita-Rodríguez, A and Vargas-López, V and Pinzón, A and Sandoval-Hernandez, A and Kang, K and Li, L and Papin, J and Puentes-Rozo, P and Aristizábal, AF and González, J},
title = {Transcriptome-informed metabolic modeling reveals astrocyte-specific vulnerabilities in mild cognitive impairment and Alzheimer's disease progression.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1816121},
pmid = {42311824},
issn = {2673-7647},
abstract = {INTRODUCTION: Astrocytes are essential for maintaining neuronal homeostasis, yet their stage-specific contribution to mild cognitive impairment (MCI) and Alzheimer's disease (AD) remains insufficiently understood. This study aimed to investigate astrocyte-associated transcriptional and metabolic alterations across the control-MCI-AD continuum using integrated transcriptomic and genome-scale metabolic modeling approaches.

METHODS: Transcriptomic profiles from hippocampal CA1 tissue (GSE28146) were analyzed across four clinical conditions (control, early MCI, advanced MCI, and AD). Astrocyte-associated expression programs were inferred using the unsupervised deconvolution algorithm CDSeq and validated through canonical marker enrichment, correlation with external reference signatures, and comparison with an independent single-nucleus RNA-seq astrocyte pseudobulk dataset. The inferred profiles were integrated into a curated human astrocyte genome-scale metabolic model to generate condition-specific models, which were analyzed using flux balance analysis (FBA) and flux variability analysis (FVA).

RESULTS: The analyses supported stage-dependent remodeling of astrocyte-associated transcriptional and metabolic programs during disease progression. Early MCI was associated with signaling and stress-adaptation changes, whereas advanced MCI and AD showed broader disruption of synaptic support, redox homeostasis, and inflammatory-related programs. Model predictions indicated a progressive reduction in a biomass-derived maintenance proxy from control to advanced MCI, followed by a partial rebound in AD, suggesting a compensatory shift toward reactive-like astrocyte states rather than full functional recovery. Flux variability analysis revealed reduced metabolic flexibility across disease stages, particularly in glutamate-glutamine cycling, glutathione/redox metabolism, glycolysis-pyruvate metabolism, cholesterol handling, and one-carbon/folate metabolism.

DISCUSSION: These findings support the view that astrocytes undergo progressive, stage-specific metabolic reprogramming during the transition from healthy aging to AD. Early alterations in redox regulation, neurotransmitter cycling, and mitochondrial function may contribute to early neuronal vulnerability. This work highlights astrocyte-centered pathways as potential targets for future experimental validation and therapeutic exploration.},
}

@article {pmid42311857,
year = {2026},
author = {Snowball, E and Casey, R and Myers Barnett, K and Campill, S and Eliassen, JR and Tur Eliassen, M and Anderton, B and Stockwell-Lance, C and Warbelow, M and Bacsu, JD and Lanza, E and Bethell, J},
title = {National and international models of involving people with lived experience in dementia policy, advocacy and research.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1816031},
pmid = {42311857},
issn = {2813-3919},
abstract = {Globally, there is growing recognition of the need to advance approaches to involve people with lived experience of dementia as collaborators in policy, advocacy and research activities. Involvement is viewed as a right by dementia advocates and others, and some organizations have developed mechanisms to support this collaboration, such as through dedicated resources for infrastructure or as a condition of research funding. However, there is limited literature on how national and international organizations support the involvement of people with lived experience of dementia. In this perspective article, we describe different approaches to involving people with lived experience in policy, advocacy and research activities across national and international network contexts. We outline and compare the approaches taken by the Engagement of People with Lived Experience of Dementia program and advisory group (Canadian Consortium on Neurodegeneration in Aging), Alzheimer Society Research Network (Alzheimer's Society UK), European Working Group of People With Dementia and European Dementia Carers Working Group (Alzheimer Europe), and the Lived Experience Advisory Group (Global Brain Health Institute, Trinity College Dublin). For each example presented, we describe the initiative (e.g., purpose, brief history, structure). We discuss the four initiatives in order to identify common and context-specific barriers and enablers to involvement. We hope that the findings will help others to develop their own initiatives to involve people with lived experience of dementia.},
}

@article {pmid42311879,
year = {2026},
author = {Subramanian, A and Reddy, RA and Ravichandran, A and Sekar, M and Wong, LS and Chandra, Y and R, M and T, T and K, M and Kumarasamy, V and Subramaniyan, V},
title = {Virtual Dementia in the Digital Age: Neurocognitive Mechanisms, Behavioural Impact and Public Health Implications of Technology Overuse.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531261420601},
pmid = {42311879},
issn = {0972-7531},
abstract = {BACKGROUND: Digital technology has rapidly transformed how people communicate, learn, and perform professional activities. While technological advancements have improved access to information, productivity, and global connectivity, excessive reliance on digital devices has raised concerns regarding cognitive and behavioral health. Emerging evidence suggests that prolonged screen exposure, constant multitasking, and dependence on digital aids may contribute to cognitive symptoms resembling dementia, including impaired attention, memory difficulties, reduced problem-solving ability, and emotional disengagement. This phenomenon, often described as "virtual dementia" or "digital dementia," has become an area of growing scientific and public health interest.

SUMMARY: Current evidence indicates that excessive digital technology use may alter neural circuits involved in cognition, particularly within the prefrontal cortex, hippocampus, and the Default Mode Network. These changes may manifest as digital amnesia, attentional fragmentation, mental fatigue, reduced social engagement, and emotional blunting. Adolescents and young adults appear especially vulnerable due to ongoing neurodevelopment, although many of these changes may be reversible with behavioral modification. Unlike neurodegenerative disorders such as Alzheimer's disease, virtual dementia is characterized by lifestyle-associated and potentially reversible cognitive dysfunction. At the same time, digital technologies also show therapeutic potential in cognitive monitoring, rehabilitation, and preventive interventions, highlighting their dual role in brain health.

KEY MESSAGE: Virtual dementia represents a potentially reversible form of technology-associated cognitive impairment driven by maladaptive digital behaviours. Promoting digital hygiene, mindful technology use, cognitive training, and responsible technology policies may help protect cognitive health. Future longitudinal and mechanistic studies are needed to establish diagnostic criteria, clarify long-term neurological effects, and develop evidence-based prevention and intervention strategies.},
}

@article {pmid42312368,
year = {2026},
author = {Wang, C and Zhang, C and Li, H and Wang, L and Chen, X and Wang, C and Zhang, Y and Zhang, Z and A, M and Wang, J and Wu, J and Sun, Y and Du, A},
title = {Deep white matter injury and cognitive decline in cerebral small vessel disease: Mediation by a unified atrophy network.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457126},
doi = {10.1177/13872877261457126},
pmid = {42312368},
issn = {1875-8908},
abstract = {BackgroundIn cerebral small vessel disease (CSVD), the burden of white matter hyperintensities (WMH) does not fully account for cognitive impairment, suggesting the involvement of intermediary mechanisms.ObjectiveWe investigated whether a gray matter atrophy network acts as the key mediator linking topologically specific (deep) WMH to multidomain cognitive dysfunction.MethodsIn this retrospective study, 260 patients with CSVD (62 cognitively normal, 125 with mild impairment, 73 with dementia) were included. Cognitive status was assessed neuropsychologically. 3.0 T MRI identified an atrophy network. We then conducted pre-specified mediation analyses and a primary confirmatory analysis using structural equation modeling (SEM) to test whether this atrophy network mediated the effect of deep WMH on cognitive performance.ResultsA 41-region atrophy network was identified, primarily involving the medial temporal lobe and thalamus, that was significantly associated with cognitive status. The final SEM demonstrated excellent fit, showing that higher deep WMH burden was associated with greater network atrophy (β = 0.145, p < 0.05), which in turn was strongly associated with poorer executive function (β = -0.64, p < 0.001) and memory (β = -0.572, p < 0.001). The direct effect of WMH on cognition was not statistically significant in the model.ConclusionsOur findings suggest that in CSVD, a unified network of gray matter atrophy acts as a powerful statistical mediator in the effect of deep white matter injury on cognitive decline. This atrophy pattern may represent a more direct biomarker of the neurodegenerative process underlying cognitive impairment than WMH burden alone.},
}

@article {pmid42312371,
year = {2026},
author = {Yasar, S and Anderson, A and Hayden, KM and Carmichael, OT and Clark, JM and Carlson, MC and Asby, DJ and Kehoe, PG and Miners, S and Espeland, MA},
title = {Association between renin angiotensin system and cognitive outcomes over 15 years: The Look AHEAD study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458824},
doi = {10.1177/13872877261458824},
pmid = {42312371},
issn = {1875-8908},
abstract = {BackgroundEvidence suggests that dysregulation of the renin angiotensin system (RAS) is associated with the pathophysiologic process of Alzheimer's disease (AD). Few studies have evaluated the relationship between circulating RAS components and incident cognitive decline or impairment.ObjectiveOur study aims to evaluate the relationship between circulating RAS biomarkers (angiotensin II [ANGII], angiotensin 1-7 [ANG1-7], angiotensin converting enzyme-1 [ACE-1], and 2 [ACE-2]), in initially cognitively healthy adults, and incident cognitive decline and cognitive impairment.MethodsIn this secondary analysis, 310 community-dwelling participants from the randomized controlled Action for Health in Diabetes (Look AHEAD) study without dementia, who were not on RAS-altering medication, were included.ResultsParticipants, compared to those excluded, were more likely to be female (65%), white (76%), overweight (34%), have lower baseline HbA1c (6.7%), lower SBP (119.7 mmHg), lower serum creatinine (0.79 mg/dL), higher total cholesterol (190.1 mg/dL) and LDL (112.5 mg/dL), and higher history of dyslipidemia (65%) at baseline. 1 SD increase of ANG1-7 measured in year 1 was associated with lower odds of cognitive impairment (OR = 0.35, 95% CI 0.16-0.77; p = 0.001), while higher ANG1-7 levels predicted better global cognitive function [β x 10[-3] = 1.03 (0.50); p = 0.039], 15 years later.ConclusionsThese results provide preliminary evidence that circulating RAS components are predictive of protection against cognitive impairment and decline and may serve as a marker of the early stages of dementia. Further research is warranted to fully understand the relationship between the brain and the circulatory RAS.},
}

@article {pmid42312374,
year = {2026},
author = {Kim, EW and , },
title = {Metabolic context modulates neuroinflammation: Type 2 diabetes mellitus moderates the association of interleukin-8 with amyloid pathology and cognitive decline in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457565},
doi = {10.1177/13872877261457565},
pmid = {42312374},
issn = {1875-8908},
abstract = {BackgroundInterleukin-8 (IL-8) exhibits dual roles in Alzheimer's disease (AD), yet how the metabolic milieu of type 2 diabetes mellitus (T2DM) influences its impact in mild cognitive impairment (MCI) remains unclear.ObjectiveThis study aimed to investigate how T2DM status moderates the longitudinal association between baseline plasma IL-8 levels and AD-related outcomes, including cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration.MethodsData from 373 MCI participants (Alzheimer's Disease Neuroimaging Initiative cohort) were analyzed. Moderation analyses examined the IL-8 × T2DM interaction on cognitive trajectories, amyloid-β (Aβ) accumulation, and regional atrophy, adjusting for key covariates.ResultsIn the T2DM group, higher baseline IL-8 was significantly associated with a slower longitudinal increase in Clinical Dementia Rating-Sum of Boxes (p = 0.005), indicating preserved clinical function. Furthermore, elevated IL-8 in the T2DM cohort correlated with lower hippocampal Aβ burden (p = 0.041) and attenuated atrophy rates in the parahippocampal cortex (p = 0.044). In contrast, no significant associations between IL-8 and any AD biomarkers or cognitive trajectories were observed in the non-T2DM group.ConclusionsThis research demonstrates that the role of IL-8 in MCI is "context-dependent," contingent upon the patient's metabolic state. The author suggests that under chronic metabolic stress, IL-8 may reflect an adaptive immune response that mitigates amyloid pathology and slows neurodegeneration. These results emphasize the necessity of integrating metabolic profiles into the interpretation of neuroinflammatory biomarkers to facilitate personalized therapeutic strategies for AD.},
}

@article {pmid42312378,
year = {2026},
author = {Vellone, D and Guan, DX and Crockford, JFE and Warring, I and Ballard, C and Creese, B and Corbett, A and Pickering, E and Roach, P and Smith, EE and Ismail, Z},
title = {Validation of the care partner stress scale in the CAN-PROTECT study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457652},
doi = {10.1177/13872877261457652},
pmid = {42312378},
issn = {1875-8908},
abstract = {BackgroundFamily and friend care partners play a vital role in supporting individuals with neurocognitive disorders, such as Alzheimer's disease dementia. Care partners are often uncompensated and face multifaceted challenges that contribute to stress. The Care Partner Stress Scale (CPSS) was developed to assess caregiver stress across seven domains: cognition, behavior, function; unmet needs and emotional impact; work and financial strain; family and interpersonal conflict; and situational perception.ObjectiveTo evaluate psychometric properties of the CPSS in care partners of individuals with neurocognitive or neurodegenerative diseases of aging.MethodsThe CPSS was completed by 168 (83.93% female, age = 61.98 years) care partners in the CAN-PROTECT online cohort. Participants completed measures of depression, anxiety, quality of life, function, loneliness, and life satisfaction and engagement. We assessed internal consistency, item-total correlations, convergent and discriminant validity, and floor/ceiling effects.ResultsThe CPSS demonstrated excellent internal consistency (α = 0.95, 95% CI: 0.94-0.96), with item-total correlations >0.23. Higher CPSS scores were associated with greater depression (b = 2.38, 95%CI [0.72, 4.03], p = 0.005), anxiety (b = 4.47, 95%CI [2.44, 6.50], p < 0.001), and anxious distress (b = 6.37, 95%CI [3.54, 9.21], p < 0.001), as well as lower life satisfaction (b = -3.42, 95%CI [-5.61, -1.23], p = 0.002), poorer social relationships (b = -2.31, 95%CI [-4.54, -0.09] p = 0.042), greater loneliness (b = 5.26, 95%CI [1.33, 9.19], p = 0.009), and poorer life engagement (b = 2.89, 95%CI [1.23, 4.65], p = 0.001). CPSS scores were not associated with self-care (b = -1.06, 95%CI [-5.03, 2.92], p = 0.600). Floor effects were minimal (0.60%), with no ceiling effects.ConclusionsFindings provide initial support for multidimensional assessment of care partner stress in neurocognitive disorders.},
}

@article {pmid42312432,
year = {2026},
author = {Ahmed Abbasi, A and Norouziyan, F and Moradikor, N},
title = {Role of suvorexant in Alzheimer's disease: Targeting sleep, orexin signaling, and disease pathophysiology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461161},
doi = {10.1177/13872877261461161},
pmid = {42312432},
issn = {1875-8908},
abstract = {The defining features of Alzheimer's disease (AD) include neurodegeneration, a decline in cognition, and tau and amyloid-β protein pathologies. Sleep problems affect many individuals with AD and could be an aggravating factor in the disease because it creates a barrier to the glymphatic system's ability to clear neurotoxic proteins, disrupt the plasticity of synapses, and increase neuroinflammation. Suvorexant, which works as a dual orexin receptor antagonist, has proven effective in the management of sleep problems by fine-tuning the orexin system, which regulates arousal. Preliminary studies indicate that, in addition to improving sleep, Suvorexant could potentially help in the reduction of amyloid and tau buildup, as well as the improvement of synaptic activity and reduction of neuroinflammation. Recent clinical studies show improvements in sleep quality among older adults, in addition to safety and efficacy, and suggest increasing cognitive functioning in mild cognitive impairment and early AD. This review summarizes the existing research on the potential of Suvorexant as a therapeutic to address the mechanisms of orexin signaling in AD, as well as the sleep-targeted interventions to address the symptoms and modify the disease to improve cognitive functioning. We also emphasize future research directions such as cognitive outcomes over extended periods, potential optimal dosing, and combinatory strategies with lifestyle and/or medication therapies. This review will discuss the current evidence regarding the therapeutic effects of suvorexant and orexin signaling in AD.},
}

@article {pmid42312433,
year = {2026},
author = {Yang, L and Zeng, J and Huang, L and Li, L},
title = {The evolving burden of early-onset Alzheimer's disease and other dementias in BRICS countries: Insights from the Global Burden of Disease Study 2023 and projections to 2035.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261460745},
doi = {10.1177/13872877261460745},
pmid = {42312433},
issn = {1875-8908},
abstract = {BackgroundThe burden of early-onset Alzheimer's disease and other dementias (EOAD) in BRICS nations (Brazil, Russia, India, China, South Africa, Egypt, Ethiopia, Iran, Saudi Arabia, the United Arab Emirates, and Indonesia) is poorly characterized.ObjectiveOur aims are to characterize national trends, identify high-burden populations, quantify sex- and risk factor-specific burdens, and inform targeted prevention and age-inclusive healthcare strategies in these key nations.MethodsUsing data from the Global Burden of Disease Study (GBD) 2023, we analyzed EOAD (ages 40-64) across BRICS countries from 1990-2023, employing decomposition, Joinpoint regression, and Bayesian Age-Period-Cohort modeling to project trends to 2035.ResultsPrevalent cases increased in all nations, led by China. Age-standardized incidence rose in China (average annual percentage change 0.461%) but declined in India and Iran. Females consistently bore a higher burden. Ambient particulate matter drove substantial disability-adjusted life years in Iran (74.43/100,000) and Saudi Arabia, while household air pollution was key in Ethiopia and India. Projections indicate divergence by 2035, with Russia's incidence rising to 56.22 and Saudi Arabia's prevalence falling to 160.10 per 100,000.ConclusionsEOAD burden in BRICS is heterogeneous, driven by aging, sex, and modifiable risks, necessitating tailored public health strategies.},
}

@article {pmid42312440,
year = {2026},
author = {Du, J and An, Z and Niu, X and Luo, Y and Jing, Y and Yu, A},
title = {Serum SIRT3 Levels and Their Relationship With Alzheimer Disease Pathological Markers in Individuals With Mild Cognitive Impairment.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {},
number = {},
pages = {},
pmid = {42312440},
issn = {1543-3641},
support = {20250900//Medical Science Research Project of Hebei Province/ ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) sits between normal aging and Alzheimer disease (AD). Identification of accessible serum biomarkers linked with Alzheimer pathology may facilitate early detection and intervention, potentially delaying disease progression.

OBJECTIVE: To explore the associations between serum sirtuin-3 (SIRT3) levels in individuals with MCI with AD pathological markers related to cognitive function.

METHODS: This prospective observational study included 106 participants with MCI and 100 age- and sex-matched cognitively healthy controls (HC). We quantified SIRT3, inflammatory cytokines (IL-6 and IL-17), and AD biomarkers (Aβ40, Aβ42, and p-Tau) by enzyme-linked immunosorbent assay. We used standardized neuropsychological tests to assess cognitive function. Logistic regression and receiver operating characteristic curve analyses were conducted to evaluate the diagnostic potential of serum SIRT3.

RESULTS: SIRT3 levels were significantly lower in individuals with MCI compared to HC (p < 0.05). Individuals with MCI exhibited decreased serum Aβ42, reduced Aβ42/Aβ40 ratio, and increased p-Tau levels (p < 0.05). SIRT3 levels were positively correlated with cognitive performance scores, positively associated with Aβ42 and Aβ42/Aβ40 ratio, and negatively correlated with p-Tau levels. Receiver operating characteristic curve analysis demonstrated that SIRT3 had promising diagnostic value in differentiating individuals with MCI from HC. Logistic regression analysis identified lower SIRT3 levels, reduced Aβ42, and a decreased Aβ42/Aβ40 ratio as significant independent risk factors for MCI.

CONCLUSION: Reduced SIRT3 levels were associated with cognitive impairment and AD biomarkers in individuals with MCI, suggesting that SIRT3 might serve as a novel, minimally invasive adjunctive biomarker for early identification of MCI.},
}

@article {pmid42312515,
year = {2026},
author = {M, M and Kaliyaperumal, R},
title = {Taxifolin-Functionalized Rivastigmine Liposomal Nanoformulation: A Synergistic Approach for Alzheimer's Disease Management.},
journal = {Pharmaceutical nanotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0122117385456970260609153349},
pmid = {42312515},
issn = {2211-7393},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative condition characterized by cognitive decline, oxidative stress, and amyloid plaque accumulation. Current therapies, including cholinesterase inhibitors, mainly provide symptomatic relief and are limited by suboptimal brain delivery, necessitating multifunctional nanocarrier-based strategies. This study aimed to formulate and evaluate a Taxifolin-decorated Rivastigmine liposomal nanocarrier (Tax-Riva-Lipo) to achieve synergistic neuroprotection through combined cholinesterase inhibition, antioxidant defense, and anti-amyloid activity.

METHODS: Taxifolin was covalently conjugated to DSPE-PEG using EDC/NHS chemistry and incorporated into Rivastigmine-loaded liposomes prepared by thin-film hydration. The optimized formulation was characterized by DLS, TEM, FTIR, and DSC. In vitro evaluations included release kinetics, cholinesterase inhibition, antioxidant assays, and neuroprotection studies, followed by in vivo assessment in an ICV-STZ-induced AD rat model.

RESULTS: Tax-Riva-Lipo formed uniform nanosized vesicles (~145 nm) with high encapsulation efficiency (≈85%) and sustained drug release up to 48 h. The formulation showed enhanced AChE and BuChE inhibition (IC₅₀: 0.08 μM and 0.52 μM), strong free radical scavenging activity, and significant protection of SH-SY5Y cells (92% viability). In vivo studies demonstrated improved cognitive performance, restoration of antioxidant enzymes (SOD, CAT, GSH), suppression of proinflammatory cytokines (TNF-α, IL-6), and preservation of hippocampal architecture without detectable toxicity.

DISCUSSION: These findings indicate that Taxifolin functionalization enables complementary multitarget actions, integrating antioxidant and anti-amyloid effects with sustained cholinesterase inhibition.

CONCLUSION: Tax-Riva-Lipo represents a promising synergistic nanotherapeutic platform for improved management of Alzheimer's disease.},
}

@article {pmid42312520,
year = {2026},
author = {R, N and Dubey, S and Kumar, D and Walhekar, V and Tiwari, P},
title = {In Silico Prediction, Characterization, and Pre-clinical Appraisal of the Neuroprotective Effect of the Methanolic Extract of Cassytha filiformis.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026456568260601100209},
pmid = {42312520},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a severe neurodegenerative disorder that progressively worsens with age. Medicinal plants have demonstrated potential for the management of AD. Cassytha filiformis, a native plant of the Indian subcontinent, has been reported to exhibit antioxidant activity, which could be beneficial in neurodegenerative disorders.

METHODS: This study evaluates the anti-neurodegenerative effect and possible mechanism of action of a methanolic extract of Cassytha filiformis (MECF). Two compounds, AC-2 and AC-4, were isolated from the extract and assessed for cognitive behavior using the Morris water maze and probe test, followed by evaluation of antioxidant, neurochemical, and anti-inflammatory parameters, as well as in silico studies.

RESULTS: Neurochemical abnormalities (acetylcholinesterase (AChE), NMDA (N-methyl-Daspartate), dopamine (DA)), neuro-inflammatory markers (TNF-α, IL-6), and antioxidant parameters (superoxide dismutase (SOD), lipid peroxidation (LPO), nitric oxide (NO)) were evaluated. Histological examination of brain cells assessed the regenerative impact of the isolated compounds. Antioxidant levels and neuroinflammation were significantly reduced (p < 0.05) in the MECF-, AC-2-, and AC-4-treated groups. Additionally, superoxide dismutase and catalase levels were significantly increased in the treated groups. Acetylcholine, NMDA, and dopamine levels showed marked improvement. Histopathological analysis revealed neuroregeneration in the test groups, and hematological evaluations supported these findings by demonstrating normalization of elevated blood profiles observed in the scopolamine-induced groups.

DISCUSSION: MECF and its isolated compounds, AC-2 and AC-4, exhibited notable antioxidant and neuro-anti-inflammatory properties, enhancing cognitive function, learning, and memory. The observed neuroprotective effects suggest a potential therapeutic role for these compounds in the management of AD.

CONCLUSION: Phenolic compounds present in AC-2 and AC-4 may be integral to the mechanism of action of MECF. Further investigations, including clinical validation, are necessary to explore the therapeutic potential of MECF, AC-2, and AC-4 in AD treatment.},
}

@article {pmid42312809,
year = {2026},
author = {Hajek, T and Munthe, S and Licht, RW},
title = {Lithium orotate: distinct compound or simply Li[+] after administration?.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-3},
doi = {10.1192/bjp.2026.10699},
pmid = {42312809},
issn = {1472-1465},
abstract = {The recent study by Aron et al about lithium deficiency and the onset of Alzheimer's disease provides a valuable explanatory framework for understanding how very small doses of lithium, delivered via environmental exposure, can exert neuroprotective effects. It also contains results which will need to be reconciled with foundational chemistry and existing evidence and which could be potentially misleading. The suggestion that lithium orotate (LiO) exhibits benefits relative to the more traditionally used lithium carbonate (LiC) requires further scrutiny in light of the following arguments: (a) no study has demonstrated the presence of stable LiO in physiological fluids; (b) acid-base chemistry predicts that LiO will be largely protonated in the stomach, causing it to dissociate and be absorbed as Li[+]; (c) experimental studies indicate that LiO and LiC have comparable pharmacokinetics after oral administration; and (d) previous research has shown that LiC also has neuroprotective effects, including at very low doses. Disproportionate focus on a specific lithium salt could have safety implications and may distract from answering fundamental questions about the effects of very low doses of lithium. More experiments are needed to provide evidence of a stable LiO complex in physiological fluids before this becomes the main form of lithium in future clinical trials.},
}

@article {pmid42312952,
year = {2026},
author = {Huang, F and Liu, Y and Wang, Y and Lv, Z and Xu, J and Zhang, J and Ding, F and Sun, Y},
title = {Coaggregation with Aβ Drives β-Sheet Formation in tau Microtubule-Binding Repeats.},
journal = {Biomacromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biomac.5c02524},
pmid = {42312952},
issn = {1526-4602},
abstract = {Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau aggregates, yet the molecular basis of Aβ-tau coaggregation remains unclear. Here, we used multiple microsecond-scale discrete molecular dynamics simulations to examine homodimerization of tau microtubule-binding repeats (R1-R4) and their heterodimerization with Aβ. R1, R2, and R4 showed weak homodimerization, whereas heterodimerization with Aβ markedly enhanced interpeptide contacts and β-sheet formation. R3 exhibited strong intrinsic aggregation propensity and was further stabilized into β-sheet-rich conformations upon interacting with Aβ. Residue-level analyses identified Aβ11-21 and Aβ30-41 as structural templates promoting β-sheet transitions in tau. Thermodynamic analyses further supported an energy-entropy compensation mechanism in which aggregation-prone β-sheet edges of Aβ lowered the potential energy to offset entropic costs, thereby stabilizing low-free-energy coaggregated states. These findings provide atomistic insights into Aβ-facilitated tau coaggregation relevant to early AD pathology.},
}

@article {pmid42313213,
year = {2026},
author = {Arab, ZN and Razavi, SM and Golikhatir, K and Momeni, A and Hashemi, N and Ramezani, F and Momtaz, S and Eid, AH and Jamialahmadi, T and Kesharwani, P and Abdolghaffari, AH and Sahebkar, A},
title = {Mechanistic interactions between curcumin and statins: pharmacological convergence and therapeutic implications.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42313213},
issn = {1573-4978},
mesh = {Humans ; *Curcumin/pharmacology/therapeutic use ; Animals ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Antioxidants/pharmacology ; Neurodegenerative Diseases/drug therapy ; Drug Synergism ; },
abstract = {Cardiovascular and neurodegenerative disorders remain major contributors to global morbidity and mortality, underpinned by overlapping pathogenic processes including chronic inflammation, oxidative stress, endothelial dysfunction, and mitochondrial impairment. Therapeutic strategies capable of simultaneously modulating these interconnected pathways are increasingly recognized as essential for improving clinical outcomes. Curcumin (CUR), a pleiotropic polyphenolic compound derived from Curcuma longa, and statins, widely prescribed lipid-lowering agents, exhibit a broad spectrum of anti-inflammatory, antioxidant, and cytoprotective effects that extend beyond their canonical pharmacological actions. This review critically examines the molecular and pharmacological synergy between CUR and statins, with particular emphasis on their coordinated regulation of key signaling cascades, including NF-κB, iNOS, MAPK, and Nrf2-mediated antioxidant responses. Evidence from in vitro, in vivo, and emerging clinical studies indicates that CUR-statin co-administration may elicit additive or synergistic protective effects across diverse pathological contexts, such as atherosclerosis, myocardial ischemia-reperfusion injury, Alzheimer's disease, Parkinson's disease, and spinal cord injury, Myopathy, wound healing, and anti-cancer effects. Unfortunately, the majority of available experiments are preclinical and fewer clinical studies have been performed until now. At the cellular and tissue levels, this combinatorial approach appears to restore vascular homeostasis, preserve mitochondrial function, enhance neuronal survival, and suppress sustained inflammatory signaling. Collectively, the available data underscore a compelling pharmacological rationale for CUR-statin combination therapy as a multitarget intervention for complex cardiometabolic, neurodegenerative diseases, and a wide variety of disorders. Future investigations should focus on optimizing dosing regimens, improving CUR bioavailability, elucidating pharmacokinetic-pharmacodynamic interactions, and validating therapeutic efficacy through well-designed clinical trials.},
}

Humans
*Curcumin/pharmacology/therapeutic use
Animals
*Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/therapeutic use
Signal Transduction/drug effects
Oxidative Stress/drug effects
Antioxidants/pharmacology
Neurodegenerative Diseases/drug therapy
Drug Synergism

@article {pmid42313214,
year = {2026},
author = {Lüleci, HB and Jones, A and Neff, RA and Bennett, DA and Zhang, B and Çakır, T and Thambisetty, M},
title = {Unraveling Aberrant Metabolic Patterns in Alzheimer's Disease Subtypes: From Perturbed Metabolic Pathways to Candidate Drug Targets.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42313214},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/genetics/classification ; *Metabolic Networks and Pathways/drug effects ; Metabolome ; *Molecular Targeted Therapy ; },
abstract = {Alzheimer's Disease (AD) is characterized by multiple metabolic abnormalities that differ between individuals. In this study, we aimed to elucidate metabolic dysregulations associated with five distinct molecular subtypes of AD, defined in a recent report, based on brain transcriptome data from two autopsy-derived datasets with approximately 550 AD patients. We mapped transcriptome data from each individual on a human genome-scale metabolic network to create personalized metabolic models. We identified aberrant metabolic patterns common across AD subtypes as well as those specific to each AD subtype. More than 20 metabolic pathways were found to be dysregulated in both datasets, with a majority of these pathways unidentified by a conventional subtype-agnostic approach. Among these, fatty acid metabolism was found to be dysregulated commonly in all subtypes while inositol phosphate metabolism and nucleotide metabolism were among the subtype-specific perturbed pathways. These results were independently validated through analyses of metabolome data available in one of the datasets. Moreover, upregulated secretion of pregnenolone and N-acetylneuraminate and therapeutic targeting of ALDH18A1 and SLC6A12 were among the subtype-specific candidate metabolite biomarkers and drug targets, respectively, predicted by our metabolic modeling approach, with available literature support. Subtype-specific metabolic abnormalities catalogued in our study may provide novel insights for understanding biological mechanisms implicated in AD pathogenesis as well as precision-guided treatments targeting dysregulated metabolism in AD.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/genetics/classification
*Metabolic Networks and Pathways/drug effects
Metabolome
*Molecular Targeted Therapy

@article {pmid42313219,
year = {2026},
author = {Kashif, M and Majumder, D},
title = {Alzheimer's Disease and MERC Dysfunction: Integrating Mechanisms, Biomarkers, and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42313219},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/pathology ; Animals ; *Mitochondria/metabolism/pathology ; *Endoplasmic Reticulum/metabolism/pathology ; *Biomarkers/metabolism ; Mitochondria Associated Membranes ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, memory loss, and neuronal dysfunction. The pathological hallmarks are characterized by extracellular amyloid-β (Aβ) plaques, intracellular tau tangles, neuroinflammation, and synaptic failure. However, these only partially explain disease onset and progression. Recent evidence highlights mitochondria-endoplasmic reticulum contact sites (MERCs) as crucial hubs of cellular homeostasis, integrating calcium exchange, lipid metabolism, redox balance, and autophagy regulation. Dysregulation of MERC signaling is emerging as a central contributor to AD pathogenesis. MERCs orchestrate processes that intersect with amyloidogenic processing, tau hyperphosphorylation, mitochondrial dysfunction, and impaired clearance of protein aggregates. Aberrant tethering protein expression, disrupted calcium transfer, and altered lipid trafficking at MERCs have been reported in both familial and sporadic AD models, underscoring their pathogenic relevance. Moreover, MERCs influence neuroinflammatory cascades and synaptic remodeling, bridging molecular alterations with clinical manifestations. This review synthesizes current knowledge on MERC biology in the context of AD, highlighting molecular mechanisms, disease-specific perturubations, and therapeutic opportunities. In this review, we discussed pharmacological and genetic interventions targeting MERCs, including small molecules, natural compounds, and nanotechnology-based approaches. Taken together, this review outlines open research questions and future directions, underscoring MERC signaling as a promising frontier for therapeutic innovation in AD.},
}

Humans
*Alzheimer Disease/metabolism/therapy/pathology
Animals
*Mitochondria/metabolism/pathology
*Endoplasmic Reticulum/metabolism/pathology
*Biomarkers/metabolism
Mitochondria Associated Membranes

@article {pmid42313222,
year = {2026},
author = {Deng, P and Deng, W and Wang, L and Ye, W and Li, S},
title = {Exercise-Driven NRF2 Activation as a Systemic Neuroprotective Strategy: Integrating Redox Biology, Muscle-Brain Crosstalk, and Therapeutic Targeting in Neurodegeneration.},
journal = {Biochemical genetics},
volume = {},
number = {},
pages = {},
pmid = {42313222},
issn = {1573-4927},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, are characterized by progressive neuronal dysfunction and loss. Recent evidence highlights the importance of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of cellular defense mechanisms, in maintaining neuronal health and function. A narrative literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant experimental, clinical, and review studies on NRF2 signaling, physical exercise, oxidative stress, muscle-brain crosstalk, and neurodegenerative diseases. Keywords included "NRF2", "Nrf2/Keap1/ARE", "physical exercise", "exercise-induced oxidative stress", "myokines", "exerkines", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", and "amyotrophic lateral sclerosis". NRF2 modulates the expression of a variety of antioxidant and cytoprotective genes, contributing to the protection of neurons against oxidative stress, inflammation, and protein aggregation, processes central to the pathogenesis of neurodegenerative diseases. Additionally, physical activity has been identified as a powerful modulator of NRF2 activation, with exercise offering neuroprotective effects through the induction of NRF2-mediated pathways. This review explores the interplay between NRF2 activation and physical exercise in the context of neurodegenerative diseases, detailing the molecular mechanisms by which exercise influences NRF2 activity to combat cellular damage and enhance neuroprotection. We discuss the therapeutic potential of combining exercise regimens with NRF2-targeted therapies, highlighting the promise of this dual approach in slowing disease progression, improving cognitive function, and enhancing quality of life in affected individuals. Furthermore, we examine the challenges and future directions for clinical implementation, including optimal exercise protocols and the development of NRF2-based pharmacological interventions. This review underscores the importance of NRF2 as a central mediator of neuroprotection and the therapeutic promise of physical activity in the management of neurodegenerative diseases.},
}

@article {pmid42313223,
year = {2026},
author = {Yuan, Z and Zhang, J and Zhou, Z and Chen, X and Qi, N and Wang, W and Cheng, X and Lin, Y and Zhao, J},
title = {Radiomics-enhanced [18]F-AV45 PET/MRI for integrative assessment and centiloid estimation of amyloid-β burden in Alzheimer's disease.},
journal = {European radiology experimental},
volume = {10},
number = {1},
pages = {},
pmid = {42313223},
issn = {2509-9280},
support = {2022YFC2406900//National Key Research and Development Program of China/ ; PWZxk2022-12//Key Discipline Construction Project of Shanghai Pudong New Area Health Commission/ ; },
mesh = {Humans ; Radiomics ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods ; *Magnetic Resonance Imaging/methods ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; *Aniline Compounds ; Retrospective Studies ; Aged ; Multimodal Imaging ; *Ethylene Glycols ; Radiopharmaceuticals ; Aged, 80 and over ; },
abstract = {OBJECTIVE: Reliable assessment of cerebral amyloid-β (Aβ) deposition is essential for the diagnosis and management of Alzheimer's disease (AD). This study aimed to evaluate the feasibility of integrating radiomics-enhanced [18]F-florbetapir positron emission tomography/magnetic resonance imaging ([18]F-AV45 PET/MRI) features for Aβ status evaluation and to further explore their potential for continuous Centiloid prediction in AD.

MATERIALS AND METHODS: Ninety-four subjects who underwent ([18]F-AV45 PET/MRI (60 Aβ-positive, 34 Aβ-negative) were retrospectively included. Standardized uptake value ratio (SUVr) features were extracted from seven cortical regions (frontal, temporal, parietal, occipital, insular, cingulate, and white matter), and corresponding T1-weighted images' radiomics features were computed. Three feature sets (PET, radiomics, and combined) were analyzed using logistic regression (LR), k-nearest neighbor (kNN), and linear discriminant analysis (LDA) with 10-fold cross-validation. The best performing model was further interpreted using SHapley Additive exPlanations (SHAP) analysis. Additionally, Centiloid regression was performed using random forest, ElasticNet, and ExtraTrees regressors.

RESULTS: The combined feature achieved the best performance with the LR model, with area under the receiver operating characteristic curve = 0.9373, accuracy = 0.8723, F1-score = 0.898). SHAP analysis identified biologically meaningful features derived from both radiomics and PET modalities, showing clear inter-group separation. In Centiloid regression, the ExtraTrees model achieved strong agreement with measured values.

CONCLUSION: This framework provides an interpretable and quantitative solution for amyloid evaluation, enabling both categorical Aβ status discrimination and continuous Centiloid estimation from routine PET/MRI data. This approach represents a proof-of-concept for supporting [18]F-AV45 PET-based assessment in AD.

RELEVANCE STATEMENT: This study demonstrates that radiomics-enhanced PET/MR features can reliably predict both Aβ status and Centiloid values without specialized processing platforms, offering a clinically deployable, standardized, and interpretable approach to improve AD diagnosis and monitoring.

KEY POINTS: Radiomics-enhanced [18]F-AV45 PET/MRI enabled quantitative Aβ evaluation in AD. Radiomics-enhanced [18]F-AV45 PET/MRI provided a noninvasive and interpretable assessment to improve clinical confidence. Radiomics-enhanced [18]F-AV45 PET/MRI allowed Centiloid estimation without specialized platforms for wider clinical use.},
}

Humans
Radiomics
*Alzheimer Disease/diagnostic imaging/metabolism
*Positron-Emission Tomography/methods
*Magnetic Resonance Imaging/methods
*Amyloid beta-Peptides/metabolism
Female
Male
*Aniline Compounds
Retrospective Studies
Aged
Multimodal Imaging
*Ethylene Glycols
Radiopharmaceuticals
Aged, 80 and over

@article {pmid42313252,
year = {2026},
author = {Freitas da Costa, B and Reuwsaat, K and Emele, N and Carvalho, CM and Caparelli-Dáquer, E and Panizzutti, R},
title = {Targeting brain rhythms to support cognition in aging: a systematic review and meta-analysis of tACS across healthy aging, mild cognitive impairment, and Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42313252},
issn = {2509-2723},
abstract = {Cognitive decline is a major challenge in aging. Transcranial alternating current stimulation (tACS) modulates neural oscillations, potentially aiding cognition. Due to variation in late-life tACS studies, we conducted the first meta-analysis in older adults (≥ 60 years) to estimate pooled cognitive effects and determine if protocol parameters explain outcome variability. We searched Medline/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov (up to September 17, 2025) for studies examining tACS effects on cognition in adults age ≥ 60 years, including healthy aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). Risk of bias was assessed using RoB 2 and ROBINS-I. Random-effects meta-analyses using Hedges' g were performed, with sensitivity analyses to handle outliers and heterogeneity. Twenty-two studies (n = 826 participants) were included. The primary meta-analysis revealed a significant moderate effect of tACS on cognition (g = 0.70, 95% CI 0.38-1.02), though with high heterogeneity (I[2] = 88.5%). Excluding one influential outlier yielded a more conservative and stable estimate (g = 0.55, 95% CI 0.39-0.70, I[2] = 47.1%). Subgroup analyses showed homogenous effects in MCI (g = 0.59, I[2] = 0%). Memory was the most responsive domain. Meta-regressions did not identify significant associations between outcomes and specific stimulation parameters. tACS was associated with improvements in cognitive outcomes in older adults, with more consistent evidence observed for memory in individuals with MCI. However, findings in healthy older adults and AD were more variable and should be interpreted in light of substantial methodological heterogeneity. Overall, the pooled estimate reflects an average across diverse populations and intervention protocols rather than a single, clinically uniform effect. Future research should prioritize standardized, dose-response protocols to support clinical translation. PROSPERO CRD42025629824.},
}

@article {pmid42313307,
year = {2026},
author = {Saini, K and Dhiman, P},
title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42313307},
issn = {1573-4978},
mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; },
abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.},
}

Humans
*Microglia/metabolism/pathology/immunology
*Neurodegenerative Diseases/metabolism/therapy/pathology/immunology
Animals
Signal Transduction
*Neuroinflammatory Diseases/metabolism/pathology/immunology
Blood-Brain Barrier/metabolism
Cytokines/metabolism
Astrocytes/metabolism

@article {pmid42313600,
year = {2026},
author = {Yu, G and Ying, H and Liu, J and Amin, N and van Duijn, CM and Yang, Y},
title = {GENIE: A Two-Stage Interpretable Deep Learning Framework for Revealing the High-Order Genetic Interaction Network of Alzheimer's Disease.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3705398},
pmid = {42313600},
issn = {2998-4165},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. The underlying mechanisms of AD onset and progression remain unclear. To date, no effective method has been able to uncover the complex, high-order single nucleotide polymorphism (SNP)/gene associations that could elucidate the pathogenesis of AD. Existing computational methods, which are either based on single-site detection with limited analytical capacity or multi-site modeling with low computational efficiency, struggle to handle the growing volume of large-scale, high dimensional data and are only capable of identifying low-order associations. To address these challenges, we propose a novel framework for explaining high-order multi-locus AD associations via deep neural networks, termed GENIE. This method accurately and efficiently calculates high-order associations between SNPs and genes, prioritizing potential interaction networks for downstream biomedical research. Our experimental results are supported by existing research and literature. Additionally, statistical validations of the model and its findings confirm the reliability of GENIE as a hypothesis generation tool.},
}

@article {pmid42302219,
year = {2026},
author = {Jayakody, O and Milman, S and Barzilai, N and Weiss, EF and Wang, C and Jin, Y and Blumen, H and Verghese, J},
title = {Cognitive Aging and Brain Health: A Comparison of Super Movers vs Nonsuper Movers.},
journal = {Neurology},
volume = {107},
number = {1},
pages = {e214776},
doi = {10.1212/WNL.0000000000214776},
pmid = {42302219},
issn = {1526-632X},
mesh = {Humans ; Female ; Aged, 80 and over ; Male ; *Brain/diagnostic imaging/pathology ; *Cognitive Aging/physiology ; Retrospective Studies ; *Cognitive Dysfunction/epidemiology/diagnostic imaging ; *Aging ; *Walking Speed/physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Super movers are individuals aged ≥80 years with gait speeds ≥1.5 SDs above age- and sex-adjusted means. Super movers tend to have lower prevalence of chronic medical conditions, healthier lifestyles, and younger biological age. The aim of this study was to examine their risk of incident cognitive impairment, trajectories of cognitive decline, and brain health.

METHODS: This study used a retrospective study design using data from older adults aged ≥80 without Alzheimer disease or dementia enrolled in 5 Health and Retirement Study International Network of Studies (HRS-INS), the LonGenity Study, and the RUSH Memory Aging Project (RUSH MAP). HRS-INS data were used to assess incident cognitive impairment (>1.5 SD below the age-adjusted means on any cognitive test plus impaired Instrumental Activities of Daily Living) in super movers vs nonsuper movers. Age- and sex-adjusted hazard ratios (HRs) from Cox models were pooled in a meta-analysis to obtain risk of incident cognitive impairment. LonGenity data were used to examine (1) decline in cognitive domains using linear mixed-effects models adjusted for age, sex, education, and parental longevity; (2) trajectories of global cognition before and after age 80; and (3) brain structural differences (cortical thickness, hippocampal volume) between super vs nonsuper movers. RUSH MAP data were used to assess dementia-related pathology.

RESULTS: HRS-INS study (n = 3,989, baseline age 83.6-84.4 years, 47%-65% females, 358 super movers), after excluding 274 adults with cognitive impairment at baseline, super movers had lower risk of incident cognitive impairment (HR 0.49, 95% CI 0.28-0.71) over follow-ups ranged between 3.4 and 5.4 years. In LonGenity (n = 197, baseline age 84.6 [SD 3.3], 57.8% women), super movers showed slower memory and non-memory-related cognitive decline and preserved hippocampal volume in specific subfields. In RUSH MAP (n = 692, baseline age 85.6 [SD 4.0], 68.9% women), super movers had better antemortem cognition and lower Alzheimer disease and dementia prevalence, but no differences in postmortem dementia-related pathologies.

DISCUSSION: Super movers show slower cognitive aging-indicated as lower risk for cognitive impairment and slower cognitive decline-and preserved hippocampal volumes. Investigating their behavioral and biological traits may reveal novel protective mechanisms against cognitive decline and dementia.},
}

Humans
Female
Aged, 80 and over
Male
*Brain/diagnostic imaging/pathology
*Cognitive Aging/physiology
Retrospective Studies
*Cognitive Dysfunction/epidemiology/diagnostic imaging
*Aging
*Walking Speed/physiology

@article {pmid42302369,
year = {2026},
author = {Al-Abboodi, ARR and Azman, KF},
title = {Lupeol in neurodegenerative and neuropsychiatric disorders: Mechanisms and translational perspectives.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119673},
doi = {10.1016/j.biopha.2026.119673},
pmid = {42302369},
issn = {1950-6007},
abstract = {Lupeol is a naturally occurring lupane-type pentacyclic triterpenoid widely distributed in dietary and medicinal plants and has attracted increasing interest as a potential neuroprotective compound. However, despite growing experimental evidence, its mechanistic and translational relevance has not been comprehensively evaluated. This review critically examines current evidence regarding the molecular, cellular and neurobehavioural effects of lupeol in neurodegenerative and neuropsychiatric disorders. Available preclinical studies indicate that lupeol modulates several interconnected pathological processes implicated in neurological disorders, including oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, excitotoxicity and synaptic impairment. These effects include preservation of neuronal integrity, improved cognitive and behavioural outcomes, and enhanced neurotrophic and synaptic plasticity across multiple experimental models of Alzheimer's disease, Parkinson's disease, cerebral ischemia, traumatic brain injury and neuroinflammation. Current findings suggest that lupeol exerts multi-target neuroprotective effects through coordinated regulation of oxidative, inflammatory and neuronal signalling networks rather than through a single molecular mechanism. Despite these encouraging findings, clinical translation remains limited by poor aqueous solubility, low bioavailability and insufficient pharmacokinetic and human safety data. Overall, lupeol represents a promising candidate for further investigation in neurological disorders, although rigorous translational studies remain necessary to clarify its therapeutic applicability.},
}

@article {pmid42302428,
year = {2026},
author = {Contador, J and Pozzi, FE and Sánchez-Benavides, G and Fernández-Arcos, A and Lantero-Rodríguez, J and Montoliu-Gaya, L and Minguillon, C and Fauria, K and González-Escalante, A and Ortiz-Romero, P and Blasco-Forniés, H and de Diego-Osaba, M and Jiménez Moyano, E and Quijano-Rubio, C and Kollmorgen, G and Le Bastard, N and Nadal, A and Vanmechelen, E and Jeromin, A and Torres-Torronteras, J and Ashton, NJ and Zetterberg, H and Blennow, K and Gispert, JD and Molinuevo, JL and Del Campo, M and Grau-Rivera, O and Suárez-Calvet, M and , },
title = {Detecting amyloid-β pathology in subjective cognitive decline using plasma and CSF biomarkers.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106331},
doi = {10.1016/j.ebiom.2026.106331},
pmid = {42302428},
issn = {2352-3964},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) may represent an early stage of Alzheimer's disease (AD), but biomarker studies in this population are limited. Therefore, we compared the performance of a comprehensive panel of novel cerebrospinal fluid (CSF) and blood biomarkers across different platforms for detecting amyloid-β (Aβ) pathology in SCD.

METHODS: 143 individuals with SCD (20% Aβ-positive) from the β-AARC cohort were included. Aβ status was determined by CSF Aβ42/40. CSF and blood biomarkers of Aβ, tau, synaptic function, neurodegeneration, and glial reactivity were measured cross-sectionally.

FINDINGS: In CSF, novel tau variants (p-tau205, p-tau217, p-tau231, p-tau235, NTA-tau) were elevated in Aβ-positive individuals with SCD. In plasma, p-tau217, p-tau217/Aβ42 (across multiple platforms), as well as p-tau181, p-tau181/Aβ42 and Aβ42/40 (platform-dependent) demonstrated strong discriminatory performance and high negative predictive value, but limited positive predictive value because of the low prevalence of Aβ pathology.

INTERPRETATION: In conclusion, several plasma biomarkers can exclude Aβ pathology in SCD, while some CSF and plasma markers indicate early AD-related changes. These plasma biomarkers could serve as accessible, cost-effective tools for early AD detection and risk stratification, and expedite the selection of candidates for disease-modifying treatments or preventive strategies.

FUNDING: The research leading to these results has received funding from the Alzheimer's Drug Discovery Foundation (ADDF) grants #RDADB-201906-2018897 and #201809-2016862. Additionally, the study has been funded by the Health Department of the Catalan Government, the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 948677), and PI22/00456, funded by Instituto de Salud Carlos III (ISCIII).},
}

@article {pmid42302487,
year = {2026},
author = {Hatakama, H and Sugao, K and Kassai, M and Miyauchi, M and Baba, S and Takeda, Y and Miyazaki, K and Yamada, K and Niu, M and Natsutani, I and Saito, K and Nishikawa, H and Kato, T},
title = {DSP-2342, a novel 5-hydroxytryptamine 2A/7 receptor antagonist, has therapeutic potential for behavioral and psychological symptoms of dementia.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {7},
pages = {104949},
doi = {10.1016/j.jpet.2026.104949},
pmid = {42302487},
issn = {1521-0103},
abstract = {In an aging society, behavioral and psychological symptoms of dementia (BPSD) have emerged as a major public health concern. BPSD includes diverse symptoms such as psychosis, anxiety, and agitation/aggression. Although antipsychotics are widely used to manage BPSD, their use is limited because of safety concerns, particularly extrapyramidal symptoms associated with dopamine D2 receptor antagonism. Therefore, there is a need for antipsychotic drugs that are effective without relying heavily on D2 receptor blockade. Here, we report DSP-2342, a novel selective 5-hydroxytryptamine 2A/7 (5-HT2A/5-HT7) receptor antagonist, which exhibits very low affinity for D2 receptors. A mouse-behavior phenotyping platform predicted that DSP-2342 possesses antipsychotic, anxiolytic, mood-stabilizing, and antidepressant signatures. Consistent with these predictions, DSP-2342 suppressed phencyclidine-induced hyperlocomotion in mice, reduced freezing in rat contextual fear conditioning test. DSP-2342 also attenuated aggressive behavior in resident-intruder test in Alzheimer disease model mice. Furthermore, DSP-2342 restored cognitive performance in another Alzheimer disease model mice, as assessed by the novel object recognition test. To explore the underlying mechanism, a rat microdialysis study showed that DSP-2342 increased extracellular levels of noradrenaline, dopamine, and glutamate in the medial prefrontal cortex. The whole-brain c-Fos mapping revealed that DSP-2342 activated multiple brain regions and demonstrated a synergistic integration of 5-HT2A and 5-HT7 receptor antagonism, potentially underlying its distinctive pharmacological profile. Collectively, these findings suggest that the broad pharmacological effects of DSP-2342 through dual antagonism of 5-HT2A and 5-HT7 receptors may enable the management of diverse BPSD while maintaining a favorable safety profile. SIGNIFICANCE STATEMENT: DSP-2342, a novel 5-hydroxytryptamine 2A/7 antagonist, shows preclinical efficacy across behavioral and psychological symptoms of dementia (BPSD)-including psychosis, anxiety, and agitation-while improving cognition. Unlike typical antipsychotics, it has very low dopamine D2 affinity, suggesting lower motor side-effect risk and a safer profile for BPSD.},
}

@article {pmid42302500,
year = {2026},
author = {Habib, YH and Gwaily, NA and Ali, MY and Fawzy, MA and Zakaria, MA and Ali, MA},
title = {Repurposing anti-inflammatory therapeutics fordisorders of the microbiome-gut-brain axis.},
journal = {Journal of neuroimmunology},
volume = {419},
number = {},
pages = {579000},
doi = {10.1016/j.jneuroim.2026.579000},
pmid = {42302500},
issn = {1872-8421},
abstract = {The microbiome-gut-brain axis (MGBA) redefines the field of anti-inflammatory therapeutics by shifting from targeting isolated immune pathways in an organ to a bidirectional, integral network, composed of gut microbiota, the peripheral immune system, barrier tissues, and neural circuits. Such reframing is predominantly pertinent for certain CNS and systemic diseases, including Alzheimer's disease and ischemic stroke. These diseases have been resistant to conventional anti-inflammatory agents that either poorly pass the blood-brain barrier or do not inhibit the upstream inflammatory drivers. Increasing evidence demonstrates that microbial communities and their metabolites modulate systemic and central immune tone, and affect barrier integrity, hence brain inflammation frequently presents with a measurable fingerprint in the gut and vice versa. Targeted microbiome therapies, metabolite replacement, and biomarker-guided patient stratification all emerge as promising new strategies when acknowledging the gut is a modifiable source. Mechanistically, the crosstalk between neuro-immune-microbial trails creates concrete therapeutic entry points. These include: (1) altering microbial enzymes that produce pro-inflammatory metabolites, (2) delivering beneficial metabolites to support homeostatic glial states, and (3) modulating afferent neural pathways like vagus nerve stimulation, which triggers the cholinergic anti-inflammatory pathway (CAP). The future of MGBA-targeted therapeutics will mostly repurpose current anti-inflammatory agents and neuromodulatory strategies into combinatorial ones that pair source control (gut-restricted drugs) with targeted central modulation (microglial modulators such as minocycline) and neural orchestration (vagus nerve stimulation, VNS). These repurposing strategies are increasingly guided by baseline inflammatory and microbiome biomarkers and may help in establishing new therapeutic paradigms for these intersecting disorders of the gut, immune system, and brain in appropriately defined patient subgroups.},
}

@article {pmid42302540,
year = {2026},
author = {Pietilä, E and Karrasch, M and Helin, S and Snellman, A and Viitanen, M and Jula, A and Rinne, JO and Ekblad, LL},
title = {Midlife insulin resistance and brain beta-amyloid accumulation as predictors of change in late-life cognitive function - A 20-year follow-up study.},
journal = {Neurobiology of aging},
volume = {167},
number = {},
pages = {29-41},
doi = {10.1016/j.neurobiolaging.2026.06.004},
pmid = {42302540},
issn = {1558-1497},
abstract = {The number of people with dementia will increase as populations age. Insulin resistance (IR) is associated with cognitive decline and dementia. We studied in this longitudinal, population-based cohort study, if change in late-life cognitive function during 5-year follow-up would be predicted by midlife IR (measured 15 years before the first late-life visit) or by late-life brain beta-amyloid (Aβ) accumulation or longitudinal change in late-life Aβ accumulation. Participants (n = 43) were recruited from the population-based Finnish Health 2000 study according to their homeostatic model assessment of insulin resistance (HOMA-IR) values measured in midlife (mean age at midlife 55.1 years), and their APOE ε4 genotype. [[11]C]PIB-PET imaging (n = 42) and neurocognitive testing (n = 43) were conducted at late-life baseline in 2014 -2016 and after 5-year follow-up in 2019 -2021 (mean age at follow-up 74.8 years). During 5-year follow-up, the decline in late-life (from 2014 -2016 to 2019 -2021) episodic memory was greater in midlife insulin resistance (IR+) group than in the group with normal midlife insulin sensitivity (IR-): IR+ group -0.92 (0.22) vs. IR- group -0.43 (0.26), p = 0.03, (adjusted mean change in episodic memory z-score (standard error)). Late-life brain Aβ burden predicted a greater decline in episodic memory (p = 0.02). The association between midlife IR and episodic memory decline was mediated through late-life Aβ burden. Change in Aβ accumulation during the follow-up was not associated with change in cognition at late-life. In conclusion, midlife IR and late-life brain Aβ burden increased the risk of episodic memory decline in late-life. Our results suggest a link between IR and Alzheimer´s disease.},
}

@article {pmid42302727,
year = {2026},
author = {Kim, MS and Kang, D},
title = {Why Deep Cervical Lymphovenous Anastomosis for Alzheimer Disease Lacks Scientific Foundation.},
journal = {The Journal of craniofacial surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/SCS.0000000000013042},
pmid = {42302727},
issn = {1536-3732},
abstract = {Deep cervical lymphovenous anastomosis (DCLVA) has been rapidly adopted as a surgical treatment for Alzheimer disease (AD), based on the hypothesis that enhancing cervical lymphatic drainage may promote glymphatic clearance of neurotoxic proteins. By mid-2025, an estimated 382 hospitals in China had performed the procedure before any randomized controlled trial was completed, prompting China's National Health Commission to prohibit its clinical use on the grounds of insufficient evidence. That prohibition addressed the absence of clinical trial data but did not articulate a specific physiological objection. Following a recent critical review of lymphovenous anastomosis in the lower extremity, the senior author investigated the status of this technique in the craniofacial region and found that its dominant application is not for head and neck lymphedema but for AD. This review identifies fundamental scientific gaps in the rationale for DCLVA in AD. The target pathology-cervical lymphatic insufficiency-has never been confirmed in living patients with AD. Preclinical evidence is contradictory: modulating dural lymphatic vessels in either direction does not alter amyloid pathology in mouse models. No study has controlled for confounding anesthetic effects. No standardized surgical protocol exists. Hemodynamic conditions at the anastomotic site during supine sleep-when glymphatic clearance is most active-have never been measured. Serious adverse events have already been reported. These gaps represent deficiencies in the fundamental science that must be resolved before clinical investigation can be justified.},
}

@article {pmid42302756,
year = {2026},
author = {Reekes, TH and Upadhya, VR and Merenstein, JL and Cooter Wright, M and Madden, DJ and Reese, MA and Boykin, PC and Timko, NJ and Mathew, JP and Devinney, MJ and Browndyke, JN and Berger, M and , },
title = {Association of Preoperative Posterior Cingulate Cortex Microstructural Damage With Postoperative Delirium.},
journal = {Anesthesia and analgesia},
volume = {},
number = {},
pages = {},
doi = {10.1213/ANE.0000000000008127},
pmid = {42302756},
issn = {1526-7598},
abstract = {BACKGROUND: Postoperative delirium is the most common postsurgical complication in older adults and is associated with an increased risk of long-term cognitive decline and Alzheimer's disease (AD) and related dementias (ADRD). However, the neurological basis of this increased risk-whether postoperative delirium unmasks latent preoperative pathology or leads to AD-relevant pathology after perioperative brain injury-remains unclear.

METHODS: To investigate potential brain microstructural abnormalities associated with postoperative delirium and cognitive function, we analyzed pre- and post-operative Neurite Orientation Dispersion and Density Imaging (NODDI) MRI data within the posterior cingulate cortex (PCC) from 110 patients aged ≥60 years who underwent non-cardiac/non-intracranial surgery.

RESULTS: We found increased free water (FISO) and decreased neurite density index (NDI) and orientation dispersion index (ODI) in the dorsal PCC before surgery among those who later developed postoperative delirium (n = 12) versus those who did not (n = 98). Preoperative dorsal PCC NDI and ODI values were also positively associated with preoperative attention/concentration performance, independent of age, education level, and global brain atrophy (NDI: = 0.29 (95% CI, 0.10-0.50), P = .008; ODI: = 0.29 (95% CI, 0.03-0.44), P = .004). Yet, these diffusion metrics were not correlated with cerebrospinal fluid amyloid beta (Aβ) positivity or levels.

CONCLUSIONS: These results suggest that preoperative latent brain abnormalities within the dorsal PCC may underlie attention/concentration deficits and susceptibility to postoperative delirium, yet these dorsal PCC NODDI abnormalities were not significantly associated with CSF Aβ levels (a measure of brain Amyloid deposition). Our findings highlight microstructural vulnerability within the PCC, a key region of the default mode network, as a neuroanatomic locus that can help explain the link between preoperative attention/concentration deficits and increased postoperative delirium risk among vulnerable older surgical patients.},
}

@article {pmid42302882,
year = {2026},
author = {Fotoohinasab, A and Ugonna, CP and Calhoun, VD and Chen, NK},
title = {Adaptive Gaussian graph-spectral filtering for scale-specific connectivity inference.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122055},
doi = {10.1016/j.neuroimage.2026.122055},
pmid = {42302882},
issn = {1095-9572},
abstract = {Functional connectivity changes in neurodegeneration involve not only regional disconnection but also scale-specific reorganization of brain networks. We introduce the Multiscale Spectral Gaussian Filtering (MSGauF) framework, which transforms each subject's Laplacian spectrum into a data-driven coordinate system for connectivity analysis. MSGauF defines adaptive frequency bands from spectral changepoints, and within each band, normalized similarity measures enable sign-separated, cluster-level permutation testing without requiring eigenvector alignment. Simulations show improved precision when connectivity changes are confined to specific spectral ranges. Applied to resting-state fMRI from Alzheimer's and Parkinson's cohorts, the method revealed distinct spectral signatures of disease. In Alzheimer's disease, connectivity shifted from large-scale attenuation in mild impairment to fine-scale polarity reversal, reflecting disrupted long-range inhibition and local hyperexcitability. In Parkinson's disease, polarity was preserved but spectrally compressed, indicating reduced flexibility and rigid synchronization of local circuits. These findings highlight the advantages of frequency-resolved analysis in revealing structured, multiscale connectivity changes that are missed by conventional broadband approaches.},
}

@article {pmid42303509,
year = {2026},
author = {Ebrahim, N and Al Saihati, HA and Alali, Z and Aleniz, FQ and Mahmoud, SYM and Badr, OA and Dessouky, AA and Mostafa, O and Hussien, NI and Farid, AS and El-Sherbiny, M and Salim, RF and Forsyth, NR and Ali, FEM and Alsabeelah, NF},
title = {Retraction notice to "Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway" [Biomedicine & Pharmacotherapy 176 (2024) 116836].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119641},
doi = {10.1016/j.biopha.2026.119641},
pmid = {42303509},
issn = {1950-6007},
}

@article {pmid42303527,
year = {2026},
author = {Ali, K and Justo, M and Badiee, B and Mahrokhi, S and Rosenthal, RJ and Benharash, P and Chen, Y},
title = {Association of metabolic and bariatric surgery and risk of cognitive impairment among U.S. adults.},
journal = {Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.soard.2026.05.017},
pmid = {42303527},
issn = {1878-7533},
abstract = {BACKGROUND: Evidence suggests metabolic health plays a significant role in long-term cognitive outcomes. Whether this association stems from weight loss operations or other factors, remains controversial. Although a link between metabolic and bariatric surgery (MBS) and reduced likelihood of cognitive impairment has also been reported, a large-scale analysis of this association is lacking.

OBJECTIVE: To evaluate the association of prior metabolic surgery and the odds of cognitive impairment.

SETTING: Academic, university-affiliated; US.

METHODS: All adult (≥18 years) hospitalizations with a diagnosis of obesity were identified in the 2016-2022 Nationwide Inpatient Sample. The association of MBS with odds of cognitive impairment and its subclasses was characterized after doubly robust risk adjustment using entropy balancing followed by multivariable regression models.

RESULTS: Of 4,597,465 admissions with a diagnosis for obesity, 22.1% had a history of MBS. Following adequate risk-adjustment, prior MBS was associated with lower odds of Alzheimer's disease (AD) (adjusted odds ratio [AOR] .67, 95% confidence interval [CI] .59-.75) and vascular dementia (AOR .55, 95% CI .47-.64), but greater odds of Wernicke's Encephalopathy (AOR 5.03, 95% CI 3.76-6.72). These findings persisted across all age groups. Among the three classes of obesity, patients with a history of MBS with class III obesity had the lowest odds of dementia (AOR .66, 95% CI .60-.72).

CONCLUSIONS: Prior MBS is associated with lower odds ratio of AD and vascular dementia, among those with obesity. These findings suggest that MBS may reduce the odds of cognitive impairment across various demographics.},
}

@article {pmid42303596,
year = {2026},
author = {Sadeghi, A and Hajati, F and Argha, A and H Lovell, N and Yang, M and Alinejad-Rokny, H},
title = {Interpretable graph-based models on multimodal biomedical data integration: a technical review and benchmarking.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74126-5},
pmid = {42303596},
issn = {2041-1723},
abstract = {Integrating diverse biomedical modalities is essential for robust healthcare insights, and graph-based models are increasingly used to capture complex relational structures. Yet, their clinical translation hinges on interpretability. This review surveys interpretable graph-based models applied to multimodal biomedical data, highlighting dominant trends in disease classification, static graph construction, and post-hoc explainability. We categorize explainable artificial intelligence (XAI) techniques, benchmark SHAP, saliency, sensitivity, and graph masking on Alzheimer's disease data, and reveal complementary strengths. A development flowchart and future directions, such as dynamic graphs, knowledge integration, and LLM-based explainability, position this work as a key reference for trustworthy biomedical AI.},
}

@article {pmid42304066,
year = {2026},
author = {Kim, JP and Nho, K and Wang, T and Huynh, K and Arnold, M and Risacher, SL and Bice, PJ and Han, X and Kristal, BS and Blach, C and Baillie, R and Kastenmüller, G and Meikle, PJ and Saykin, AJ and Kaddurah-Daouk, R and , and , },
title = {Circulating lipids are related to longitudinal changes of ATN biomarkers for Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42304066},
issn = {1476-5578},
support = {RF1AG051550//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; RF1AG057452//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG059093//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; RF1AG058942//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01AG061359//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U19AG063744//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; DAOU16AMPA//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; },
abstract = {Investigating the relationship of circulating lipidome profiles with cross-sectional and longitudinal changes of central Alzheimer's disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a holistic view between the lipidome and AD pathophysiology. In this study, we quantified a total of 749 plasma lipid species at baseline using liquid chromatography-mass spectrometry and performed cross-sectional and longitudinal association analysis of plasma lipidome profiles with longitudinal A/T/N biomarkers for AD in the Alzheimer's Disease Neuroimaging Initiative cohort (N = 1395). We identified several lipid species, classes, and network modules of correlated lipids that were significantly associated with cross-sectional and longitudinal changes of A/T/N biomarkers. Notably, we identified lysoalkylphosphatidylcholine (LPC(O)) as associated with cross-sectional "A/N" biomarkers at the lipid species, class, and module levels. Also, Phosphatidylethanolamine (PE) ethers were associated with A/T/N biomarkers in the species level and with "N" biomarkers in the class and module levels. GM3 ganglioside showed association with cross-sectional and longitudinal changes of "N" biomarkers at the species and class levels. Furthermore, 20 lipid species, out of all 57 species identified as associated with "less severe" AD biomarkers, contained docosahexaenoic acid (DHA), indicating that the previously reported beneficial effects of DHA on AD were significant at the central biomarker level. In conclusion, our approach linking peripheral metabolic changes with brain metabolic, structural, and functional states strengthens evidence from previous studies that were performed using only clinical AD diagnosis. Importantly, our study also enabled identification of novel lipids that play potential roles in progression of AD pathophysiology, suggesting dysregulation of lipid metabolic pathways as precursors to AD development and progression.},
}

@article {pmid42304136,
year = {2026},
author = {Pardo, E and Kim, T and Wallrabe, H and Zengeler, KE and Sagar, VK and Mingledorff, G and Sun, X and Periasamy, A and Lukens, JR and Bloom, GS and Norambuena, A},
title = {Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71594},
pmid = {42304136},
issn = {1552-5279},
support = {//University of Virginia's School of Medicine/ ; //Rick Sharp Alzheimer's Foundation/ ; //Cure Alzheimer's Fund/ ; //Owens Family Foundation/ ; OD025156//NIH Office of the Director/ ; R01AG067048/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Animals ; *Neurons/metabolism ; *tau Proteins/metabolism ; *Mitochondria/metabolism ; *NADP/metabolism ; Mice ; *Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Alzheimer Disease/metabolism/pathology ; Mice, Transgenic ; Brain/metabolism ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; },
abstract = {INTRODUCTION: Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is poorly understood. We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor.

METHODS: Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.

RESULTS: Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons.

DISCUSSION: Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.},
}

Humans
Animals
*Neurons/metabolism
*tau Proteins/metabolism
*Mitochondria/metabolism
*NADP/metabolism
Mice
*Phosphotransferases (Alcohol Group Acceptor)/metabolism
Alzheimer Disease/metabolism/pathology
Mice, Transgenic
Brain/metabolism
Low Density Lipoprotein Receptor-Related Protein-1/metabolism

@article {pmid42304162,
year = {2026},
author = {Madhu, LN and Attaluri, S and Kotian, S and Upadhya, R and Somayaji, Y and Rao, S and Tarale, P and Ganesh, SV and Huard, C and Kodali, M and Shuai, B and Rao, VV and Shetty, AK},
title = {Human iPSC-NSC-Derived Extracellular Vesicles Can Alleviate Alzheimer's Disease-Linked Impairments in Mitochondria, mTOR Signaling, Autophagy, and Hippocampal Neurogenesis.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70590},
pmid = {42304162},
issn = {1474-9726},
support = {RF1AG074256/AG/NIA NIH HHS/United States ; R01AG075440/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *TOR Serine-Threonine Kinases/metabolism ; Humans ; Animals ; *Mitochondria/metabolism ; *Hippocampus/metabolism/pathology ; *Neurogenesis ; Mice ; Signal Transduction ; *Induced Pluripotent Stem Cells/metabolism ; *Autophagy ; Male ; *Extracellular Vesicles/metabolism/transplantation ; *Neural Stem Cells/metabolism ; Female ; },
abstract = {Intranasal (IN) administrations of extracellular vesicles (EVs) derived from human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) have shown promise in reducing chronic neuroinflammation mediated by microglia and astrocytes in 5x familial Alzheimer's disease (5xFAD) mice, a model for early-onset Alzheimer's disease (AD). The current study rigorously investigated whether treatment with hiPSC-NSC-EVs could also alleviate several other neuropathological changes contributing to progressive cognitive decline. Three-month-old male and female 5xFAD mice received IN administrations of either hiPSC-NSC-EVs (~30 × 10[9]/week for 2 weeks) or vehicle. Two months later, the hippocampus of both male and female 5xFAD mice treated with the vehicle showed increased levels of markers of oxidative stress and mechanistic target of rapamycin (mTOR) signaling, altered expression of genes and/or proteins linked to mitochondria and autophagy, and diminished neurogenesis. In contrast, treatment with hiPSC-NSC-EVs restored levels of oxidative stress markers and the expression of genes and/or proteins linked to various mitochondrial complexes, mitochondrial biogenesis, fission, fusion, and mitophagy closer to naïve control levels, indicating alleviation of mitochondrial impairments. These improvements were accompanied by reduced phosphorylated mTOR levels and multiple autophagy markers matching those in naïve controls, suggesting a dampening of mTOR signaling and an enhancement of autophagy. Furthermore, mice treated with hiPSC-NSC-EVs showed increased hippocampal neurogenesis, associated with enhanced brain-derived neurotrophic factor signaling. Overall, the results highlight that IN administrations of hiPSC-NSC-EVs in the early stages of AD can help slow the progression of multiple neuropathological changes associated with cognitive decline in 5xFAD mice and potentially AD.},
}

*Alzheimer Disease/metabolism/pathology
*TOR Serine-Threonine Kinases/metabolism
Humans
Animals
*Mitochondria/metabolism
*Hippocampus/metabolism/pathology
*Neurogenesis
Mice
Signal Transduction
*Induced Pluripotent Stem Cells/metabolism
*Autophagy
Male
*Extracellular Vesicles/metabolism/transplantation
*Neural Stem Cells/metabolism
Female

@article {pmid42304165,
year = {2026},
author = {Callow, DD and Rani, N and Smith, JC and Soldan, A and Pettigrew, C and Spira, AP and Albert, M and Bakker, A and , },
title = {APOE ε4 and amyloid status moderate the associations between sleep, physical activity, and tau-PET burden in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71555},
pmid = {42304165},
issn = {1552-5279},
support = {S10OD034232/NH/NIH HHS/United States ; U19-AG033655/NH/NIH HHS/United States ; P30-AG005146/NH/NIH HHS/United States ; K01-AG092954/NH/NIH HHS/United States ; S10OD034232//NIH Office of the Director/ ; K01-AG092954/AG/NIA NIH HHS/United States ; U19-AG033655/AG/NIA NIH HHS/United States ; P30-AG005146/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Positron-Emission Tomography ; Female ; Aged ; *tau Proteins/metabolism ; Male ; *Apolipoprotein E4/genetics ; *Amyloid beta-Peptides/metabolism ; *Exercise/physiology ; *Sleep/physiology ; Actigraphy ; Sleep Duration ; Brain/metabolism/diagnostic imaging ; Aged, 80 and over ; Alzheimer Disease/genetics ; },
abstract = {INTRODUCTION: Disturbed sleep and physical inactivity are associated with increased risk for dementia. However, associations with Alzheimer's disease (AD) pathology, and whether these associations differ depending on underlying disease risk, remain unclear.

METHODS: We examined associations of actigraphy-derived total volume of physical activity (TVPA), total sleep time (TST), and wake after sleep onset (WASO) with tau burden measured by positron emission tomography (PET) in Braak I-II subregions among 120 cognitively unimpaired older adults. Moderation by APOE ε4 carrier status and amyloid positivity, based on amyloid PET, was examined to evaluate risk-dependent associations.

RESULTS: Greater WASO was associated with higher tau burden among APOE ε4 carriers and amyloid beta (Aβ)-positive individuals. TVPA was associated with higher tau burden among Aβ-positive individuals and lower tau burden among Aβ-negative individuals.

DISCUSSION: Associations of sleep and physical activity with early tau pathology differ by genetic risk and Aβ status, highlighting the importance of risk stratification.},
}

Humans
Positron-Emission Tomography
Female
Aged
*tau Proteins/metabolism
Male
*Apolipoprotein E4/genetics
*Amyloid beta-Peptides/metabolism
*Exercise/physiology
*Sleep/physiology
Actigraphy
Sleep Duration
Brain/metabolism/diagnostic imaging
Aged, 80 and over
Alzheimer Disease/genetics

@article {pmid42304169,
year = {2026},
author = {Marola, OJ and Uyar, A and Keezer, KJ and Chong Chie, JAK and Elk, KJ and Cullen, AE and Eldridge, K and Persohn, S and Kanyinda, JN and Whitesell, JD and Harris, JA and Salama, P and Walker, AE and Carter, GW and Sasner, M and Territo, PR and Howell, GR and Onos, KD},
title = {WSB.APP/PS1 mice develop age-dependent cerebral amyloid angiopathy, cerebrovascular dysfunction, and white matter deficits.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71476},
pmid = {42304169},
issn = {1552-5279},
support = {1RF1NS139948-01/NS/NINDS NIH HHS/United States ; U01-AG088683/AG/NIA NIH HHS/United States ; AARF-22-971325/ALZ/Alzheimer's Association/United States ; DoD-HT9425-23-1-0308//U.S. Department of Defense/ ; R01-EY011996/EY/NEI NIH HHS/United States ; //GRH holds the Diana Davis Spencer Foundation Endowed Chair/ ; //GWC holds the Bernard and Lusia Milch Endowed Chair/ ; },
mesh = {Animals ; *Cerebral Amyloid Angiopathy/pathology/genetics ; Mice, Transgenic ; Mice ; Amyloid beta-Protein Precursor/genetics ; Disease Models, Animal ; Brain/pathology ; *White Matter/pathology ; *Alzheimer Disease/genetics/pathology ; Presenilin-1/genetics ; Humans ; Plaque, Amyloid/pathology ; *Cerebrovascular Disorders/pathology/genetics ; Aging/pathology ; },
abstract = {INTRODUCTION: Cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimer's disease (AD) pathogenesis. Here, we characterize the susceptibility of the WSB/EiJ genetic context to human AD-relevant cerebrovascular phenotypes.

METHODS: CAA and parenchymal plaque analysis and in vivo neurovascular imaging were performed on WSB.APP/PS1 brains. Transcriptomics was performed on WSB.APP/PS1 and B6.APP/PS1 brains. B6 and WSB cerebrovascular reactivity was assayed ex vivo. Additional CAA and parenchymal plaque analysis was performed on WSB.APP/PS1 mice with APOE[2], APOE[3], or APOE[4] alleles.

RESULTS: WSB.APP/PS1 brains exhibited plaque deposition, CAA, transcriptomic overlap with human AD, myelin deficits, cerebrovascular/metabolic uncoupling, and altered cerebrovascular morphology. Aged WSB vasculature retained vasoreactivity but exhibited increased stiffness. Compared to WSB.APOE[2/2]APP/PS1, WSB.APOE[4/4]APP/PS1 mice had increased CAA and plaque-associated microglial area.

DISCUSSION: These data illustrate the utility of the WSB genetic context to model CAA and uncover vascular contributions to AD.},
}

Animals
*Cerebral Amyloid Angiopathy/pathology/genetics
Mice, Transgenic
Mice
Amyloid beta-Protein Precursor/genetics
Disease Models, Animal
Brain/pathology
*White Matter/pathology
*Alzheimer Disease/genetics/pathology
Presenilin-1/genetics
Humans
Plaque, Amyloid/pathology
*Cerebrovascular Disorders/pathology/genetics
Aging/pathology

@article {pmid42304400,
year = {2026},
author = {Long, T and Satyal, S and Kuo, YF and Gao, J},
title = {DAG-VAERL: a novel causal inference method for building causal gene regulatory networks.},
journal = {BioData mining},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13040-026-00571-z},
pmid = {42304400},
issn = {1756-0381},
abstract = {BACKGROUND: Causal discovery methods provide a powerful tool for uncovering the causal relationships between lncRNAs and target genes in gene regulations. In many causal inference and structure learning tasks, learning the Directed Acyclic Graph (DAG) structure from data is a challenging problem. Traditional DAG learning methods often rely on heuristic searches or strict constraints, which fail to effectively handle complex nonlinear relationships and discrete data.

METHODS: To address this, we propose a novel deep generative model-DAG-VAERL, which combines Graph Neural Networks (GNN) as well as Reinforcement Learning (RL) frameworks and Graph Attention Networks (GAT) module, leveraging Variational Autoencoders (VAE) to learn the DAG structure. DAG-VAERL is capable of modeling complex dependencies between nodes through GNNs and optimizing the graph structure using RL strategies.

RESULTS: We conduct extensive experiments on synthetic and real-world datasets, including Alzheimer's disease data, to validate the superiority of DAG-VAERL in structural discovery and parameter estimation. Experimental results demonstrate that DAG-VAERL significantly outperforms traditional methods in structure recovery, especially when dealing with complex data involving nonlinear and discrete variables.

CONCLUSIONS: This model not only effectively learns the DAG structure from data but also serves as a powerful tool for causal inference and other graph-bard analysis tasks, providing a new approach for related fields.},
}

@article {pmid42304429,
year = {2026},
author = {Kim, J and Ku, D and Park, I and Ye, S and Cho, I and Park, M and Seo, W and Lee, S and Kim, HY and Kim, I and Kim, Y},
title = {A small molecule modulating heterogeneous amyloid-β isoforms improves cognitive and pathological outcomes in acute and 5XFAD Alzheimer's disease models.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02113-5},
pmid = {42304429},
issn = {1758-9193},
support = {RS-2018-NR031048//National Research Foundation of Korea/ ; RS-2018-NR031048//National Research Foundation of Korea/ ; RS-2018-NR031048//National Research Foundation of Korea/ ; RS-2025-00523607//Mid-Career Researcher Program/ ; RS-2021-NR059653//Mid-Career Researcher Program/ ; RS-2024-00349158//Ministry of Health & Welfare, Republic of Korea/ ; RS-2024-00418203//Ministry of Trade, Industry and Energy/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the pathological aggregation of amyloid-β (Aβ) peptides into neurotoxic assemblies. While recent antibody therapies targeting Aβ have shown clinical efficacy, they face limitations including specificity for particular Aβ species and accessibility challenges. The structural heterogeneity of Aβ isoforms, including Aβ40, Aβ42, and pyroglutamate-modified AβpE3-42, necessitates therapeutic strategies with broad-spectrum activity.

METHODS: The effects of YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, were evaluated in vitro using Thioflavin T fluorescence assays and A11 dot blot to assess fibrillization and dissociation of preformed aggregates across Aβ40, Aβ42, and AβpE3-42. In vivo efficacy was examined in an acute Aβ42-induced AD model and in 5XFAD transgenic mice. Cognitive performance was assessed using spatial and associative memory tests. Amyloid pathology, including soluble Aβ and fibrillar deposition, and neuroinflammation markers were quantified by biochemical and histological analyses.

RESULTS: YIAD-1003 inhibited fibril formation and promoted dissociation of preformed aggregates across multiple Aβ isoforms in vitro. In the acute model, co-administration of YIAD-1003 ameliorated Aβ42-induced memory impairment. In 5XFAD mice, oral administration improved cognitive performance, reduced plaque burden and soluble Aβ levels, and attenuated pathological alterations associated with neuroinflammation.

CONCLUSIONS: YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, exhibits broad-spectrum intervention in Aβ assembly across multiple isoforms and confers functional and pathological benefits in AD mouse models. These findings support the development of multi-isoform small-molecule modulators as a possible AD therapeutic strategy.},
}

@article {pmid42304519,
year = {2026},
author = {Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Zhang, W and Kunkle, BW and Chen, XS and Martin, ER and Wang, L and , },
title = {From aging to Alzheimer's disease: concordant brain DNA methylation changes in late life.},
journal = {Genome medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13073-026-01698-8},
pmid = {42304519},
issn = {1756-994X},
support = {R01AG062634/AG/NIA NIH HHS/United States ; R61NS135587/NS/NINDS NIH HHS/United States ; },
abstract = {BACKGROUND: Aging is the strongest risk factor for Alzheimer's disease (AD), but the molecular connections between aging and AD remain unclear. DNA methylation (DNAm) is implicated in both processes.

METHODS: We conducted a meta-analysis of DNAm in prefrontal cortex from two independent postmortem cohorts: the Religious Orders Study and Memory and Aging Project (ROSMAP) and Brains for Dementia Research (BDR). Age-associated CpG sites were identified using cohort-specific linear models adjusted for neuronal proportion, sex, and batch, followed by meta-analysis. We computed epigenetic age acceleration in brain samples as delta-age (DNAmAge - chronological age), and compared clinically diagnosed AD with cognitively unimpaired participants. Functional analyses included genomic feature enrichment, pathway analysis, brain-blood DNAm correlation, and colocalization with genome-wide association study (GWAS) loci. Prognostic relevance of age-associated CpGs was tested in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset using Cox proportional hazards models for disease progression.

RESULTS: We identified 3264 CpG sites associated with aging; most were hypermethylated and enriched in promoters and CpG islands, and involved genes related to immune regulation and metabolism. Comparison with AD neuropathology-associated methylation showed substantial overlap, with nearly all shared CpGs and regions showing concordant directional changes. Cortical epigenetic age acceleration was higher in ROSMAP participants with clinical AD than in cognitively unimpaired individuals after covariates adjustment, and this association persisted when the cortical clock was restricted to the aging-associated CpGs identified here, suggesting that acceleration in AD is attributable to age-related CpGs. Several CpGs showed significant brain-blood methylation correlations or were linked to AD GWAS risk loci through colocalization analyses. In ADNI, among 33 candidate CpGs selected for concordant aging- and AD-associated changes in cortex and significant brain-blood methylation correlations, baseline methylation at one CpG (cg10752406 in AZU1 promoter) was associated with progression at a 5% false discovery rate after covariate adjustment.

CONCLUSIONS: Aging-associated DNAm changes in prefrontal cortex overlap with AD neuropathology-related changes and are involved in accelerated epigenetic aging in clinical AD. Our study provides valuable insights into the epigenetic landscape of aging and its implications for AD.},
}

@article {pmid42304745,
year = {2026},
author = {Kainth, R and Kushwah, AS},
title = {Modulating the Microbiota-gut-brain Axis: A Promising Strategy for Alzheimer's Disease Prevention and Management.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273444471260608194550},
pmid = {42304745},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder evident by cognitive decline and neuropathological hallmarks such as amyloid-β (Aβ) plaques and tau protein hyperphosphorylation. Recent evidence links gut microbiota dysbiosis to AD pathogenesis through the microbiota-gut-brain axis (MGBA), a complex bidirectional communication system entailing neural, immune, and metabolic pathways. This study aims to explore the mechanistic relationship between gut microbiota alterations and AD development and to assess the therapeutic potential of microbiota modulation through dietary, probiotic, and metabolite-based interventions. A thorough analysis was undertaken, blending evidence from preclinical animal models and clinical investigations. The effects of bacterial metabolites, microbial components (e.g., lipopolysaccharides, microbial amyloids), and interventions like probiotics, dietary fibers, and polyphenols were examined. Emphasis was placed on neuroinflammatory markers, Aβ deposition, blood-brain barrier integrity, and behavioral outcomes. Findings revealed that gut dysbiosis contributes to increased neuroinflammation, microglial activation, reduced short-chain fatty acid (SCFA) levels (especially butyrate), and compromised blood-brain barrier function. Bacterial LPS and amyloids may enhance Aβ aggregation and tau hyperphosphorylation. Probiotic supplementation and high-fiber/polyphenol-rich diets were noticed to restore microbial balance, increase SCFA production, attenuate Aβ deposition, and improve cognitive functions in animal models. Modulating gut microbiota shows potential as a complementary strategy for delaying or managing AD. Restoration of microbial equilibrium via dietary or probiotic approaches can mitigate neurodegeneration by targeting inflammation, microbial metabolite production, and immune responses. Further mechanistic studies and longitudinal human trials are needed to validate the clinical efficacy of MGBA-targeted therapies. Personalized microbiome-based interventions may pave the way for novel, non-invasive strategies to combat AD progression.},
}

@article {pmid42304746,
year = {2026},
author = {Maity, S and Srinivas, MG and Nayak, G and M I, MA and M, M and Prabhu, PP and Nair, A},
title = {Multi-target Agents in Complex Diseases: From Design Principles to Therapeutic Applications.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501460128260608052953},
pmid = {42304746},
issn = {1873-5592},
abstract = {INTRODUCTION: Multifactorial complex diseases such as cancer, neurodegeneration, and infections are poorly treated with traditional single-target therapies because biological networks are redundant and adaptively resistant.

METHODS: A comprehensive literature review was conducted to investigate the theoretical basis, design approaches (pharmacophore linking, fusing, and merging), and clinical uses of multi-target agents using network pharmacology and systems biology.

RESULTS: Multi-kinase inhibitors (imatinib, sunitinib, cabozantinib) approved by the Food and Drug Administration have shown superior efficacy to traditional monotherapies due to multiple driver inhibition; dual acetylcholinesterase and Beta-site amyloid precursor protein cleaving enzyme 1 inhibitors show enhanced neuroprotective effects against Alzheimer's disease; and β-lactam/βlactamase inhibitor combinations address drug resistance. Artificial intelligence can accelerate target identification, and novel design technologies, such as fragment-based screening, can generate balanced polypharmacology.

DISCUSSION: Multi-target strategies are ideal for overcoming redundancy in biological networks and minimizing drug resistance. However, several issues remain, including the complexity of target selection, the need to achieve balanced efficacy across multiple targets, ADMET optimization, and regulatory hurdles. Emerging technologies, such as quantum computing, precision polypharmacology based on multiomics profiling, and digital health integration, could improve target selection and optimization.

CONCLUSION: Multi-target agents are no longer constrained by single-target effects; however, issues of balanced potency, ADMET, and control still exist. The combination of AI, quantum computing, and precision polypharmacology may enable more effective multi-target interventions to address unmet demands in complex diseases.},
}

@article {pmid42304748,
year = {2026},
author = {Katiyar, S and Yadav, D and Rabbee, MF},
title = {Neuroinflammation in Alzheimer's Disease: New Approaches.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501442692260608092400},
pmid = {42304748},
issn = {1873-5592},
abstract = {Alzheimer's Disease (AD), the most prevalent neurodegenerative disorder, is the leading cause of dementia in older adults and is closely associated with chronic neuroinflammation within the central nervous system. The hallmark pathological features of AD include neurofibrillary tangles, amyloid -β plaques, and extensive neuronal loss. Although amyloid-β has been extensively studied, the development of effective disease-modifying therapies remains limited in clinical practice. Novel therapeutic approaches are increasingly focused on modulating these immune mechanisms, such as altering microglial phenotypes, inhibiting the NLRP3 inflammasome, regulating NF-κB and JAK/STAT signalling, and employing cytokine-based interventions. Additionally, stem cell-derived therapies and extracellular vesicles with strong immunomodulatory properties have emerged as promising candidates. This review aims to deepen the understanding of immunoregulatory and inflammatory mechanisms in Alzheimer's disease and to support the development of novel antiinflammatory therapies that may slow or prevent disease progression.},
}

@article {pmid42304749,
year = {2026},
author = {Yohannan, DJ and Brunden, KR and Alle, T},
title = {Microtubule Stabilization as a Therapeutic Strategy: Updated Perspectives on Alzheimer's Disease and Neurodegenerative Tauopathies.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266465362260603045901},
pmid = {42304749},
issn = {1873-4294},
}

@article {pmid42304897,
year = {2026},
author = {Kim, S and Park, SK},
title = {Fucoxanthin Promotes Longevity and Neuroprotection in Caenorhabditis elegans via DAF-16 and Autophagy Pathways.},
journal = {Rejuvenation research},
volume = {},
number = {},
pages = {15491684261460844},
doi = {10.1177/15491684261460844},
pmid = {42304897},
issn = {1557-8577},
abstract = {Identification of natural compounds that delay aging and prevent age-related neurodegeneration is a key goal in gerontology. Fucoxanthin, a marine-derived xanthophyll, exhibits potent antioxidant properties, yet its effects on organismal aging and specific molecular mechanisms remain underexplored. Here, we investigated the pro-longevity and neuroprotective effects of fucoxanthin using Caenorhabditis elegans. Fucoxanthin supplementation significantly extended the mean lifespan of wild-type nematodes by 12.1% and improved health span, as evidenced by delayed age-related motility decline and enhanced resistance to oxidative stress. Notably, this lifespan extension occurred without compromising reproductive fitness. Genetic analysis revealed that the beneficial effects of fucoxanthin require the FOXO transcription factor DAF-16 and the autophagy-essential gene bec-1. Furthermore, fucoxanthin treatment increased autophagic flux and upregulated the expression of SKN-1/Nrf2-dependent detoxification genes, hsp-16.2 and gst-4. In nematode models of Alzheimer's and Parkinson's disease, fucoxanthin significantly ameliorated Aβ-induced paralysis and protected against dopaminergic neurodegeneration and α-synuclein accumulation in a DAF-16-dependent manner. Collectively, our findings demonstrate that fucoxanthin acts as a multitarget geroprotector that promotes healthy aging through the coordinated activation of DAF-16 and autophagy, suggesting its potential as a therapeutic intervention for age-related decline.},
}

@article {pmid42304913,
year = {2026},
author = {Wang, T and Wu, M and Liang, L and Pei, L and Wang, D},
title = {Nicotine Versus Non-Nicotine Constituents in Neurodegenerative Risk: Evidence from Multivariable Mendelian Randomization.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X503957260608154111},
pmid = {42304913},
issn = {1875-6190},
abstract = {BACKGROUND: Nicotine has complex neuropharmacological actions through nicotinic acetylcholine receptors, but its independent role in neurodegenerative diseases remains unclear because tobacco smoke contains many non-nicotine toxicants. This uncertainty limits the interpretation of nicotine- and nAChR-targeted therapeutic strategies, especially as electronic nicotine delivery sys-tems become more common. We used Mendelian randomization to genetically separate nicotine-related effects from smoking-related non-nicotine effects on major neurodegenerative diseases and related prodromal conditions.

METHODS: We performed univariable two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Summary-level exposure data for cigarettes per day (CPD) and the nicotine metabolite ratio (NMR) were analyzed against individual-level, smoking-stratified outcome data derived from 337,334 UK Biobank participants, to evaluate their respective causal effects across six neurodegenerative outcomes: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tremor, early cognitive impairment (EC), and other neurodegenerative diseases (OND).

FINDINGS: MVMR analyses revealed that nicotine exposure was a causal risk factor for AD (ever smokers: OR=0.90, 95% CI 0.83-0.98; current smokers: OR=0.76, 95% CI 0.64-0.91). Nicotine exerted a causal protective effect against tremor (OR=1.24, 95% CI 1.03-1.49) and EC (OR=1.14, 95% CI 1.04-1.24) in current smokers. Non-nicotine tobacco constituents were identified as risk factors among former smokers for EC (OR=1.61, 95% CI 1.04-2.50).

CONCLUSIONS: Exposure to nicotine can increase the risks of AD, while conferring protective effects against tremor and EC. Furthermore, exposure to non-nicotine tobacco constituents acts as a risk factor for the incidence of EC.},
}

@article {pmid42304917,
year = {2026},
author = {Sinha, S and Gupta, S and Tiwari, P},
title = {Therapeutic Potential of Natural Chalcones Against Alzheimer's Disease: A Mechanistic Insight.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454130260605061515},
pmid = {42304917},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, amyloid-beta (Aβ) plaque deposition, tau hyperphosphorylation, oxidative stress, and chronic neuroinflammation. Therapeutic strategies are at present mainly symptomatic and do not modify the course of the disorder. Natural chalcones, precursors of flavonoids, are emerging as multi-target agents for neuroprotection since they have the ability to protect neurons and exert anti-inflammatory and antioxidant activities.

METHODS: A systematic literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar utilizing keywords that associate chalcones with Alzheimer's disease. Studies were included if they reported in silico docking, in vitro assays, or mechanistic insights on AD-related targets (AChE, BACE1, GSK-3β, NF-κB). Data extraction included information about the compound's identity, structural changes, docking scores, enzyme inhibition, oxidative stress, and cytokine modulation. The findings were synthesized both qualitatively and quantitatively, with structure-activity relationship (SAR) analysis emphasizing patterns of hydroxylation and methoxylation. These helped in the rational design of chalcone derivatives, which showed potential as multi-target agents against AD pathology.

RESULTS: Several chalcones exhibited potent inhibition against AChE and BACE1, besides reducing reactive oxygen species (ROS) generation and preventing the release of pro-inflammatory cytokines. These findings demonstrate their potential to mitigate cholinergic deficits and neuroinflammatory signaling. SAR studies revealed a significant enhancement in bioactivity for certain hydroxylation and methoxylation substituents. This provides insights into the rational design of improved chalcone derivatives.

DISCUSSION: Chalcones display multifunctional properties and are able to modulate several AD pathological signatures, suggesting potential application in the prevention of AD symptoms. Their therapeutic importance is emphasized by their combined ability to target cholinergic dysfunction, oxidative stress, and neuroinflammation. The SAR analysis further supports the focused development of chalcone-based derivatives with improved potency.

CONCLUSION: The present study provides insights into the mechanistic basis of the neuroprotective activity of chalcones and paves the way for subsequent preclinical evaluation. The chalconebased strategy holds promise for the development of potential drug candidates for the treatment of neurodegenerative diseases such as Alzheimer's disease by addressing the multi-target nature of this complex disease.},
}

@article {pmid42304926,
year = {2026},
author = {Mukherjee, S and Ray, SK and Mukherjee, S},
title = {Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273450093260523224914},
pmid = {42304926},
issn = {1996-3181},
abstract = {Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-β deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and müller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.},
}

@article {pmid42305190,
year = {2026},
author = {Sedlacek Miskerikova, M and Houfkova, A and Benkova, M and Andrys, R and Janousek, J and Soukup, O and Musilek, K and Benek, O},
title = {Development of Novel 17β-HSD10 Inhibitors and Their Evaluation in an In Vitro Model of Alzheimer's Disease.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {6},
pages = {1347-1354},
pmid = {42305190},
issn = {1948-5875},
abstract = {17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and a potential drug target for the treatment of various pathologies, including Alzheimer's disease (AD). In this study, five new benzothiazole-derived 17β-HSD10 inhibitors were developed based on structure-activity relationship (SAR) analyses of previously published compounds. To evaluate the inhibitory effects, cytotoxicity, and therapeutic potential of these new compounds, several enzyme- and cell-based methods were employed. All prepared compounds exhibited high inhibitory potential and confirmed good biomembrane permeation. Three inhibitors (9b, 9c, and 15a) showed lower IC50 values in both enzyme- and cell-based assays than the formerly published hit compounds. The compounds were also found to reduce the pathological effects associated with 17β-HSD10 overexpression, although not the combined pathological effects of 17β-HSD10 overexpression within an amyloid-β rich environment.},
}

@article {pmid42305194,
year = {2026},
author = {Magniez, A and Giovannini, J and Zipfel, P and Rémondin, C and Saïdoun, H and Davis, A and Rivera, S and Dallemagne, P and Rochais, C and Lepailleur, A},
title = {Structure-Guided Discovery of a Nonpeptidic MT5-MMP Inhibitor.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {6},
pages = {1407-1415},
pmid = {42305194},
issn = {1948-5875},
abstract = {Membrane type 5-matrix metalloproteinase (MT5-MMP, MMP-24), an η-secretase involved in amyloid precursor protein processing, is a promising but unexplored target in Alzheimer's disease. We report here the identification of a first nonpeptidic hit for MT5-MMP through a structure-guided approach. A homology model of the MT5-MMP catalytic domain was built from the MT3-MMP/batimastat structure and validated by both docking and experimental inhibition data obtained with batimastat (IC50 = 3 nM). To account for binding-site plasticity, especially that of the S1' pocket, molecular dynamics and ensemble docking were applied to a zinc-binding group (ZBG)-focused library of 3851 compounds. Although the initial screening campaign yielded only weakly active candidates, analysis of docking poses identified a relevant scaffold for optimization. Replacement of a carboxylic acid ZBG by a hydroxamic acid led to compound 17, which inhibited MT5-MMP with an IC50 of 6 μM and established a first nonpeptidic hit for future optimization.},
}

@article {pmid42305210,
year = {2026},
author = {Sabnis, RW and Sabnis, AR},
title = {Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {6},
pages = {1236-1237},
pmid = {42305210},
issn = {1948-5875},
abstract = {Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.},
}

@article {pmid42305347,
year = {2026},
author = {Zhao, L and Xu, Y and Xia, L and Zhang, Y},
title = {Causal associations between sleep apnea and dementia: a two-sample Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {22},
number = {2},
pages = {822-833},
pmid = {42305347},
issn = {1734-1922},
abstract = {INTRODUCTION: Observational studies suggest an association between sleep apnea and dementia, but causality and directionality are unclear. This study investigated bidirectional causal relationships between sleep apnea and various dementia types using two-sample Mendelian randomization (MR).

MATERIAL AND METHODS: This study used summary-level data from genome-wide association studies (GWAS). Sleep apnea (including obstructive sleep apnea (OSA) and generalized sleep apnea) exposure data were from a European ancestry study. Dementia (general, Alzheimer's, vascular, etc.) outcome/exposure data were from the Finnish FinnGen consortium. The inverse variance weighted (IVW) method was used as the primary analysis, supplemented by multiple analyses (MR-Egger, weighted median, weighted mode). Robustness was assessed using several sensitivity analyses, including MR-PRESSO, Cochran's Q test, and leave-one-out analysis.

RESULTS: Forward analysis, after MR-PRESSO outlier correction, showed that OSA was associated with reduced unspecified dementia risk (IVW, OR = 0.830, 95% CI = 0.700-0.970). Reverse analysis, after outlier removal, indicated that general dementia was associated with reduced OSA risk (IVW, OR = 0.9399, 95% CI = 0.9187-0.9615) and generalized sleep apnea risk (IVW, OR = 0.9141, 95% CI = 0.8863-0.9427). Alzheimer's dementia was also associated with reduced OSA and generalized sleep apnea risk. Sensitivity analyses did not reveal significant horizontal pleiotropy for the main findings, and heterogeneity was generally within acceptable limits.

CONCLUSIONS: This MR study revealed complex, bidirectional genetic associations between sleep apnea and dementia subtypes. These findings provide new genetic insights into the complex interplay between sleep apnea and dementia, highlighting subtype-specific associations.},
}

@article {pmid42305617,
year = {2026},
author = {Shinohara, M and Momota, H and Saito, T and Takenobu, C and Kasuga, K and Gheni, G and Kawai, K and Morishima, M and Saito, Y and Shindo, A and Yasuno, F and Ikeuchi, T and Fukumori, A and Sato, N},
title = {CCN1/Cyr61 associates with β-amyloid levels in human cerebrospinal fluids.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116244},
pmid = {42305617},
issn = {2589-0042},
abstract = {CCN1, also called Cyr61, is a secreted protein involved in diverse biological processes including senescence. While elevated in brains of Alzheimer's disease (AD) models and patients, CCN1/Cyr61 levels in cerebrospinal fluid (CSF) remain unclear. Using a high-sensitive quantification method, we analyzed CSF samples from 79 subjects (age: 77.7 ± 5.4 years [63-94], MMSE: 20.1 ± 5.9 [0-30]) who underwent CSF tap test. CCN1/Cyr61 showed strong associations with Aβ40 (r = 0.67), Aβ42 (r = 0.48), Aβ42/40 ratio (r = -0.53), and phospho-tau levels (r = 0.53) (all; p < 0.0001). CCN1/Cyr61 also moderately associated with glial markers, YKL-40, sTREM2, CD163, and a lymphatic endothelial marker, LYVE-1 (r ≈ 0.4). While these cellular markers also associated with Aβ and phospho-tau, effects were much weaker. Collectively, CCN1/Cyr61 is associated with Aβ species and p-tau in CSF. These associations are considerably stronger than those observed with typical glial or other cellular markers, providing a clue to understanding the link between senescence and AD pathology at the levels of fluid biomarkers.},
}

@article {pmid42305665,
year = {2026},
author = {Vignesh Pandi, A and Malakar, V and Jeyabalan, JB and Sanjai, M and Shevate, K and Rajagopal, K and Prashantha Kumar, BR and Justin, A},
title = {Integrated computational-based design of putative dual TrkA/TrkB agonists for Alzheimer's disease: pharmacophore modelling, docking, MM/GBSA, DFT and dynamics studies.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1779769},
pmid = {42305665},
issn = {2673-7647},
abstract = {BACKGROUND: The rapid progression of Alzheimer's disease (AD) is primarily caused by compromised neurotrophin functions and decreased tropomyosin receptor kinase expression in the basal forebrain area. The two main pathogenic features of AD are cholinergic-dependent cognitive dysfunctions and amyloidogenic-induced neurodegeneration. Concurrent stimulation of major neurotrophin signalling pathways, such as tropomyosin receptor kinases receptor A and B (TrkA and TrkB), may reduce amyloid-β-mediated neurotoxicity and cholinergic denervation in the basal forebrain, improving cognitive performance and re-establishing neuronal communication. The development of new medications with dual agonist action towards TrkA and B receptors holds enormous therapeutic potential for managing the symptoms of neurodegenerative diseases.

AIM: This study aims to develop novel dual TrkA/TrkB receptor agonists for the treatment of AD by enhancing neurotrophin signalling, reducing cholinergic denervation, and mitigating amyloid-β-induced neurotoxicity.

METHODS: An in silico drug discovery pipeline was employed, involving homology and pharmacophore modelling of amitriptyline, virtual screening of ChEMBL compounds, molecular docking, ADMET, MM/GBSA analysis, DFT calculations and molecular dynamics (MD) simulations for 100 and 300 ns to assess ligand stability and binding behaviour of the ligand-protein complexes.

RESULTS: Six novel optimised quinoline analogues (OP-1 to OP-6) were identified as computationally predicted dual TrkA/TrkB agonists by molecular docking (-8.90 to -5.07 kcal/mol), MM/GBSA (-40.47 to -30.71 kcal/mol), ADMET and DFT analysis. Furthermore, OP-1, OP-2, and OP-3 exhibit stable binding interactions over 300 ns of MD simulations. The optimised compounds demonstrated favorable computational binding profiles, predicted pharmacokinetic properties, and stable receptor-ligand interactions, identifying them as promising candidates for further experimental validation as potential dual TrkA/TrkB modulators in Alzheimer's disease.},
}

@article {pmid42305952,
year = {2026},
author = {Saraiva, LA and Resende, EPF and Mariano, LI and Paula, DS and Caramelli, P and Salgado, JV and de Souza, LC},
title = {Neuropsychiatric symptoms and social cognition in frontotemporal dementia and Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250409},
pmid = {42305952},
issn = {1980-5764},
abstract = {UNLABELLED: Neuropsychiatric symptoms (NPS) are common in dementia and may hinder differential diagnosis between behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Despite investigations of NPS and social cognition, particularly Theory of Mind (ToM) and emotion recognition, their precise, differential impact on social cognition in bvFTD versus AD remains less characterized.

OBJECTIVE: This study examined NPS in bvFTD and their association with social cognition, comparing results to AD.

METHODS: Patients with bvFTD (n=13) and AD (n=18) were assessed using neuropsychiatric and cognitive batteries measuring depression, anxiety, mania, and psychosis. Social cognition was evaluated with the Mini-Social and Emotional Assessment (mini-SEA), including the Faux-Pas test (ToM) and the Facial Emotion Recognition Test (FERT).

RESULTS: The groups did not differ in sex, education, or disease duration. Compared to AD, bvFTD patients had higher manic symptoms (p<0.001) and schizophrenia spectrum symptoms, particularly in negative (p<0.001) and resistance/hostility (p=0.034) symptoms. In bvFTD, depressive (p=0.020) and anxious (p=0.045) symptoms positively correlated with the Faux-Pas test, while positive psychotic symptoms correlated negatively (p=0.005). In AD, obsessive-compulsive (p=0.013) and disorganized psychotic symptoms (p=0.009) negatively correlated with the Faux-Pas test, while manic symptoms negatively correlated with the FERT (p=0.033).

CONCLUSION: bvFTD patients displayed more schizophrenic and manic symptoms than AD, with NPS impacting social cognition differently in each condition.},
}

@article {pmid42305954,
year = {2026},
author = {Alyaqoobi, HIR and Lopez-Guede, JM and Dara, OA and Ramos-Hernanz, JA and Aramendia, I and Teso-Fz-Betoño, D},
title = {Advances in AI-based diagnosis of Alzheimer's disease using MRI: a comprehensive survey.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1767090},
pmid = {42305954},
issn = {2296-858X},
abstract = {Artificial intelligence (AI), especially Deep Learning (DL), has been shown significant in accelerating the detection and diagnosis of neurological disorders via medical imaging. This study is mainly focused on Alzheimer's disease (AD), which reveals distinctive structural modifications observable by Magnetic Resonance Imaging (MRI). Although several studies employing convolutional neural networks (CNNs) and other artificial intelligence models indicate promising diagnostic accuracy, many issues related to methodology exist. This research offers a comprehensive assessment of recent studies (2000-2025) to synthesize the key limitations limiting the clinical application of AI for AD detection using MRI. The study identify the main challenges, namely: (1) restricted access to extensive, curated, and diverse multimodal datasets; (2) elevated model complexity with associated risks of overfitting on small cohorts; (3) insufficient interpretability and clinical validation of AI decisions; (4) computational inefficiency and excessive energy consumption; and (5) challenges in generalizing models across heterogeneous cohorts and imaging guidelines. Our study indicates that modern research frequently emphasizes marginal improvements in accuracy rather than solving these essential translational obstacles. The authors conclude by outlining essential research progressions, highlighting the necessity for federated learning for dealing with data scarcity, the advancement of explainable AI (XAI) frameworks, and the creation of standardized benchmarking protocols to flexible, clinically-adoptable AI methods for early AD detection.},
}

@article {pmid42306035,
year = {2026},
author = {Kalpaktsi, I and Panara, A and Mavroidi, B and Niforos, GG and Kalampaliki, AD and Vlachogianni, IC and Georgiou, EA and Fragopoulou, E and Tsarbopoulos, A and Skaltsounis, AL and Pelecanou, M and Palikaras, K and Gikas, E and Kostakis, IK},
title = {Novel hydroxytyrosol esters as potential anti-amyloid and neuroprotective agents for Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42306035},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is associated with the aggregation of β-amyloid (Aβ) peptides and oxidative stress, two interconnected processes that contribute to neuronal dysfunction and cognitive decline. Natural polyphenols such as oleuropein and its metabolite hydroxytyrosol display antioxidant and anti-amyloidogenic properties, but oleuropein suffers from limited stability due to glycosidic hydrolysis. To develop more robust and potent oleuropein analogs, we synthesized a series of hydroxytyrosol-based esters in which the secoiridoid glucoside scaffold of oleuropein was replaced by lipophilic substituents designed to enhance molecular stability and interactions with Aβ peptide. The compounds were evaluated for their ability to interact with Aβ40 using ESI-MS, circular dichroism (CD), and thioflavin-T fluorescence (ThT), along with complementary antioxidant assays. Most of the compounds formed stable non-covalent complexes with Aβ40, inhibited early aggregation events, and prevented the peptide's conformational transition from random coil to β-sheet. To assess biological efficacy and safety in vivo, the most promising analog (3b) was evaluated in Caenorhabditis elegans models of amyloid-β toxicity. Treatment with 3b exhibited no detectable toxicity in wild-type animals, as evidenced by normal development, growth, and reproductive efficacy. Importantly, 3b rescued lifespan shortening and locomotor deficits in transgenic nematodes expressing human Aβ42 pan-neuronally, while having no effect on control strains lacking Aβ42 expression. These findings demonstrate that 3b confers functional protection against amyloid-induced toxicity in vivo. Overall, our results identify the newly synthesized hydroxytyrosol-derived esters as promising multifunctional scaffolds that combine potent anti-aggregation activity with strong antioxidant properties and in vivo neuroprotective efficacy, supporting their further development as anti-amyloidogenic agents for AD therapy.},
}

@article {pmid42306137,
year = {2026},
author = {Han, X and Cao, X and Liu, L and Wang, Z and Gao, D and Lv, H and Yang, H and Wang, Y and Cui, C and Li, S and Yang, Q and Cui, J and Zhang, Z and Wang, H and Cheng, S and Song, B and Geng, Z},
title = {Analysis of structural alterations in olfactory-related brain regions in patients with cognitive impairment and the correlation with olfactory function.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1778960},
pmid = {42306137},
issn = {1663-4365},
abstract = {OBJECTIVE: To evaluate the differences in olfactory function, volumes of brain regions related to olfaction, and subregion volumes of the amygdala and hippocampus among the healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD), as well as the association of volumes and olfactory function.

METHODS: Clinical data for the participants included age, gender, education level, Mini-Mental State Examination (MMSE). Participants underwent olfactory function test, including three sub-experiments as namely threshold test (TT), discrimination test (DT) and identification test (IT) and brain magnetic resonance imaging (MRI), including a three dimensions T1-weighted sequence (3D-T1WI). The brain subregions were extracted automatically by the uAI research portal.

RESULTS: A total of 107 participants were recruited, including 35 HC, 28 MCI and 44 AD. The volumes of hippocampal subregion (HC_Body_L and HC_Tail_L) were significant difference in HC and MCI groups while the global hippocampal volumes were not. All tested domains (TOS, TT, DT, and IT) showed statistically significant differences in olfactory function between the three groups. Furthermore, we found only IT showed significant differences across all three pairwise comparisons among the HC, MCI, and AD groups. The hippocampus and amygdala volumes showed the strongest correlation with olfactory function, followed by the PHG, PCC, lOFC and ERC, and more sub-region volumes had moderate-strength correlations with DT, IT, and TOS, according to Spearman correlation analysis.

CONCLUSION: The olfactory function and the volumes of the hippocampal subnuclei maybe good candidates as early biomarkers of preclinical AD.},
}

@article {pmid42306139,
year = {2026},
author = {Liao, Z and Chen, R and Yang, X and Shen, K and Zeng, J and Zhou, H and Fang, C and Liu, Y and Chen, C},
title = {Imaging biomarkers of glymphatic system dysfunction in Alzheimer's disease: a systematic review and meta-analysis with a focus on DTI-ALPS index.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1749316},
pmid = {42306139},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) has been linked to impaired clearance of metabolic waste, and glymphatic dysfunction is increasingly considered a potential contributor to its pathogenesis. The diffusion tensor imaging-based analysis along the perivascular space (ALPS) index has been proposed as a non-invasive imaging marker, although findings across clinical studies remain inconsistent.

METHODS: We systematically searched PubMed, Embase, Web of Science, Scopus, CENTRAL, and PEDro up to August 2025 in accordance with PRISMA guidelines. Studies reporting ALPS index values in adults with AD, mild cognitive impairment (MCI), or cognitively normal controls (NC) were included. Risk of bias was assessed using the AHRQ checklist, and the certainty of evidence was evaluated with GRADE.

RESULTS: Fifteen studies involving 1,756 participants were included in the meta-analysis. Pooled results showed a stepwise decrease in ALPS values, with significantly lower values in AD compared with NC (mean difference -0.20, I [2] = 93%) and MCI (-0.09, I [2] = 78%), as well as in MCI compared with NC (-0.11, I [2] = 92%). Subgroup and sensitivity analyses supported the stability of these findings despite methodological heterogeneity.

CONCLUSION: The ALPS index shows a progressive decrease across the AD continuum, which is consistent with the presence of glymphatic alterations during disease progression. As a non-invasive MRI-derived marker, ALPS may have potential for use in early detection and monitoring; however, further validation with standardized imaging protocols and longitudinal studies is required before clinical application.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251119624, PROSPERO, CRD420251119624.},
}

@article {pmid42306175,
year = {2026},
author = {Liu, L and Yang, D and Fu, J},
title = {Therapeutic Potential of Naive Hair Follicle Stem Cells in Alzheimer's Disease: A Comprehensive Evaluation of Neuroprotection and Neurogenesis.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {601127},
pmid = {42306175},
issn = {1176-6328},
abstract = {BACKGROUND: As a highly prevalent neurological condition, Alzheimer's disease (AD) imposes considerable economic pressure on global societies. Its core pathological feature is progressive degeneration within the central nervous system (CNS), a feature which establishes it as the leading trigger for dementia worldwide. Currently available therapies for AD are largely palliative and lack restorative efficacy. While stem cell transplantation holds promise for brain regeneration, the shortage of transplantable neural stem cells and ethical constraints remains a significant limitation. Hair follicle stem cells (HFSCs) are easily accessible, proliferative, low immunogenicity, and free of ethical concerns, making them an ideal candidate for neurodegenerative disease therapy. However, the application of naive, unmodified HFSCs in AD therapy has not been thoroughly explored. In contrast to our previous study using NGF-modified HFSCs, the present study used unmodified naive HFSCs to systematically evaluate their therapeutic effects in AD rats, focusing on neurogenesis, synaptic protection, and microglial polarization. Therefore, the present assessment sought a more complete understanding of HFSCs' intrinsic therapeutic potential.

METHODS: We induced AD in rats via intrahippocampal injection of Aβ1 -4 2. Fourteen days post-modeling, HFSCs were stereotaxically transplanted into the hippocampal region of AD rats. Learning and memory were assessed using the Morris water maze test, and neuronal damage was evaluated by Nissl staining. Synaptic protein levels were measured by Western blot and immunohistochemistry. The same staining approach was used to assess hippocampal neurogenesis and quantify Iba-1‑positive microglia. Moreover, qPCR was performed to measure mRNA levels of key pro‑inflammatory and anti‑inflammatory factors.

RESULTS: HFSCs transplantation not only markedly upregulated the synaptic proteins SYP and PSD-95, but also promoted neurogenesis and alleviated microglial overactivation in the AD rat hippocampus.

CONCLUSION: HFSCs represent a highly promising therapeutic strategy for AD. When delivered via transplantation, these cells protect against synaptic and neuronal injury, boost hippocampal neurogenesis, and prevent abnormal overactivation of microglia in the cerebral tissues of AD model rats. Together, these results offer comprehensive preclinical proof of the intrinsic therapeutic potential of unmodified HFSCs, distinguishing it from previous studies using genetically modified cells and laying a solid foundation for future clinical translation.},
}

@article {pmid42306480,
year = {2026},
author = {Giorelli, M and Fazio, PD and Dimatteo, T},
title = {Equity and budget challenges associated with the employment of anti-amyloid monoclonal antibodies for early Alzheimer's Disease in Italy: A scenario analysis.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100076},
pmid = {42306480},
issn = {2534-773X},
abstract = {BACKGROUND: Anti-amyloid monoclonal antibodies (lecanemab and donanemab) represent the first disease-modifying therapies for early symptomatic Alzheimer's disease (AD)- Italy's National Health Service (SSN) must determine whether to include these therapies within Essential Levels of Care (LEA), requiring reimbursement across all regions.

OBJECTIVE: To conduct a three-year budget impact analysis and implementation feasibility assessment for anti-amyloid therapies in Italy. The analysis was scenario-based rather than empirical.

METHODS: Deterministic budget modeling, combined with Proctor's 8-Domain Implementation Outcomes Framework and the Consolidated Framework for Implementation Research (CFIR), was employed. Four implementation scenarios were modeled based on cumulative patient uptake rates. Cost analysis incorporated diagnostic pathways, drug acquisition, clinical surveillance, and management of amyloid-related imaging abnormalities (ARIA). Infrastructure capacity was assessed through national survey data of Centers for Cognitive Disorders and Dementia (CCDDs).

RESULTS: An estimated 42,000 patients in Italy are potentially eligible for anti-amyloid therapy. The moderate scenario (5-10-15% uptake over three years, reaching 14,100 cumulative patients) represents the optimal policy target, with estimated three-year total costs of €557.3 million (0.4% of the annual SSN budget), penetration of 33.6% of eligible patients, and a feasibility score of 1.5, underscoring a high implementation success probability. The moderate scenario remains financially sustainable but requires targeted infrastructure investment in the Central and Southern regions.

CONCLUSIONS: Anti-amyloid therapy implementation is feasible within Italian healthcare system constraints under a moderate uptake scenario. However, achievement of equitable access requires substantial capacity building in underserved regions, clarified reimbursement policies, integrated diagnostic networks, and robust workforce planning before full LEA inclusion is recommended.},
}

@article {pmid42306774,
year = {2026},
author = {Rodriguez Martinez, PJ and Yslas, AR and Inoue, Y and Parsons, TM and Baker, SK and Lu, W and Raulin, AC and Kanekiyo, T},
title = {APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1778856},
pmid = {42306774},
issn = {2296-889X},
abstract = {Aging and neurodegenerative disorders like Alzheimer's Disease (AD) are associated with progressive dysfunction of the blood-brain barrier (BBB) and neurovascular unit (NVU), contributing to impaired vascular integrity and neuronal vulnerability. Apolipoprotein E (APOE) is a key regulator of neurovascular function, and the rare APOE3-R136S "Christchurch" variant (APOE3Ch) confers protection against AD. Mesenchymal stromal cells (MSCs) represent a promising cell-based therapy for the treatment of neurodegenerative diseases due to their paracrine effect exerted on vascular and neural cells. To investigate how APOE3Ch influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous APOE3Ch or APOE3. We found that APOE3Ch iMSCs have stronger immunosuppressive effect on LPS-induced NFκB activation of THP1 cells. APOE3Ch iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to APOE3 iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from APOE3Ch iMSCs promoted neurite outgrowth more efficiently than that from APOE3 iMSCs. Metabolic profiling revealed differences between APOE3Ch and APOE3 iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that APOE3Ch variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective APOE variants to target BBB and NVU dysfunction in aging and neurodegeneration.},
}

@article {pmid42307318,
year = {2026},
author = {Sharma, D and Sarkar, AK},
title = {Alzheimer detection using multivariate decomposition of EEG signals and BDEO feature selection: with lobe-wise and overall feature analysis.},
journal = {Computer methods in biomechanics and biomedical engineering},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/10255842.2026.2681796},
pmid = {42307318},
issn = {1476-8259},
abstract = {In this paper, we propose a multivariate fast iterative filtering (MvFIF) decomposition algorithm, entropy-based features, and a nature-inspired feature selection approach for Alzheimer's disease (AD) detection using electroencephalogram (EEG) signals. Where, the MvFIF decomposes the multichannel EEG signals into multichannel intrinsic mode functions (MIMFs). The entropy features: dispersion entropy (DispEn) and distribution entropy (DistEn) are extracted from the MIMFs. Afterward, five nature-inspired feature selection algorithms are applied to reduce the feature space by selecting the relevant features for the AD. The selected features are finally used for the binary classification to distinguish AD patients from healthy control (HC) subjects using different classifiers. In addition, lobe-wise analysis is performed to understand the neural activity, diagnose AD, and guide targeted treatments. We show that the binary differential evolution optimization (BDEO) feature selection method with the support vector machine (SVM) classifier achieves the highest accuracy of 90.78% with standard deviation (SD) of 1.96% using 10-fold cross-validation (CV) and 75% with SD of 18.20% using leave-one-subject-out CV (LOSO-CV). In lobe-wise analysis, XGBoost classifier with temporal lobe gives the highest accuracy of 80.06% with SD of 1.53% using 10-fold CV and 70.78% with SD of 23.93% using LOSO-CV. The proposed approach surpasses the current leading techniques in AD detection utilizing EEG signals.},
}

@article {pmid42307397,
year = {2026},
author = {Drzazga, J and Segiet-Hojda, NM and Początek, G and Gorzkowska, A and Klimkowicz-Mrowiec, A and Cunha, I and Griffiths, AW},
title = {Narratives about the reasons for wandering in people with Alzheimer's disease: The perspective of Polish family members. Preliminary report.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261459071},
doi = {10.1177/13872877261459071},
pmid = {42307397},
issn = {1875-8908},
abstract = {BackgroundPeople living with Alzheimer's disease often require support from their relatives, who may face emotional and physical challenges in their role. Up to 90% of people living with cognitive impairment experience unmet needs such as wandering.ObjectiveThe aim of the study was to analyze the narrative of relatives of people living with Alzheimer's disease experiencing unsatisfied behavioral needs and whether this has a relationship with levels of burden.MethodsRelatives who cared for a family member with Alzheimer's disease at home participated in a structured interview with a psychologist and completed the Zarit Burden Interview to assess caregiver burden. An analysis was conducted of the frequency of words used in the relatives' responses to the question "What is your experience of your loved one's wandering?".ResultsA total of 15 relatives participated in the study. Relatives with higher levels of burden related to their role as caregivers were more likely to use words such as "disorder" (on average once per interview), "problem" (on average three times per interview), and "difficulty" (on average twice per interview), than people with low levels of burden. For people with low levels of burden, the word "need" appeared as a significant expression (on average four times per interview).ConclusionsRelatives who experience less burden are more likely to understand the reasons behind their loved ones' need or desire to wander. They are less likely to perceive this behavior as a problem and restrict the person's freedom of movement for their own safety.},
}

@article {pmid42307453,
year = {2026},
author = {},
title = {Retraction: Aqua-soluble DDQ reduces the levels of Dr1 and Ab and inhibits abnormal interactions between Ab and Dr1 and protects Alzheimer's disease neurons from Ab- and Dr1-induced mitochondrial and synaptic toxicities.},
journal = {Human molecular genetics},
volume = {35},
number = {12},
pages = {},
doi = {10.1093/hmg/ddag049},
pmid = {42307453},
issn = {1460-2083},
}

@article {pmid42307649,
year = {2026},
author = {Dogra, KA and Sharma, M and Ghosh, N and Kaur, G and Singh, J and Sinha, P},
title = {Gut microbiota and immune modulation: role in neurodegenerative disorders and cancer.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42307649},
issn = {1573-4978},
mesh = {Humans ; *Neurodegenerative Diseases/immunology/microbiology ; Animals ; *Neoplasms/immunology/microbiology ; *Gastrointestinal Microbiome/immunology ; Probiotics ; Prebiotics ; *Immunomodulation ; },
abstract = {The gut microbiota plays a crucial role in maintaining host metabolic balance and immune homeostasis, with increasing evidence linking its dysregulation to neurodegenerative diseases and cancer. This review aims to provide a comprehensive and integrative analysis of gut microbiota-mediated immune modulation in Parkinson's disease, Alzheimer's disease, and cancer. A structured literature-based approach was employed to examine recent studies focusing on microbial composition, metabolite production, and host microbe immune interactions. We summarize the role of key microbial metabolites, particularly short-chain fatty acids, in regulating immune responses, maintaining gut barrier integrity, and modulating systemic inflammation. In addition, the bidirectional communication along the gut-brain axis is discussed, highlighting its differential involvement in neurodegenerative disorders, while microbiota driven immune mechanisms contributing to tumorigenesis are also evaluated. Importantly, this review emphasizes the translational relevance of microbiome-targeted interventions, including prebiotics, probiotics, synbiotics, and emerging postbiotic strategies, in modulating disease progression and therapeutic outcomes. Although limitations lies in correlating the human gut microbiota to the results obtained from the animal studies which may not fully reflect the physiological conditions of the human gut as it is affected by several factors, this work provides a unified framework linking gut microbiota, immune regulation, and disease pathogenesis, and outlines future directions for the development of targeted and personalized microbiome-based therapies which may be achieved through well designed longitudinal and large scale clinical studies further.},
}

Humans
*Neurodegenerative Diseases/immunology/microbiology
Animals
*Neoplasms/immunology/microbiology
*Gastrointestinal Microbiome/immunology
Probiotics
Prebiotics
*Immunomodulation

@article {pmid42307791,
year = {2026},
author = {Wang, YH and Ding, PL and Qin, H and Zhang, KX and Ge, JW and Wu, DH and Xie, L and Liang, K},
title = {Glycogen Synthase Kinase-3β Inhibition Ameliorates Synaptic and Mitochondrial Dysfunction in a Sporadic Alzheimer's Disease-Like Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42307791},
issn = {1559-1182},
support = {82205064//Natural Science Foundation of China/ ; 2026JJ60631//Natural Science Foundation of Hunan Province/ ; 20254247//Research Project of the Health Commission of Hunan Province/ ; 2023RC3215//Hunan Provincial Science and Technology Innovation Program/ ; 2024JJ5236//Hunan Provincial Natural Science Foundation/ ; 2023SK2113-2//Furong Laboratory Science and Technology Research Project/ ; },
mesh = {Animals ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Alzheimer Disease/pathology/metabolism/enzymology/drug therapy ; Male ; *Mitochondria/metabolism/pathology/drug effects/ultrastructure ; *Synapses/metabolism/pathology/drug effects/ultrastructure ; Mice, Inbred C57BL ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mice ; Glucose/metabolism ; Wnt Signaling Pathway/drug effects ; Cell Line ; tau Proteins/metabolism ; },
abstract = {Abnormal glucose metabolism in the central nervous system is a major cause of sporadic Alzheimer's disease (SAD). We hypothesize that glycogen synthase kinase 3β (GSK3β) mediates cognitive impairment by inhibiting the Wnt/β-catenin pathway, which in turn induces abnormal glucose metabolism, synaptic damage, and mitochondrial dysfunction. To test this hypothesis, we injected streptozotocin bilaterally into the lateral ventricles of 100 male C57BL/6 J mice to establish in vivo models of SAD, and into HT22 cells to establish in vitro models of SAD. GSK3β expression was knocked down via adeno-associated virus (AAV) injection into the hippocampal CA1 region in vivo and via lentiviral transfection in vitro. We assessed cognitive function using the Morris water maze, Y-maze, and novel object recognition tests (n = 10). Glucose metabolism was evaluated by 18F-FDG PET imaging (n = 3), while synaptic and myelin sheath ultrastructure was examined using transmission electron microscopy (n = 6). Cell viability, mitochondrial function, and key protein expression were measured using CCK-8 assays, Seahorse analysis, and molecular biology techniques, respectively (n = 3, n = 6). In both in vivo and in vitro STZ-induced SAD models, GSK3β knockdown significantly reduced amyloid-β (1-42) deposition and tau hyperphosphorylation, activated the Wnt/β-catenin pathway, enhanced glucose metabolism, reversed glycolytic inhibition and mitochondrial dysfunction, and repaired synaptic and myelin sheath damage, ultimately improving cognitive deficits. Our findings demonstrate that GSK3β knockdown ameliorates STZ-induced SAD-like pathologies by restoring Wnt/β-catenin signaling and normalizing glucose metabolism, highlighting GSK3β as a potential therapeutic target for SAD.},
}

Animals
*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism
*Alzheimer Disease/pathology/metabolism/enzymology/drug therapy
Male
*Mitochondria/metabolism/pathology/drug effects/ultrastructure
*Synapses/metabolism/pathology/drug effects/ultrastructure
Mice, Inbred C57BL
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mice
Glucose/metabolism
Wnt Signaling Pathway/drug effects
Cell Line
tau Proteins/metabolism