@article {pmid42146353,
year = {2026},
author = {Xu, Z and Wang, K},
title = {LongAllele: a joint inference framework for allele-specific analysis on long-read bulk and single-cell RNA sequencing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.05.722992},
pmid = {42146353},
issn = {2692-8205},
abstract = {Allele-specific analysis from RNA-seq is a powerful approach to characterize cis -regulatory effects. However, existing methods remain limited in both haplotype inference and allelic testing. Their haplotype-inference workflows separate variant calling, haplotype phasing, and read-haplotype assignment into sequential steps, failing to fully exploit within-read single-nucleotide variant (SNV) linkage information and propagating errors into downstream allelic analysis. At the testing stage, they ignore non-phasable reads lacking heterozygous SNVs, biasing calls and inflating false positives, and remain incomplete across gene-, isoform-, and local-event-level variant effects. Here, we present LongAllele, a statistical framework that employs an expectation-maximization algorithm to jointly infer heterozygous variants, haplotype structure, and read-haplotype assignments from long-read bulk and single-cell RNA sequencing. LongAllele further introduces phasability-aware testing that explicitly accounts for non-phasable reads, avoiding inflated false-positive calls when haplotype information is incomplete. It also enables comprehensive allelic testing across gene-level allele-specific expression (ASE), isoform-level allele-specific transcript usage (ASTU), and local-event-level haplotype-associated exon and junction usage (HAEU and HAJU), providing a multi-scale view of cis -regulation across biological contexts. We applied LongAllele to long-read RNA-seq datasets spanning GTEx (multi-tissue bulk), peripheral blood mononuclear cells (single-cell), human hippocampus (single-nucleus), and human cortex from two Alzheimer's disease (AD) case-control cohorts (bulk, Oxford Nanopore and PacBio). LongAllele consistently revealed greater context dependence in expression-level than isoform-level allelic regulation across tissues, cell types, and disease states, and pinpointed high-impact regulatory variants including rare splice-site mutations missed by standalone variant callers. It further showed that purifying selection constrains allelic imbalance at both gene and isoform levels and resolved AD-associated variant effects in individual transcriptomes across long-read platforms.},
}

@article {pmid42335444,
year = {2026},
author = {Gallaccio, G and Müller, A and Wang, M and Diekmann, LM and Otto, C and Dinoto, A and Chiodega, V and Schwake, C and Jarius, S and Usnich, T and Sperber, PS and Anderhalten, L and Ongphichetmetha, T and Byars, A and Subasic, D and Kunkel, D and Ayzenberg, I and Mariotto, S and Samadzadeh, S and Paul, F and Böttcher, C},
title = {Immuno-Proteomic Features Associated to Relapse Risk in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.},
journal = {Neurology(R) neuroimmunology & neuroinflammation},
volume = {13},
number = {4},
pages = {e200615},
doi = {10.1212/NXI.0000000000200615},
pmid = {42335444},
issn = {2332-7812},
mesh = {Humans ; *Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease/immunology/cerebrospinal fluid/blood/diagnosis ; Female ; Male ; Proteomics ; Recurrence ; Middle Aged ; Adult ; *Alzheimer Disease/immunology/blood/cerebrospinal fluid ; *Multiple Sclerosis/immunology/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Myelin-Oligodendrocyte Glycoprotein/immunology ; },
abstract = {BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder that overlaps clinically with multiple sclerosis (MS) but immunopathologically distinct. Although often considered an acute inflammatory disease, recurrent attacks in MOGAD can lead to demyelination, axonal injury, and secondary neurodegeneration. Reliable biomarkers associated with relapse risk and disease subphenotypes, including optic neuritis, remain limited. Here, we aimed to define molecular and cellular signatures that distinguish MOGAD from MS as a prototypical neuroinflammatory disease and from Alzheimer disease (AD) as a proxy of neurodegeneration and to identify candidate immune-proteomic features associated with relapse frequency and clinical phenotype in MOGAD.

METHODS: CSF, serum, and whole-blood samples from patients with MOGAD (n = 67), MS (n = 49), and AD (n = 36) were profiled using NULISAseq™ CSF proteomics, Olink Explore 3072 CSF and serum proteomics, and high-dimensional mass cytometry for immune cell characterization. In MOGAD, longitudinal clinical data, including total attack counts from the earliest documented attack through follow-up, were integrated with immune and proteomic profiles to assess associations with disease course and clinical phenotype.

RESULTS: CSF and blood proteomic profiling revealed distinct inflammatory and cardiometabolic proteomic profiles in MOGAD, differentiating it from both MS and AD. Compared with MS, MOGAD showed relative reductions in lymphocyte populations with regulatory phenotypes. Within MOGAD, relapsing disease was associated with reduced frequencies of CD8[+]CCR7[+]CD31[+]CTLA4[+] T cells and concurrent expansion of double-negative γδ T-cell subsets. IL-13 correlated positively with relapse frequency and inversely with circulating regulatory T cells, whereas IL-32 and CASP4 showed opposite associations, correlating negatively with relapse count and positively with Treg frequency. IL-13 was also inversely associated with CD31-expressing CD8[+] T cells. Phenotype-stratified analyses suggested that these immune-proteomic relationships differed according to clinical presentation, including optic neuritis vs nonoptic neuritis phenotypes.

DISCUSSION: This integrative immune-proteomic analysis identifies cellular and molecular features associated with relapsing vs monophasic MOGAD, suggesting a model of impaired peripheral immune regulation in relapsing disease. While exploratory, these findings generate a concrete hypothesis for future longitudinal and functional studies aimed at refining biomarker-based monitoring and informing individualized therapeutic strategies in MOGAD.},
}

Humans
*Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease/immunology/cerebrospinal fluid/blood/diagnosis
Female
Male
Proteomics
Recurrence
Middle Aged
Adult
*Alzheimer Disease/immunology/blood/cerebrospinal fluid
*Multiple Sclerosis/immunology/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
Myelin-Oligodendrocyte Glycoprotein/immunology

@article {pmid42335451,
year = {2026},
author = {Liao, Q and Wang, X and Duan, Y and Guo, L and He, S and Lyu, W and Shi, J and Fu, R and Zhang, H and Han, Y and Li, Q},
title = {Discovery of New Butyrylcholinesterase Inhibitors and Evaluation of Their Biological Activity against Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00302},
pmid = {42335451},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a degenerative disease of the central nervous system (CNS), which is relatively common in the elderly population and is the main cause of senile dementia. Its typical pathological features mainly lie in hyperphosphorylated tau proteins in the form of neurofibrillary tangles (referred to as tau tangles) and β-amyloid plaques. Using DrugCLIP website, we investigated the effects of butyrylcholinesterase (BChE) inhibitors on AD. From virtual screening, molecule W1 (inhibitory concentration (IC50) = 0.63 ± 0.19 μM) was identified as the lead compound of this research. Subsequently, the lead compound molecule was obtained through chemical synthesis, and its structure was modified to synthesize and evaluate 21 derivatives. Derivatives W3 and W13 also showed micromolar-level BChE inhibitory activity (W3: IC50 = 0.28 ± 0.14 μM, W13: IC50 = 0.03 ± 0.02 μM), with W13 demonstrating superior inhibitory activity. The results of binding patterns demonstrated that both compounds can bind to the target and form multiple interactions with amino acid residues. From the enzyme kinetics results, it can be observed that both compounds were BChE inhibitors in a mixed manner, which was consistent with the docking results. Due to W3 not occupying the acyl-binding pocket, its activity was inferior to W13. In pharmacodynamic studies, W3 and W13 protected nerve cells from toxicity, hydrogen peroxide (H2O2), and Aβ1-42 stimulation in vitro, reduced the production of reactive oxygen species, and alleviated Aβ-induced cognitive impairment in mice. In addition, optimal compound W13 presented considerable pharmacokinetic properties, with a high oral bioavailability (80%). Moreover, it could penetrate the blood-brain barrier and take effect in the CNS. Therefore, these findings support further investigation of W3 and W13 as potential therapeutic candidates for advanced AD.},
}

@article {pmid42335456,
year = {2026},
author = {Ha, J and Bok, J and Lee, Y and Kim, YS and Kim, JS and Kim, HJ and Jang, Y},
title = {Noninvasive Electrophysiological Biomarkers of Olfactory Responses Across Cognitive States in Alzheimer Dementia: Cross-Sectional Study.},
journal = {JMIR mHealth and uHealth},
volume = {14},
number = {},
pages = {e76245},
doi = {10.2196/76245},
pmid = {42335456},
issn = {2291-5222},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/physiopathology/complications/psychology/diagnosis ; Aged ; *Biomarkers/analysis ; Cross-Sectional Studies ; Electroencephalography/methods/instrumentation ; Cognitive Dysfunction/physiopathology/diagnosis ; *Cognition/physiology ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is characterized by progressive cognitive decline, with olfactory dysfunction emerging among its earliest symptoms. Conventional olfactory tests rely on subjective self-reports and patient cooperation, limiting their clinical applicability. Noninvasive olfactory bulb (OB) recordings may provide objective physiological measures for early detection of cognitive decline.

OBJECTIVE: This study investigated the relationship between olfactory dysfunction and cognitive decline across the AD spectrum and evaluated whether noninvasive OB recordings obtained via a wearable electroencephalography-based device could serve as digital biomarkers for early detection and home-based monitoring.

METHODS: We recruited 71 participants, including individuals who were cognitively normal (CN; n=18), patients with mild cognitive impairment (MCI) subdivided into early MCI (n=30) and late MCI (n=9), and patients with dementia of the Alzheimer type (n=14). OB activity was recorded noninvasively during odor stimulation using a 6-channel wearable electroencephalography system. Behavioral olfactory function was assessed using a culturally adapted 6-item modified Brief Smell Identification Test and compared with electrophysiological responses. Time-frequency analyses identified disease-related components via nonparametric permutation testing (1000 iterations; P<.05). A support vector machine classifier was applied for group discrimination. Structural brain integrity was assessed through diffusion tensor imaging and magnetic resonance imaging, and cognitive performance was evaluated using comprehensive neuropsychological testing. Beta-band power (reflecting top-down cortical feedback) and gamma-band power (representing OB activity) were analyzed to characterize neural communication patterns.

RESULTS: Beta-band power progressively declined from CN to dementia of the Alzheimer type, while gamma-band power decreased and response latency increased beginning in late MCI. Behavioral olfactory testing failed to differentiate CN from early MCI (P=.77), whereas electrophysiological recordings revealed significant differences (P=.02). The support vector machine classifier achieved 83.1% accuracy in distinguishing all groups based on olfactory spectral features. Reduced beta-band power showed a trend-level association with cingulum-hippocampal tract diffusivity (R²=0.28; P=.061), whereas gamma-band power correlated with OB volume in later disease stages (R²=0.21; P<.001). Electrophysiological features explained 91.7% of the variance in cognitive scores (Seoul Neuropsychological Screening Battery II; P<.001). The brief 5 to 10-minute testing protocol, requiring less than 2 minutes to fit the device, supports its feasibility for repeated, home-based assessments.

CONCLUSIONS: Bidirectional interactions between the OB and higher-order brain regions appear altered early in the AD continuum, with beta-band changes emerging first and gamma-band alterations occurring later. Digital OB recordings offer objective, noninvasive biomarkers for detecting cognitive decline before overt structural changes. Their portability and short duration make this approach ideal for longitudinal, home-based cognitive assessments within mobile health frameworks and for evaluating therapeutic efficacy in future interventional studies.},
}

Humans
Female
Male
*Alzheimer Disease/physiopathology/complications/psychology/diagnosis
Aged
*Biomarkers/analysis
Cross-Sectional Studies
Electroencephalography/methods/instrumentation
Cognitive Dysfunction/physiopathology/diagnosis
*Cognition/physiology
Aged, 80 and over
Middle Aged

@article {pmid42335710,
year = {2026},
author = {Bruno, D and Jauregi-Zinkunegi, A and Studer, RL and Wilson, R and Zetterberg, H and Johnson, SC and Mueller, KD},
title = {A multiverse analysis of the logical memory test and plasma biomarkers of Alzheimer's disease.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {202},
number = {},
pages = {181-192},
doi = {10.1016/j.cortex.2026.06.005},
pmid = {42335710},
issn = {1973-8102},
abstract = {BACKGROUND: Alzheimer's disease (AD) detection with blood-based biomarkers promises to revolutionise dementia diagnosis. However, blood testing is still a challenge in remote settings. Cognitive testing that is sensitive to plasma biomarker levels can be a useful proxy. A common test for dementia assessment is the logical memory test (LMT) - where a story is read out loud to the individual and then freely recalled. Alongside standard metrics, item-based metrics, such as recall of proper names and serial positions, are effective at detecting AD-related pathology. We set out to compare a range of LMT metrics against plasma AD biomarkers, and examine differences between men and women.

METHODS: The Wisconsin Registry for Alzheimer's Prevention cohort was used for analysis: participants (n = 1195, 69% women; mean age = 67.2, SD = 7.7) were free from dementia. Data included logical memory performance, demographics, clinical and genetic information, and plasma biomarkers. Analyses were cross-sectional with a maximum of two years between assessment and biomarker extraction. We carried out multiverse analyses to allow comparison of alternative models with permutations of covariates.

RESULTS: In the full sample, associations were most stable between LMT scores and p-tau217, and were significant across all models, while associations with other plasma biomarkers were generally less reliable. In the stratified analyses, associations were overall more robust and consistent in women than in men.

DISCUSSION: Current findings show LMT metrics are consistently associated with in vivo levels of pathology as measured by plasma p-tau217. The discrepancies observed between men and women require further investigation.},
}

@article {pmid42336030,
year = {2026},
author = {Bagri, K and Damde, P and Bhatia, A and Deshmukh, R},
title = {From Synapses to Tangles: PDE Inhibitors as Therapeutic Modulators in Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179084},
doi = {10.1016/j.ejphar.2026.179084},
pmid = {42336030},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD), historically characterized by amyloid plaques and tau tangles, is increasingly recognized as a disorder of intracellular signalling failure-where second messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) become silent before memory does. These cyclic nucleotides are critical for synaptic plasticity, memory consolidation, and neurovascular function, operating through tightly regulated pathways involving protein kinases such as protein kinase A (PKA) and protein kinase G (PKG), transcription factors like cAMP response element-binding protein (CREB), and phosphodiesterases (PDEs). In the healthy brain, cAMP and cGMP orchestrate gene transcription, long-term potentiation, and cerebral blood flow. However, in AD, these signalling networks are progressively disrupted. Although it is not clear, whether failures in cyclic nucleotide signalling lead to amyloid beta and tau pathology or these pathological hallmarks disrupt the signalling mechanisms and lead to synaptic failure. However, the evidence suggests both of these possibilities. Amyloid-β oligomers and tau pathology impair adenylyl and guanylyl cyclase activity, reduce CREB phosphorylation, and disrupt nitric oxide (NO) signalling. Concurrently, overexpression of PDEs accelerates cyclic nucleotide degradation, silencing downstream pathways essential for neuronal resilience and plasticity. Dysregulated cyclic nucleotide signalling has been linked to neurovascular dysfunction, and cognitive decline. The present review is significant as it reframes AD as a signalling failure disorder rather than solely a protein aggregation disease. By identifying cyclic nucleotide dysregulation as a central and druggable mechanism, it establishes a strong translational rationale for targeting PDE-mediated degradation. This mechanism-driven perspective provides a focused platform for therapeutic innovation aimed at restoring synaptic integrity and improving cognitive outcomes in AD.},
}

@article {pmid42336161,
year = {2026},
author = {Zhang, Y and Zhang, X and Huang, J and Sun, Z},
title = {Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.},
journal = {Brain research bulletin},
volume = {243},
number = {},
pages = {112014},
doi = {10.1016/j.brainresbull.2026.112014},
pmid = {42336161},
issn = {1873-2747},
abstract = {Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.},
}

@article {pmid42336262,
year = {2026},
author = {Bhagat, PP and Sharma, TG and Shirasath, KR and Goyal, SN and Awathale, SN},
title = {Bromodomain protein 4 (BRD4) as a central epigenetic regulator in neuropsychiatric and neurodegenerative disorders.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.033},
pmid = {42336262},
issn = {1873-7544},
abstract = {Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, is a central epigenetic regulator that links histone acetylation-dependent chromatin remodelling to transcriptional control. Through recognition of acetylated lysine residues and recruitment of transcriptional machinery, it is increasingly recognised as a critical regulator of neuronal and glial functions, influencing synaptic plasticity, neuroinflammation, learning, memory, and behavioural adaptation. A wide range of neurological, neurodevelopmental, and neuropsychiatric diseases are linked to abnormal BRD4 signalling. BRD4 coordinates common pathogenic pathways, such as dysregulated transcriptional networks, by binding to acetylated histones and recruiting positive transcription elongation factor b to stimulate RNA polymerase II-dependent transcription of genes associated with central nervous system (CNS) diseases such as Alzheimer's and post-traumatic stress disorder. These convergent roles of BRD4 positioned it as a molecular hub that connects CNS dysfunction and epigenetic control. In this review, we focus on involvement of BRD4 in various CNS disorders and provide a thorough overview of its structure, transcriptional mechanisms, and physiological and pathogenic functions in the CNS. Here, the emphasis is on common BRD4-dependent mechanisms that span multiple neurological conditions and the therapeutic opportunities and challenges associated with targeting BRD4. Collectively, current evidence supports BRD4 as a promising target for precision epigenetic therapies aimed at restoring neuronal homeostasis and modifying disease progression.},
}

@article {pmid42336284,
year = {2026},
author = {Steiner, H and Breimann, S and Kamp, F and Frishman, D},
title = {From mechanism to substratome: unraveling mysteries of γ-secretase.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113287},
doi = {10.1016/j.jbc.2026.113287},
pmid = {42336284},
issn = {1083-351X},
abstract = {γ-Secretase is a pivotal membrane-embedded protease, which cleaves more than 150 single-span membrane proteins within their transmembrane domains. While γ-secretase is involved in a wide range of physiological processes, it is best known for its critical role in Alzheimer´s disease, where it cleaves a C-terminal fragment of the amyloid precursor protein into small aggregation-prone and neurotoxic peptides. However, how γ-secretase recognizes and recruits its substrates, how it binds and unfolds them, where drug-binding sites are located, and what the full range of its substrates and functions is, have all remained unknown. These long-standing questions have been at the forefront of research for the past decade and are now increasingly being solved. In this review, we outline how recent advances in structural biology, biochemistry, and computational biology have helped to elucidate these mysteries. We also highlight future research directions needed to achieve a comprehensive understanding of this fascinating enzyme, a major therapeutic target for which Alzheimer's disease drugs are now on the horizon.},
}

@article {pmid42336347,
year = {2026},
author = {Custodio, N and Montesinos, R and Custodio, B and Malaga, M and Uribe, A and Nuñez, M and Bartolo, P and Yauri, Z and Agüero, K and Verastegui, G and Huilca, J},
title = {Cognitive impairment on the Alzheimer's Disease Centers' Uniform Data Set Version 3 Neuropsychological Test Battery in a Peruvian population with progressive supranuclear palsy.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {5},
pages = {1-9},
doi = {10.1055/s-0046-1824433},
pmid = {42336347},
issn = {1678-4227},
mesh = {Humans ; Female ; Peru ; Male ; *Neuropsychological Tests ; Cross-Sectional Studies ; *Supranuclear Palsy, Progressive/physiopathology/complications/psychology ; Aged ; Middle Aged ; *Cognitive Dysfunction/physiopathology/diagnosis/etiology ; Aged, 80 and over ; Reference Values ; Cognition Disorders/physiopathology ; },
abstract = {BACKGROUND: Research on the cognitive profile in progressive supranuclear palsy (PSP) has been scarce in Latin America.

OBJECTIVE: To outline the demographic, clinical, and cognitive profile of Peruvian PSP patients living in Lima, Peru. We sought to determine the relationship between first clinical symptoms and specific cognitive abilities.

METHODS: A cross-sectional study of 34 PSP subjects. We used the Uniform Data Set Version 3 Neuropsychological Battery (UDS3-NB), which possesses normative data for the Peruvian population, to assess global and specific cognitive functions. We also performed correlation analyses to determine the relationship between presenting clinical symptoms (parkinsonism, postural instability, and cognitive impairment) and cognitive functioning.

RESULTS: The mean age was 68 years, and mean schooling was 12.1 years in this cohort. The most common initial clinical symptom was parkinsonism (55.9%), followed by postural instability (23.5%) and dementia (20.6%). Our cohort showed poor performance on global cognition, with selective impairment of processing speed, executive function, and episodic memory. Attentional and visuospatial skills were mildly affected, with partial preservation of naming. There was no significant relationship between the initial clinical symptoms and global cognition, except for a slight correlation between parkinsonism and visuospatial function (r = 0.18; p < 0.05).

CONCLUSION: We found that PSP patients in Peru had extensive impairment in executive function, processing speed, and episodic memory, with relatively preserved naming, consistent with other international cohorts. We did not find a correlation between initial clinical signs and cognitive profile, suggesting that an interdisciplinary approach is needed to evaluate patients with suspicion for PSP. Longitudinal studies are needed to more clearly define the progression of neuropsychiatric symptoms in PSP patients.},
}

Humans
Female
Peru
Male
*Neuropsychological Tests
Cross-Sectional Studies
*Supranuclear Palsy, Progressive/physiopathology/complications/psychology
Aged
Middle Aged
*Cognitive Dysfunction/physiopathology/diagnosis/etiology
Aged, 80 and over
Reference Values
Cognition Disorders/physiopathology

@article {pmid42336352,
year = {2026},
author = {Mitsuoka, Y and Morimoto, T and Bando, K and Hara, S and Fujita, K and Nishida, K},
title = {Label-Free Detection of Cellular Aβ Accumulation and Mitochondrial Dysfunction in AD Cell Models via Raman Microscopy.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c06200},
pmid = {42336352},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a neurocognitive disorder characterized by the accumulation of amyloid beta (Aβ) in senile plaques in the brain. Aβ accumulates in nerve cells, causing cellular dysfunction through various mechanisms, including mitochondrial dysfunction, leading to apoptosis. AD cell models are being studied to elucidate the neurotoxic effect of Aβ; however, conventional methods such as immunostaining and fluorescent molecular labeling require extensive sample manipulation and may produce artifacts not reflective of natural states. In this study, we employed Raman microscopy on AD cell models and simultaneously detected Aβ accumulated in cells and associated mitochondrial dysfunction through cytochrome distribution changes. This label-free method enables the observation of AD cell models in a more natural state and is expected to contribute to elucidating the mechanism of cell damage caused by Aβ. Furthermore, applying this system to experiments involving Aβ inhibitor administration enables rapid, label-free evaluation of drug activity, which is highly valuable in drug development.},
}

@article {pmid42336662,
year = {2026},
author = {Rajender, R and Foth, N and Eggert, S and Schilling, S and Fäßler, M and Ott, C and Mühlhaus, T and Sommer, F and Schroda, M and Maritzen, T and Banicevic, M and Bengelsdorff, V and Kiss, E and Buchholz, CJ and Müller, UC and Kins, S},
title = {Trans-dimerization of Amyloid Precursor Protein family members induces pre- and postsynaptic differentiation through distinct signaling pathways.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0701-25.2026},
pmid = {42336662},
issn = {1529-2401},
abstract = {The amyloid precursor protein (APP), a key factor in Alzheimer's disease (AD) pathology, and its two mammalian homologues, amyloid precursor like proteins 1 and 2 (APLP1 and APLP2), are considered as members of the synaptic adhesion molecule (SAM) family. They are localized to the pre- and postsynapse, form trans-cellular dimers and have been shown to induce presynaptic differentiation in a heterologous synapse formation assay.We demonstrate that expression of all APP family members in non-neuronal cells also promotes dendritic excitatory postsynaptic differentiation in primary mouse neurons of either sex, similar to Neurexin1β and other SAMs. Synaptogenic activity was decreased by deletion of the E1 domain and increased upon inhibition of soluble APP (sAPP) generation, reinforcing that trans-cellular interaction of APP/APLPs can induce synaptogenesis. Consistent with this, the capacity of heterologously expressed APP to induce postsynaptic specializations in contacting dendrites was reduced by the absence of APP family members at the postsynaptic site and was lost in conditional triple knockout (cTKO) neurons. Pharmacological analyses revealed that heterologous formation of pre- and postsynapses relies on proper microtubule- and actin cytoskeleton dynamics, as well as the MAP kinase pathway, similar to what has been shown for Neurexin1β and Neuroligin1. However, inhibition of the PI3K/Akt pathway selectively impaired APP-induced postsynaptic differentiation, suggesting that distinct APP signaling pathways are required for pre- and postsynaptic differentiation. Collectively, our data highlight the role of all APP family members as SAMs in trans-synaptic signaling, providing key insights into their physiological function and advancing our understanding of AD-related synaptopathies.Significance Statement Our data show that all three amyloid precursor protein (APP) family members induce besides presynaptic also postsynaptic differentiation through distinct signaling pathways. Specifically, the c-Jun N-terminal kinase pathway is involved at pre- and postsynaptic sites, whereas the Akt pathway is selectively required for postsynaptic differentiation. Furthermore, mutagenesis studies demonstrate that pre- and postsynaptic differentiation is mediated independent of secreted APP. Finally, our analyses on knockout neurons lacking all APP family members strongly suggest that synaptogenic activity of APP is mostly mediated by APP or Amyloid precursor like proteins (APLPs) dimerization partner located at the opposing postsynaptic site. Together, these data support the hypothesis that synaptogenic activity of APP/APLPs is predominantly driven by heterotypic trans-cellular interaction as synaptic adhesion molecules.},
}

@article {pmid42336817,
year = {2026},
author = {Vari, HR and Praticò, D},
title = {Necroptosis in Down Syndrome.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-09035-y},
pmid = {42336817},
issn = {2041-4889},
abstract = {Necroptosis is a form of controlled cell death implicated in neuronal loss observed in neurodegenerative diseases such as Alzheimer's disease. Down syndrome (DS) is also characterized by the presence of neuronal cell loss, but the underlying mechanisms remain unclear. Brain tissue from a mouse model of DS, Ts65dn mice, and subjects with DS were assessed for levels of necroptosis markers including receptor-interactive protein kinase 1 and 3, necroptosis executor mixed lineage kinase domain-like protein and long non-coding RNA MEG. While no differences were observed between the Ts65dn and wild type mice at a young age, levels of these markers were significantly elevated in the brains of old DS mice when compared with matched wild type controls. Assessment of post-mortem brains from DS subjects also revealed a significant increase in these necroptosis markers. Our study is the first report showing the presence of necroptosis markers in the brains of a mouse model of DS and in DS subjects. These findings support the novel idea that this form of cell death should be also considered for developing novel therapeutic strategies for DS.},
}

@article {pmid42336952,
year = {2026},
author = {Arabhalvaei, V and Rajaei, SN and Alinaghi, MM and Talebi, M and Dashti, F and Abachi, SF and Khodayar, Z and Jafroodi, AR and Jamalaldin, M and Mehboodi, M and Maleki, MH and Rahimi, A and Baziyar, P},
title = {Investigation of the effects of sodium butyrate on SH-SY5Y neurons treated with amyloid beta42 and lipopolysaccharide: A computational and experimental study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59446-2},
pmid = {42336952},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta42 (Aβ42) aggregation, neuroinflammation, and synaptic dysfunction. This study combines computational and experimental approaches to investigate the neuroprotective effects of sodium butyrate (NaB). Differentiated SH-SY5Y neurons were exposed to lipopolysaccharide (LPS) and Aβ1-42 to model AD-like conditions, and the potential protective effects of NaB were evaluated. MD simulations indicated that NaB may be associated with destabilization of organized Aβ42 fibrils. Alterations in RMSD, Rg, and SASA values indicated structural instability of Aβ42 fibrils in the presence of NaB. Treatment with NaB (10 and 50 µM) significantly improved cell viability compared to the LPS + Aβ group (p < 0.001) and attenuated apoptosis, as evidenced by reduced expression of Bax, Caspase-3, and FOXO3a (p < 0.0001), alongside upregulation of the anti-apoptotic marker Bcl-2 (p < 0.01). Moreover, NaB markedly increased the expression of neuroprotective and antioxidant genes, including BDNF, Nrf2, SIRT1, and CREB (p < 0.001), thereby restoring pathways involved in neuronal survival, oxidative stress defense, and synaptic plasticity. Collectively, these effects mitigated LPS + Aβ-induced cytotoxicity, suggesting that NaB exerts its neuroprotective action through epigenetic regulation of stress-response and plasticity networks. Our findings provide robust evidence supporting sodium butyrate as a promising therapeutic candidate for preventing or slowing AD-related neuronal degeneration and highlight its potential translational relevance for future in vivo and clinical investigations.},
}

@article {pmid42337012,
year = {2026},
author = {Li, Z and Miao, Y and Zhang, X and Ma, Y and Jin, L},
title = {Metabolomic signatures of brain aging: A multimodal and genetic study.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42337012},
issn = {1476-5578},
abstract = {Accelerated brain aging is increasingly recognized as a transdiagnostic risk factor for neuropsychiatric and neurodegenerative disorders, yet its metabolic underpinnings remain poorly understood. Here we integrated multimodal neuroimaging (MRI), plasma metabolomics, and genomic data from the UK Biobank to identify metabolic markers of brain aging and evaluate their causal relevance. Using 1079 imaging-derived phenotypes (IDPs) from 4333 healthy participants, we trained and validated machine learning models for brain age prediction, with a least absolute shrinkage and selection operator (LASSO) regression model achieving the best performance (mean absolute error = 3.26 years, R[2] = 0.68). Brain age gap (BAG) was then estimated in 37,458 participants. Association analyses in 21,780 individuals identified nine plasma metabolites significantly linked to BAG after Bonferroni correction, with glucose showing the strongest effect (β = 0.32, P = 9.90 × 10[-12]). Genome-wide association studies (GWAS) identified 392 BAG-associated single-nucleotide polymorphisms (SNPs) (P < 5 × 10[-8]), and two-sample Mendelian randomization (MR) provided evidence supporting a potential causal role of glucose in accelerating brain aging. Clinically, elevated plasma glucose was positively associated with seven brain disorders, including all-cause dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, stroke, depression, and anxiety, and negatively associated with cognitive performance, movement function, and mental health outcomes. Higher glucose concentrations were also associated with reduced regional brain volumes across 80 cortical, subcortical, and cerebellar regions. These findings implicate glucose metabolism as a modifiable pathway in brain aging, with implications for early intervention strategies aimed at preserving brain health across the lifespan.},
}

@article {pmid42337153,
year = {2026},
author = {Han, JW and Na, S and Han, K and Lee, KN and Kim, DY and Ahn, SH and Kim, MN},
title = {Alcohol consumption and dementia risk in steatotic liver disease: a nationwide cohort study.},
journal = {Hepatology international},
volume = {},
number = {},
pages = {},
pmid = {42337153},
issn = {1936-0541},
abstract = {BACKGROUND: The relationship between steatotic liver disease (SLD) and dementia remains unclear, particularly regarding alcohol consumption patterns. We investigated the risk of dementia across SLD subtypes classified by alcohol consumption.

METHODS: We analyzed 3,071,829 adults without baseline dementia who underwent health examinations in 2012. Participants were classified into No SLD, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated alcohol-related liver disease (MetALD), and ALD groups. Primary outcomes were newly diagnosed all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD).

RESULTS: Over a median follow-up of 5.4 years, 72,545 all-cause dementia, 56,999 AD, and 8923 VD cases occurred. The risk of dementia significantly increased across all dementia outcomes in SLD (all p < 0.05). Across the SLD subtypes, ALD showed the highest risk of dementia, followed by MASLD, whereas MetALD showed largely neutral associations except for a modestly increased risk of VD. When MASLD was further stratified by alcohol consumption, the MASLD-no alcohol group showed consistently increased risk of all dementia outcomes (all p < 0.05). In contrast, MASLD with within-threshold alcohol intake showed heterogeneous associations across dementia outcomes.

CONCLUSIONS: The association between SLD and dementia differed according to SLD phenotype and alcohol consumption pattern. These findings should be interpreted as observational associations and warrant further validation in studies with longitudinal assessment of SLD status and alcohol exposure.},
}

@article {pmid42337208,
year = {2026},
author = {Ha, TY and Lim, SM and Park, H and Chang, KA},
title = {Loss of miR-204 Drives NPTX1-Dependent Mitochondrial Dysfunction and Neuronal Degeneration in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01769-9},
pmid = {42337208},
issn = {1573-6830},
support = {RS-2024-00338662//Korea Dementia Research Center/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology promotion/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by synaptic dysfunction and neuronal loss. Dysregulation of specific microRNAs (miRNAs) has been increasingly implicated in AD pathogenesis, suggesting that miRNA-mediated regulatory pathways may represent important mechanisms underlying neuronal vulnerability. Here, we identified mmu-microRNA-204-5p (miR-204) as a critical regulator of neuronal survival that is markedly downregulated in the hippocampus of 5xFAD mice. Through integrated bioinformatics analysis and experimental validation, we established neuronal pentraxin-1 (NPTX1) as a direct post-transcriptional target of miR-204. In primary cultured neurons, exposure to Aβ1-42 oligomer (oAβ) drove marked upregulation of NPTX1 and precipitated neuronal injury, manifested by aberrant reactive oxygen species (ROS) accumulation, collapse of mitochondrial membrane potential, diminished cell viability, and dendritic degeneration. Inhibition of miR-204 further exacerbated these pathological changes and engaged mitochondrial apoptotic signaling, as evidenced by Bax upregulation, cytochrome c release, and caspase-3 cleavage. Conversely, restoration of miR-204 expression or genetic knockdown of NPTX1 attenuated oxidative stress, preserved mitochondrial integrity, and restored neuronal survival. Collectively, our findings uncover a previously unrecognized miR-204-NPTX1 regulatory axis that governs mitochondrial integrity and apoptotic susceptibility in AD, highlighting miR-204 as a potential therapeutic target for AD and related oxidative stress-associated neurodegenerative disorders.},
}

@article {pmid42337295,
year = {2026},
author = {Theocharidis, G and Bisdas, S and Pazarzis, J and Zervoudakis, S and Zheng, D and Angelidis, G and Saravanos, A},
title = {Applying ensemble machine learning techniques to MRI scans to predict Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-57402-8},
pmid = {42337295},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia globally. Early prediction, prior to the onset of symptoms, is critical for enabling timely interventions. We present a machine learning framework that predicts future AD conversion in cognitively normal (CN) individuals using only structural magnetic resonance imaging (MRI) data. The approach leverages transfer learning with a pre-trained VGG16 model for feature extraction and processes five representative 2D slices per brain MRI scan to generate compact imaging descriptors. These features are classified using an ensemble composed of support vector machines (SVM), random forests (RF), and artificial neural networks (ANN), with outputs combined through soft voting. The model was evaluated using person-wise stratified cross-validation on 1,093 subjects from the OASIS-3 dataset, ensuring no data leakage and providing realistic performance estimates. Across 200 randomized runs, the ensemble achieved a median AUC-ROC of 0.951, accuracy of 0.872, recall of 0.923, and F1 score of 0.811. These results demonstrate that ensemble machine learning can detect preclinical AD signatures from structural MRI, offering a practical, relatively accessible, and cost-effective tool for early risk identification and intervention.},
}

@article {pmid42337593,
year = {2026},
author = {Pan, T and Fang, J and Wang, X and Chen, Y and Li, S and Qiu, G and Sun, C and Liu, C and Li, A and Chen, F},
title = {Localized amyloid-β oligomers in the lateral entorhinal cortex drives olfactory dysfunction through aberrant neuronal and network activity.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02354-3},
pmid = {42337593},
issn = {2051-5960},
support = {202410313103Y//Jiangsu Training Program of Innovation and Entrepreneurship for Undergraduates/ ; 32271055 and 32471058//National Natural Science Foundation of China/ ; 32100807//National Natural Science Foundation of China/ ; JC20250001//Faculty Development Grant of Basic Medical Sciences, Xuzhou Medical University/ ; },
abstract = {Olfactory dysfunction is one of the most common early features of Alzheimer's disease (AD), yet its underlying neural mechanisms remains unclear. The lateral entorhinal cortex (LEC), a central node in the olfactory network, is among the earliest regions affected by AD pathology. However, the direct evidence supporting a causal link between LEC dysfunction and olfactory disorders in early AD is limited. In the present study, we explored whether and how LEC dysfunction contributes to early AD olfactory dysfunction by injecting amyloid-β1-42 (Aβ1-42) oligomers into the LEC to induce localized Aβ oligomers accumulation in this region. Our data demonstrate that localized Aβ oligomers in the LEC impaired odor detection and discrimination in mice. In vivo recordings revealed that Aβ oligomers increased baseline firing and odor-evoked activity in LEC neurons, while also enhancing odor-evoked beta oscillations. This hyperactive state corresponded with disrupted population-level odor decoding. Furthermore, deficits in synaptic structure and impaired synaptic transmission likely underlie the observed behavioral dysfunctions. Overall, these findings indicate that LEC dysfunction is linked to olfactory deficits in early AD, providing direct evidence for the involvement of this region in AD-related olfactory impairment.},
}

@article {pmid42337598,
year = {2026},
author = {Labrador-Espinosa, MA and Franzmeier, N and Karagianni, S and Moscoso, A and Schöll, M},
title = {Clinico-biological trajectories stratified by combined tau biomarkers in preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42337598},
issn = {1758-9193},
mesh = {Humans ; Female ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/blood/metabolism/drug therapy/pathology ; Positron-Emission Tomography ; Aged ; Biomarkers/blood ; Male ; Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging/metabolism/pathology ; Magnetic Resonance Imaging ; Disease Progression ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cognitive Dysfunction/diagnostic imaging ; Longitudinal Studies ; },
abstract = {BACKGROUND: Tau pathology biomarkers provide prognostic indicators of neurodegeneration and cognitive decline in Alzheimer's disease (AD), making them crucial to early patient stratification for disease-modifying interventions. Plasma p-tau217 indexes early tau pathophysiology, whereas FDA/EMA-approved [[18]F]flortaucipir PET (tau-PET) visual assessments indicate advanced neurofibrillary tangle pathology. Here, we identified concordant and discordant profiles based on combined plasma p-tau217 status and tau-PET visual assessments in cognitively unimpaired amyloid-β (Aβ)-positive older adults and investigated whether these profiles delineate distinct longitudinal trajectories of Aβ and tau accumulation, neurodegeneration, and cognitive decline.

METHODS: We included 330 cognitively unimpaired Aβ-PET-positive participants (72.2 ± 4.8 years; 58% female; 48% randomized to receive solanezumab) from the A4 Study, who underwent plasma p-tau217 and tau-PET at baseline. Plasma positivity (T1 +) followed A4 core criteria as previously reported (≥ 0.28 U/mL), while tau-PET positivity (T2 +) was determined by three expert visual readers with strong inter-rater agreement (κ = 0.954). Participants were stratified as T1[- / +]T2[- / +] at baseline and were followed for 5.0 ± 1.7 years. Baseline and longitudinal differences in regional Aβ- and tau-PET SUVR, MRI-measured gray-matter (GM) volume, and cognitive performance were examined using ANCOVA and mixed-effects models. All models accounted for treatment, with additional sensitivity analyses excluding treated participants.

RESULTS: At baseline, 57% were negative-concordant (T1 - T2 - : n = 187), 24% were discordant (T1 + T2 - : n = 53; T1 - T2 + : n = 27), and 19% were positive-concordant (T1 + T2 + : n = 63). T1 + T2 + profile constituted the highest-risk state, showing the greatest baseline cortical Aβ burden, the strongest neocortical tau progression (fronto-temporo-parietal pattern; p(FDR) < 0.05), marked baseline atrophy with accelerated longitudinal GM loss in overlapping regions, and the fastest cognitive decline (PACC: d = -1.84, p < 0.001). Consistently, T1 + T2 + exhibited the highest hazard of progression to more advanced clinico-biological stages over follow-up (HRClinical = 3.03, HRBiological = 9.98; p < 0.001). Discordant profiles showed comparatively limited progression, suggesting earlier or low-tau states. Results were essentially unchanged after excluding treated participants.

CONCLUSIONS: Integrating plasma p-tau217 with tau-PET visual assessment reveals clinically meaningful tau-biomarker heterogeneity in preclinical AD. Our findings highlight the value of combining these biomarkers to refine early risk prediction and support prioritization strategies for prevention trials. The frequency of discordance also motivates refining tau-PET visual assessments beyond binary classification (e.g., ordinal/semi-quantitative staging) to better capture subtle early tau signal.},
}

Humans
Female
*tau Proteins/blood/metabolism
*Alzheimer Disease/diagnostic imaging/blood/metabolism/drug therapy/pathology
Positron-Emission Tomography
Aged
Biomarkers/blood
Male
Amyloid beta-Peptides/metabolism
Brain/diagnostic imaging/metabolism/pathology
Magnetic Resonance Imaging
Disease Progression
Antibodies, Monoclonal, Humanized/therapeutic use
Cognitive Dysfunction/diagnostic imaging
Longitudinal Studies

@article {pmid42337630,
year = {2026},
author = {Miyashita, A and Hara, N and Obinata, A and Tsukie, T and Hasegawa, M and Ishiguro, T and Kasuga, K and Kikuchi, M and Hashimoto, T and Kanekiyo, T and Ikeuchi, T},
title = {A reappraisal of APOE genetic effects on Alzheimer's disease risk in the Japanese population: a meta-analysis.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42337630},
issn = {1750-1326},
support = {21K07271 (AM)//JSPS Grant-in-Aid for Scientific Research (KAKENHI) (C)/ ; 21H03537 (AM)//JSPS Grant-in-Aid for Scientific Research (KAKENHI) (B)/ ; JP26dk0207082 (TI)//AMED/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; *Genetic Predisposition to Disease/genetics ; Japan/epidemiology ; *Apolipoproteins E/genetics ; *Asian People/genetics ; Risk Factors ; East Asian People ; },
abstract = {Our meta-analysis demonstrates that the risk effect of APOE-e4*4 relative to APOE-e3*3 for Alzheimer's disease in the Japanese population is approximately 12-15-fold, comparable to that reported in Caucasian populations, rather than greater than 20-fold as previously reported.},
}

Humans
*Alzheimer Disease/genetics/epidemiology
*Genetic Predisposition to Disease/genetics
Japan/epidemiology
*Apolipoproteins E/genetics
*Asian People/genetics
Risk Factors
East Asian People

@article {pmid42337751,
year = {2026},
author = {Riccietti, C and Sambati, L and Zenesini, C and Baiardi, S and Criante, MS and D'Apolito, A and Milletti, D and Albini-Riccioli, L and Polischi, B and Calandra-Buonaura, G and Magelli, E and Mascarella, D and Mazza, L and Baldelli, L and Stanzani-Maserati, M and Cortelli, P and Cevoli, S and Palandri, G and Parchi, P and Giannini, G},
title = {Alzheimer's disease core biomarkers are associated with worse baseline and postoperative cognitive profiles in idiopathic normal pressure hydrocephalus: findings from the Bologna PRO-Hydro study.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00836-z},
pmid = {42337751},
issn = {2045-8118},
support = {Reference number: GR-2021-12374049//Research program "Bando ricerca finalizzata 2021″ of the Italian Ministry of Health, Giovani Ricercatori (GR), "Theory enhancing"/ ; },
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome affecting the elderly. Recent studies have reported a high prevalence of neurodegenerative copathologies in iNPH, particularly Alzheimer's disease (AD). Neuropsychological studies in iNPH sample revealed variable and heterogeneous cognitive profile. Few studies have examined cognitive differences according to neurodegenerative copathology, and none has systematically applied a comprehensive neuropsychological battery while stratifying patients by AD biomarkers both before and after surgery. The main objective of this study was to assess baseline differences in the neuropsychological profile of iNPH patients with and without AD core biomarkers, using a comprehensive neuropsychological battery. The secondary aim was to investigate changes in neuropsychological functions from baseline to short-term postoperative outcomes in the overall sample and in subgroups with and without AD biomarkers.

METHODS: Patients underwent a standardized inpatient work-up including clinical evaluation, comprehensive neuropsychological assessment, and cerebrospinal fluid (CSF) biomarkers analysis. A multidisciplinary team selected candidates for surgery. An extensive clinical and neuropsychological reassessment was performed six months after surgery.

RESULTS: From 2015 to 2025, 226 (97 females) consecutive iNPH patients completed the baseline evaluation. Among these, 102 shunted iNPH patients (46 females) underwent six-month postoperative neuropsychological assessment. The cognitive profile in all individuals revealed deficits in attentive-executive functions with a significant improvement after surgery. Overall, 24.3% of iNPH participants showed a pathological phosphorylated tau/beta-amyloid 1-42 ratio (pTau/Aβ42+). At baseline, pTau/Aβ42+ (n = 53) patients revealed worse neuropsychological performances than those (n = 165) with normal pTau/Aβ ratio (pTau/Aβ42-), with more pronounced memory impairment. At six-month follow-up, the pTau/Aβ42 + group exhibited poorer cognitive outcomes compared to pTau/Aβ42- one, particularly in general cognition, short- and long-term verbal and visuo-spatial memory, and executive functions.

CONCLUSIONS: Nearly one-quarter of patients exhibited AD core biomarkers positivity. iNPH patients with AD core biomarkers copathology showed an earlier cognitive onset and worse neuropsychological performances at baseline. At follow-up, the pTau/Aβ42 + group demonstrated poorer cognitive outcomes in specific cognitive domains compared to the pTau/Aβ42 - group. These differences in cognitive profiles at baseline and six months after surgery in iNPH patients with AD core biomarker positivity may have clinical relevance.},
}

@article {pmid42337797,
year = {2026},
author = {Soni, H and Sutherland, GT and Hofer, MJ},
title = {The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03927-8},
pmid = {42337797},
issn = {1742-2094},
abstract = {Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these, the complement system has attracted attention because of its interactions with amyloid-β (Aβ) and tau pathology, genetic associations with AD risk, and evidence of activation within affected brain regions. However, these biological observations do not directly translate into straightforward biomarker signals. Complement activity is highly dynamic, spans multiple activation and regulatory states, and may reflect both central and peripheral immune processes. This complexity limits interpretation when complement markers are assessed in isolation, as age, systemic inflammation, vascular comorbidity, and blood-brain barrier integrity can influence measured levels. Current evidence does not support complement-derived biomarkers as stand-alone diagnostic classifiers comparable to established amyloid, tau, and neurodegeneration (AT(N)) measures. Their independent or additive value within multimodal biomarker frameworks remains unclear, partly because of cohort heterogeneity, incomplete assay harmonisation, uncertain tissue-source attribution, and limited longitudinal validation. This review critically evaluates complement-derived measures as biologically informative markers of neuroimmune activity in AD, distinguishing biological plausibility from analytical and clinical utility. We argue that their most defensible current role is within multimodal biomarker frameworks, where they may provide context-specific information on inflammatory state rather than function as independent diagnostic, staging, or treatment-monitoring tools. Progress toward clinical application will require rigorous standardisation, mechanistic clarification, and validation across large, longitudinal, and diverse cohorts.},
}

@article {pmid42337819,
year = {2026},
author = {Hao, N and Zhang, X and He, Z and Zhang, J and Li, X and Zhao, G and Fang, J and Chen, W},
title = {The Burden of Alzheimer's Disease and Other Dementias Attribute to Metabolic Risks in Western Europe From 1990 to 2023.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70978},
pmid = {42337819},
issn = {1463-1326},
support = {202510/WT_/Wellcome Trust/United Kingdom ; 2025A151501299//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {BACKGROUND: Alzheimer's disease and other dementias (ADOD) impose a growing burden in aging high-SDI regions, a composite of income, education, and fertility. Metabolic risks are major modifiable contributors, but region-specific estimates for Western Europe are limited.

METHODS: Using GBD 2023 data, we estimated deaths, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized DALYs rates (ASDR) attributable to metabolic risks in 24 countries. Analyses were stratified by sex, age, and Level 2 metabolic risks (high BMI, high FPG). Temporal trends were assessed using estimated annual percentage change (EAPC), and decomposition analysis quantified contributions from population growth, aging, and epidemiological change.

RESULTS: In 2023, ASMR and ASDR were 6.84 (95% UI: 1.38-18.30) and 117.80 (35.67-252.14) per 100 000, increasing 18.8% and 17.6% from 1990; corresponding EAPCs were 0.45 and 0.43. Metabolic risks accounted for 90094.8 deaths (18262.6-241493.9). Females had higher age-standardized rates; males showed slightly higher EAPCs. High FPG remained dominant, while high BMI increased faster, particularly among males. Monaco had the highest ASMR and ASDR, whereas Germany, Italy, and the United Kingdom contributed the largest absolute burden. Decomposition analysis showed demographic changes primarily drove high FPG burden, while epidemiological changes contributed more to high BMI outcomes.

CONCLUSIONS: ADOD burden attributable to metabolic risks continues to rise across Western Europe, with substantial variation across countries, sex, age, and risk factors. High FPG burden is largely demographic-driven; high BMI burden reflects adverse epidemiological trends. Findings support targeted metabolic interventions, including obesity control and diabetes management integrated into dementia prevention strategies.},
}

@article {pmid42337854,
year = {2026},
author = {Lee, S and Choi, BJ and Park, MH and Park, S and Kim, J and Jin, HK and Shim, H and Jeon, JW and Bae, JS},
title = {A novel antibody against CD300c ameliorates cognitive deficits and reduces pathology in the late-stage of APP/PS1 mouse model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458360},
doi = {10.1177/13872877261458360},
pmid = {42337854},
issn = {1875-8908},
abstract = {BackgroundA major pathological hallmark of Alzheimer's disease (AD), the most common cause of dementia, is the accumulation of amyloid-β (Aβ) plaques. However, currently approved therapeutic agents fail to fundamentally halt disease progression and have limitations in terms of efficacy, sustainability, and safety. CD300c is an immunoregulatory molecule that modulates monocyte differentiation and activates macrophages. We recently developed a fully human anti-CD300c antibody, CB201, demonstrating its therapeutic potential in early and late 5xFAD mice.ObjectiveThis study investigated the efficacy of CB201 in late-stage AD using the APP/PS1 transgenic mouse model. We analyzed the effects of administering CB201 on changes in memory and cognitive function and Aβ and tau protein accumulation in the brain.MethodsTo assess long- and short-term memory improvements, behavioral tests were conducted using the Morris water maze and fear conditioning. Immunostaining was performed to quantify changes in Aβ and tau accumulation.ResultsCB201-treated late-stage AD mice demonstrated improved cognitive performance and memory, comparable to wild-type controls. Histopathological analysis further revealed that CB201 treatment reduced Aβ and tau accumulation.ConclusionsCB201 exerts significant therapeutic effects on functional impairments and pathological alterations in late-stage AD. These results confirm CB201 as a potential immunotherapeutic for the treatment of AD.},
}

@article {pmid42337855,
year = {2026},
author = {Monteiro, AMF and Lima Nogueira, MM and Barbeito Lacerda, I and Belfort, T and Nascimento Dourado, MC},
title = {When caring becomes a challenge: A path analysis of coping in Alzheimer's disease caregiving.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458984},
doi = {10.1177/13872877261458984},
pmid = {42337855},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric symptoms (NPS) affect most individuals with Alzheimer's disease (AD) and are among the most burdensome aspects of the condition, negatively influencing caregivers' mental health, burden, and quality of care.ObjectiveGiven the scarcity of studies examining caregivers' characteristics and NPS simultaneously, this study investigated how sociodemographic and clinical factors relate to different coping strategies, and whether NPS moderate these associations. Path analysis was used to capture direct and conditional effects.MethodsA cross-sectional study of 176 caregiver-patient dyads assessed coping, burden, mood, and NPS. Path analysis examined the effects of caregiver education, burden, depressive symptoms, and sex on coping, with NPS as a moderator.ResultsHigher education predicted greater use of problem-focused (β = 0.43, p < 0.001) and dysfunctional coping (β = 0.22, p < 0.01). Burden was negatively linked to emotion-focused coping (β = -0.17, p < 0.05). NPS moderated the burden-problem-focused coping link (β = -0.16, p < 0.05).ConclusionsEducation plays a central role in shaping how caregivers cope with care demands. NPS moderated the relationship between caregiver burden and problem-focused coping, with limited influence on other strategies. These findings underscore the importance of considering both caregiver characteristics and patient-related factors when developing interventions, highlighting the need for personalized approaches to improve caregiver well-being and care outcomes.},
}

@article {pmid42337927,
year = {2026},
author = {Wong, J and Wang, T and Datta, R and Abdollahi, RO and Li, J and Rowe, CC and Henley, D and Kolb, HC and Saad, ZS and , },
title = {Tau positron emission tomography analysis methods for the quantification of tau spread in preclinical and early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71573},
doi = {10.1002/alz.71573},
pmid = {42337927},
issn = {1552-5279},
support = {//Johnson & Johnson/ ; //Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; *tau Proteins/metabolism ; Aged ; Female ; Disease Progression ; Male ; *Brain/diagnostic imaging/metabolism ; Cognitive Dysfunction/diagnostic imaging/metabolism ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Inhibition of pathological tau spread may slow cognitive decline in Alzheimer's disease. Here, we evaluate two tau positron emission tomography (PET) analysis methods designed for detecting tau spread.

METHODS: Spatial progression of tauopathy (SPOT) and tau-naïve anatomical region of interest (tau-naïve ROI) methods were assessed in two large observational cohorts in amyloid-positive (A+) cognitively unimpaired (CU) or mildly cognitively impaired (MCI) participants versus CU amyloid-negative (A-) participants.

RESULTS: SPOT and tau-naïve ROI demonstrated measurable annualized change in CU A+ and MCI A+ participants versus CU A- participants. These spread estimates produced effect sizes comparable to standardized uptake value ratio (SUVR) change measures in anatomically defined ROIs. Effect sizes were increased when evaluating the subset of tau positive CU A+ and MCI A+ participants.

DISCUSSION: SPOT and tau-naïve ROI methods are designed to measure tau spread and may be used in addition to traditional SUVR measures to evaluate tau progression in AD.},
}

Humans
*Positron-Emission Tomography/methods
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
*tau Proteins/metabolism
Aged
Female
Disease Progression
Male
*Brain/diagnostic imaging/metabolism
Cognitive Dysfunction/diagnostic imaging/metabolism
Aged, 80 and over

@article {pmid42337943,
year = {2026},
author = {DuBois, KN and Pal, S and Maher, AC and Heidebrink, J and Persad, C and Giordani, B and Hampstead, BM and Bakulski, KM and Morgan, DG and Kanaan, NM},
title = {Dementia etiology classification using NULISA plasma biomarkers and machine learning.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71603},
doi = {10.1002/alz.71603},
pmid = {42337943},
issn = {1552-5279},
support = {//Maibach-Smiley Endowment/ ; R35 AG072262/AG/NIA NIH HHS/United States ; R01AG068388/AG/NIA NIH HHS/United States ; R01AG058724/AG/NIA NIH HHS/United States ; R01AG072262/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood ; Female ; *Machine Learning ; *Dementia/etiology/classification/diagnosis/blood ; Male ; Aged ; Diagnosis, Differential ; Alzheimer Disease/blood/diagnosis ; Proteomics/methods ; Cognitive Dysfunction/blood/diagnosis ; Frontotemporal Lobar Degeneration/blood/diagnosis ; Lewy Body Disease/diagnosis/blood ; Classification Algorithms ; Boosting Machine Learning Algorithms ; },
abstract = {INTRODUCTION: Accurate ante mortem differentiation among dementia etiologies remains challenging, particularly for atypical or mixed clinical presentations. Multiplexed plasma proteomics paired with supervised machine learning offers a minimally invasive and accessible approach for differential diagnosis.

METHODS: Plasma from 194 participants was analyzed using the Nucleic acid Linked Immuno-Sandwich Assay (NULISA) Central Nervous System 120+ plasma biomarker panel. Differentially abundant protein patterns associated with Alzheimer's disease, frontotemporal lobar degeneration, Lewy body disease, and vascular disease were identified. These features were used to train supervised XGBoost classifier models. Models were then applied to participants with mild cognitive impairment (MCI) to generate data-driven predictions of etiology.

RESULTS: NULISA plasma biomarkers revealed disease-specific protein patterns. XGBoost classifiers differentiated disease etiologies with high specificity. Application of the models to participants with MCI yielded robust etiologic predictions.

DISCUSSION: These results support the feasibility of using multiplexed NULISA plasma proteomics, combined with machine learning, for differential diagnosis of complex neurodegenerative dementia etiologies.},
}

Humans
*Biomarkers/blood
Female
*Machine Learning
*Dementia/etiology/classification/diagnosis/blood
Male
Aged
Diagnosis, Differential
Alzheimer Disease/blood/diagnosis
Proteomics/methods
Cognitive Dysfunction/blood/diagnosis
Frontotemporal Lobar Degeneration/blood/diagnosis
Lewy Body Disease/diagnosis/blood
Classification Algorithms
Boosting Machine Learning Algorithms

@article {pmid42337953,
year = {2026},
author = {Chang, A and Kim, M and Glittenberg, M and Qu, W and Li, D and Li, L},
title = {HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71568},
doi = {10.1002/alz.71568},
pmid = {42337953},
issn = {1552-5279},
support = {AG058081/NH/NIH HHS/United States ; AG056976/NH/NIH HHS/United States ; AG059654/NH/NIH HHS/United States ; AG081426/NH/NIH HHS/United States ; AG077772/NH/NIH HHS/United States ; T32AG029796//NIH training grant/ ; //College of Pharmacy, University of Minnesota/ ; },
mesh = {Animals ; *Brain/metabolism/drug effects ; Mice ; *Apolipoprotein E4/genetics/metabolism ; *Lipid Metabolism/drug effects ; Lipidomics ; Mice, Transgenic ; Humans ; *Transcriptome/drug effects ; *Lipoproteins, HDL/pharmacology ; Alzheimer Disease/genetics/metabolism ; *Peptides/pharmacology ; Apolipoproteins E/genetics ; Disease Models, Animal ; Apolipoprotein A-I ; },
abstract = {INTRODUCTION: The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal maintenance. The high-density lipoprotein (HDL)-mimetic peptide 4F offers a potential therapeutic strategy.

METHODS: To investigate how APOE4 alters brain gene expression and lipid metabolism and to evaluate the therapeutic potential of 4F, we performed dual-omics analysis in APOE4/4 and APOE3/3 mice treated intraperitoneally with D-enantiomer of 4F (D4F) or vehicle for 12 weeks from 10 to 13 months of age.

RESULTS: APOE4/4 mice showed widespread transcriptomic and lipidomic alterations, including downregulation of lipid metabolism and synaptic pathways, increased ceramides, sphingomyelins, and cholesteryl esters, with decreased diglycerides and triglycerides. D4F treatment shifted relevant gene expression and lipid profiles toward APOE3/3 levels.

DISCUSSION: These findings reveal molecular mechanisms underlying APOE4-driven dysregulation and support the therapeutic potential of HDL-mimetic peptides to mitigate APOE4-associated alterations in AD.},
}

Animals
*Brain/metabolism/drug effects
Mice
*Apolipoprotein E4/genetics/metabolism
*Lipid Metabolism/drug effects
Lipidomics
Mice, Transgenic
Humans
*Transcriptome/drug effects
*Lipoproteins, HDL/pharmacology
Alzheimer Disease/genetics/metabolism
*Peptides/pharmacology
Apolipoproteins E/genetics
Disease Models, Animal
Apolipoprotein A-I

@article {pmid42337956,
year = {2026},
author = {Pieperhoff, L and Lorenzini, L and Almeida, F and Tranfa, M and Bollack, A and Arunachalam, P and Masserini, F and Wolz, R and Grootoonk, S and Ritchie, C and Boada, M and Marquié, M and Vijverberg, J and Vandenberghe, R and Hanseeuw, BJ and Martinez-Lage, P and Payoux, P and Visser, PJ and Schöll, M and Frisoni, GB and Pardini, M and Roccataglia, L and Stephens, AW and Buckley, C and Farrar, G and Jessen, F and Gispert, JD and Salvadó, G and Luckett, ES and Mutsaerts, HM and Wink, AM and Collij, LE and Barkhof, F and Oliveira, TG and , },
title = {Cortical gray-white matter contrast alterations precede amyloid-β positivity and macrostructural changes in older adults without dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71609},
doi = {10.1002/alz.71609},
pmid = {42337956},
issn = {1552-5279},
support = {115952//Innovative Medicines Initiative (IMI) 2 Joint Undertaking/ ; //European Union's Horizon 2020 Research and Innovation Programme/ ; WE.03-2024-27//Alzheimer Nederland/ ; //Alzheimer's Disease Data Initiative (ADDI)/ ; //European Federation of Pharmaceutical Industries and Associations/ ; },
mesh = {Humans ; *White Matter/pathology/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Female ; *Gray Matter/pathology/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Aged ; Male ; Cross-Sectional Studies ; *Cerebral Cortex/pathology/diagnostic imaging/metabolism ; Aged, 80 and over ; Atrophy ; },
abstract = {INTRODUCTION: Early Alzheimer's disease (AD) involves subtle cortical changes that may precede atrophy. Magnetic resonance imaging (MRI) microstructural markers may detect earlier pathology than classical morphometry.

METHODS: We analyzed cross-sectional MRI and amyloid-β (Aβ) positron emission tomography (PET) data from 1323 non-demented AMYPAD participants. Cortical volume, thickness, gray-white matter contrast (GWC), and mean diffusivity (MD) were related to global Aβ burden and estimated time to Aβ-positivity using regression, correlation, and change-point analyses.

RESULTS: Microstructural measures showed stronger age associations than macrostructural measures, whereas all measures were unaffected by apolipoprotein E (APOE) -ε4 carriership. GWC and MD showed minimal overlap with volume and thickness. Higher Aβ burden was most strongly associated with reduced GWC and cortical thinning. Change-point analyses showed GWC alterations preceded Aβ-positivity by several years.

DISCUSSION: Cortical microstructural MRI, particularly GWC, changes earlier than atrophy and may serve as an early in vivo marker of AD pathology.},
}

Humans
*White Matter/pathology/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Female
*Gray Matter/pathology/diagnostic imaging/metabolism
Positron-Emission Tomography
Magnetic Resonance Imaging
Aged
Male
Cross-Sectional Studies
*Cerebral Cortex/pathology/diagnostic imaging/metabolism
Aged, 80 and over
Atrophy

@article {pmid42337959,
year = {2026},
author = {Martínez-Orozco, H and Andrade-Guerrero, J and Pastén-Castrejón, NJ and Rodríguez-Tanty, C and Diaz-Miranda, SY},
title = {Redirecting Alzheimer's disease therapeutics: Multitarget drugs and complementary non-pharmacological strategies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71589},
doi = {10.1002/alz.71589},
pmid = {42337959},
issn = {1552-5279},
support = {CBF-2025-G-35//Secretaría de Ciencia, Humanidades, Tecnología e Innovación, SECIHTI/ ; PAPIIT-IN-209325//Dirección General de Asuntos del Personal Académico (DGAPA) and Programa de Posgrado UNAM, México/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy ; Animals ; *Complementary Therapies/methods ; Receptors, sigma/agonists ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by intersecting pathological processes. Persistent attrition in AD drug-development pipelines highlights the limited clinical impact of single-target therapies and has increased interest in multi-target approaches acting on shared biological hubs. Although recent strategies extend beyond amyloid-centered interventions, much of the evidence supporting multifunctional compounds remains preclinical or shows heterogeneous outcomes in advanced clinical stages. This narrative review examines drug candidates that have entered Phase III clinical trials in the last decade, with emphasis on emerging multitarget pharmacotherapies such as muscarinic M1 receptor agonists, dual M1/sigma-1 receptor (σ1R) agonists, and dual σ1R agonist/anti-amyloid agents. We also discuss complementary non-pharmacological interventions, including physical exercise and targeted nutrition, that may support cognitive and emotional outcomes. Finally, we propose the Synergistic Optimized Pharmacological and Holistic Interventions for AD (SOPHI-AD) framework as a conceptual and testable approach integrating multitarget pharmacology with lifestyle-based strategies for AD management.},
}

Humans
*Alzheimer Disease/therapy/drug therapy
Animals
*Complementary Therapies/methods
Receptors, sigma/agonists

@article {pmid42337961,
year = {2026},
author = {Yu, K and Van Bogart, K and Kang, JE and Taylor, HO and Harrington, KD and Silbert, LC and Hajjar, I and Dodge, HH},
title = {How loneliness and social isolation are linked to cognitive decline among older adults? A systematic review of underlying physiological and psychobehavioral mechanisms.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71585},
doi = {10.1002/alz.71585},
pmid = {42337961},
issn = {1552-5279},
support = {R01AG051628/AG/NIA NIH HHS/United States ; R01AG056102/AG/NIA NIH HHS/United States ; R01AG056712/AG/NIA NIH HHS/United States ; R03AG081719/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; P30AG092752/AG/NIA NIH HHS/United States ; T32AG049676/AG/NIA NIH HHS/United States ; K00AG068492/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Social Isolation/psychology ; *Loneliness/psychology ; *Cognitive Dysfunction/psychology/physiopathology ; Aged ; },
abstract = {Despite empirical evidence linking loneliness and social isolation to cognitive decline (CD) in later life, the underlying physiological and psychobehavioral mechanisms remain unclear. We conducted a systematic review to synthesize relevant evidence. Studies examining psychobehavioral pathways required mediation analyses, whereas studies on physiological pathways were included when mediation was examined or when outcomes are dementia-related neuropathological changes. Thirty-eight articles were included. Evidence pointed to multiple physiological mechanisms, including Alzheimer's disease pathology, brain structural differences, inflammation, cardiovascular risks, neurotrophic factors, hypothalamic-pituitary-adrenal (HPA) -axis function, gene expression, and general health, although findings were mixed. Psychobehavioral pathways, including depressive symptoms, neuroticism, lower sense of control, sleep disturbance, and lower engagement in social or leisure activities, mediated the association. This review identified mechanistic targets that may be leveraged in non-pharmacological interventions. Future intervention programs aimed at reducing social isolation and loneliness to delay CD could investigate whether they impact physiological and psychobehavioral pathways summarized here.},
}

Humans
*Social Isolation/psychology
*Loneliness/psychology
*Cognitive Dysfunction/psychology/physiopathology
Aged

@article {pmid42337979,
year = {2026},
author = {Park, S and Lee, Y and Kwak, M and Kim, Y and Ryu, J and Kim, KB and Kim, DE},
title = {Immunoproteasome inhibition protects the retina from Alzheimer's-associated degeneration.},
journal = {BMB reports},
volume = {},
number = {},
pages = {},
pmid = {42337979},
issn = {1976-670X},
abstract = {Alzheimer's disease (AD) is marked by progressive cognitive decline and retinal abnormalities, including degeneration of the retinal pigment epithelium (RPE). In models of AD, the accumulation of amyloid-β (Aβ) peptides triggers chronic inflammation and activates the immunoproteasome (iP), primarily driven by tumor necrosis factor-alpha (TNFα) from glial cells. Although pharmacological inhibition of iP has demonstrated protective effects against retinal damage, the precise molecular mechanisms involved remain unclear. In this study, we reveal that Aβ stimulation initiates a signaling cascade from glia to RPE, mediated by TNFα, which in turn promotes iP activation and upregulation of the NLRP3 inflammasome in RPE cells. Aβ exposure significantly increased TNFα secretion in Müller glia, whereas RPE cells exhibited only a minimal intrinsic response to TNFα secretion in response to Aβ. Inhibition of iP reduced TNFα release from glial cells. Additionally, neutralizing gliaderived TNFα decreased iP activity and mitigated epithelialmesenchymal transition (EMT) in RPE cells, highlighting TNFα's crucial role in glial-induced retinal inflammation. These findings position glia-derived TNFα as a central factor in Aβ-induced RPE degeneration through the TNFα-iP-NLRP3 pathway, supporting the use of iP inhibition as a potential therapeutic approach to maintain retinal integrity in AD.},
}

@article {pmid42338147,
year = {2026},
author = {Zong, C and Dong, Y and Yu, X and He, Y and Zhang, X and Gao, K},
title = {The Associations Between Dietary Flavonoid Intake and Neurodegenerative Diseases Risk: A Cross-Sectional Study.},
journal = {Chemical biology & drug design},
volume = {107},
number = {6},
pages = {e70350},
doi = {10.1111/cbdd.70350},
pmid = {42338147},
issn = {1747-0285},
support = {81903950//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Flavonoids/administration & dosage ; *Neurodegenerative Diseases/epidemiology/prevention & control ; Cross-Sectional Studies ; Female ; *Diet ; Male ; Nutrition Surveys ; ROC Curve ; Risk Factors ; Flavones ; Logistic Models ; },
abstract = {The incidence of neurodegenerative diseases (NDs), primarily Alzheimer's disease and Parkinson's disease, has been steadily increasing, constituting a significant global public health challenge. This study aims to evaluate the associations between dietary flavonoid intake and the risk of NDs. Data from 13,573 participants in the National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted logistic regression, receiver operating characteristic (ROC) curve analysis, weighted restricted cubic splines, subgroup analysis, and sensitivity analysis were employed to assess the associations. Overall, higher total flavonoid intake was associated with lower odds of NDs after adjustment for demographic, socioeconomic, lifestyle, and clinical covariates (Q4 vs. Q1: OR = 0.52, 95% CI: 0.31-0.90). Among flavonoid subclasses, flavones (Q4 vs. Q1: OR = 0.49, 95% CI: 0.30-0.79) and flavonols (Q4 vs. Q1: OR = 0.53, 95% CI: 0.33-0.86) showed the strongest inverse associations. In addition, restricted cubic spline analyses demonstrated significant non-linear relationships, with the lowest odds of NDs observed at intake levels of approximately 432 mg/day for total flavonoids, 1.7 mg/day for flavones, and 29 mg/day for flavonols. These findings suggest that moderate intake of flavonoids, particularly flavones and flavonols, may contribute to the observed inverse association between flavonoid intake and NDs.},
}

Humans
*Flavonoids/administration & dosage
*Neurodegenerative Diseases/epidemiology/prevention & control
Cross-Sectional Studies
Female
*Diet
Male
Nutrition Surveys
ROC Curve
Risk Factors
Flavones
Logistic Models

@article {pmid42338264,
year = {2026},
author = {Marsault, J and Vallet, GT and Joubert, S and , },
title = {Cognitive dispersion in the Alzheimer's disease spectrum.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-12},
doi = {10.1017/S1355617726102082},
pmid = {42338264},
issn = {1469-7661},
abstract = {OBJECTIVES: Subjective cognitive decline (SCD) may represent the earliest observable stage of Alzheimer's disease (AD), yet identifying individuals at risk of progressing remains challenging. Cognitive dispersion, or intra-individual variability (IIV-D), may serve as a sensitive early marker. This study examined IIV-D across diagnostic groups, focusing on SCD and amnestic mild cognitive impairment (aMCI) progressors (SCD-p, aMCI-p; progressing to a more advanced disease stage) versus non-progressors (SCD-np, aMCI-np; not progressing to a more advanced stage). We expected greater IIV-D across groups (AD > aMCI > SCD > controls) and in progressors.

METHODS: A total of 308 participants aged 65-94 (67 healthy controls [HC], 126 SCD, 79 aMCI, 36 AD) from the Consortium for the Early Identification of Alzheimer's Disease - Quebec (CIMA-Q) were included. SCD and aMCI participants were followed for up to eight years (34 SCD-p, 92 SCD-np; 29 aMCI-p, 50 aMCI-np). Analyses of covariance assessed baseline across- and verbal memory within-domain IIV-D, maximum discrepancy (MD), and domain-specific deviation.

RESULTS: IIV-D increased with disease severity (HC = SCD < aMCI < AD). Among SCD participants, progressors showed greater episodic memory deviation than non-progressors, primarily driven by poorer Logical Memory delayed recall. In aMCI, progressors showed higher IIV-D across all indices (across- and within-domain, IIV-D and MD), with domain-specific differences limited to episodic memory.

CONCLUSIONS: These findings indicate that IIV-D measures distinguish aMCI progressors from non-progressors, although they do not appear to enhance predictive accuracy for progression to AD and may not yet be a reliable marker at the SCD stage.},
}

@article {pmid42338472,
year = {2026},
author = {Rogers, BB and Anderson, AG and Rodriguez-Nunez, I and Bartley, SC and Johnston, SQ and Taylor, JW and Meadows, SK and Newberry, KM and Myers, RM and Cochran, JN},
title = {KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116412},
pmid = {42338472},
issn = {2589-0042},
abstract = {Understanding transcriptional regulatory networks (TRNs) in microglia is essential for elucidating mechanisms underlying central nervous system (CNS) disorders. Human induced pluripotent stem cell (iPSC)-derived models enable mechanistic studies of microglia but often suffer from variability across lines. Here, we use the standardized KOLF2.1J iPSC line, engineered to inducibly express six transcription factors that allow rapid generation of microglia-like cells (iTF-microglia). We profile TRNs under homeostatic and inflammatory conditions and show that iTF-microglia resemble primary brain microglia at transcriptomic and epigenomic levels. Integrative analyses identify microglia-enriched candidate cis-regulatory elements (cCREs) and reveal dynamic enhancer remodeling during differentiation and stimulation with lipopolysaccharide (LPS) or interferon-gamma (IFNγ), involving NF-κB, IRF, and STAT transcription factors. TRNs active in iTF-microglia are enriched for genetic variants linked to Alzheimer's disease and related CNS disorders. These findings establish KOLF2.1J iTF-microglia as a reproducible, genetically tractable system for dissecting microglial gene regulation and TRN remodeling in disease.},
}

@article {pmid42338505,
year = {2026},
author = {Oudaha, K and Causeret, F and Koukouli, F},
title = {A new framework for nicotinic receptor-targeted therapeutic strategies in psychiatric and neurodegenerative disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1768143},
pmid = {42338505},
issn = {1662-5102},
abstract = {The nicotinic acetylcholine receptors (nAChRs) are key modulators of synaptic transmission and cognitive processing within the central nervous system. These ligand-gated channels, composed of various α and β subunits, mediate a plethora of neuronal functions including attention, memory and executive control. The current perspective article synthesizes recent advances on the contribution of pivotal nAChRs subtypes particularly α4β2, α7, and α5-containing receptors to cortical circuit function, highlighting their relevance in health and disease. In healthy brain, nAChRs regulate excitatory-inhibitory balance and enhance cognitive mechanisms in the prefrontal cortex (PFC) and hippocampus. Recent findings demonstrate that α5-containing receptors exhibit selective resistance to amyloid-β induced dysfunction, suggesting a neuroprotective role in Alzheimer's disease (AD). Integrating molecular, cellular, and behavioral evidence, we argue that receptor-subtype-specific modulation of distinct nAChRs subunits represents a promising therapeutic avenue for restoring network balance and cognitive function across neuropsychiatric and neurodegenerative disorders. We further discuss the role of nicotine in brain circuits and suggest that future research should prioritize precision pharmacology and genetic profiling to identify optimal therapeutic windows and mitigate the long-term consequences of nicotine exposure on developing neural circuits.},
}

@article {pmid42338509,
year = {2026},
author = {Malvankar, SR and Wolfe, MS},
title = {The γ-secretase complex: from discovery to a therapeutic target.},
journal = {RSC chemical biology},
volume = {},
number = {},
pages = {},
pmid = {42338509},
issn = {2633-0679},
abstract = {γ-Secretase is an intricate intramembrane aspartyl protease that cleaves within the transmembrane domain of ∼150 substrates and is considered the 'proteasome of the membrane'. This enzyme consists of four different subunits, with presenilin being the catalytic subunit. This review provides a brief overview of γ-secretase as a proteolytic enzyme, from its biochemistry and biology to its roles in disease and potential as a therapeutic target. A detailed discussion on the discovery and structure of γ-secretase is followed by a survey of its substrates, including the most studied amyloid precursor protein and the Notch1 receptor, and a description of substrate processing and sequence specificity. The role of γ-secretase in human biology and pathology is also detailed, with a particular focus on Alzheimer's disease (AD), in which the pathogenicity of the γ-secretase product amyloid-β peptide is still a matter of controversy. Lastly, the potential of γ-secretase inhibitors and modulators for the treatment of AD and other diseases is considered.},
}

@article {pmid42338576,
year = {2026},
author = {Mansour, SR and Khalaf, MA and Moustafa, MA and Moustafa, MA and Moustafa, AA},
title = {Exploring the gut-brain axis: dietary influences on Alzheimer's disease pathogenesis.},
journal = {Frontiers in microbiomes},
volume = {5},
number = {},
pages = {1639904},
pmid = {42338576},
issn = {2813-4338},
abstract = {Alzheimer's disease (AD) is one of the most diagnosed neurodegenerative disorders worldwide and presents a significant challenge for both affected individuals and their caregivers. Alzheimer's disease is characterized by the accumulation of amyloid plaques and dysfunctional tau protein in the brain, along with the final development of dementia. Recently, in addition to the strongly developing ischemic etiology of AD, it is suggested that the gut and oral microbiota may also participate in the development of this disease. This involvement may stem from an unbalanced diet and the consumption of foods containing harmful chemical additives. An unhealthy diet can compromise the integrity of the gut barrier, facilitating the translocation of bacterial pathogens and leading to a pro-inflammatory T-cell response mediated by innate immune cells. This inflammatory response can disrupt systemic homeostasis and may contribute to neuroinflammation. The brain and gut interact through a complex network known as the "gut-brain-microbiota axis," and emerging studies suggest that the intestinal microbiota and their metabolites may play a significant role in the pathogenesis of Alzheimer's disease. Moreover, these inflammatory mediators and microbial metabolites can reach the brain via the gut-brain axis, potentially exacerbating neurodegenerative processes. Preclinical and limited clinical evidence indicates that low-fiber diets are associated with alterations in intestinal microbiota composition, which may contribute to the onset and progression of Alzheimer's disease. This review aims to explore the potential connections between AD and the gut microbiome, emphasizing the significance of dietary factors in shaping these relationships. A comprehensive understanding of the interactions between the human microbiome and the brain, particularly in the context of diet and its ingredients, may enhance our understanding of AD etiology and inform the development of preventative strategies, through dietary modifications or therapeutic interventions. This area of research holds promise for identifying novel approaches to prevent or slow the progression of AD.},
}

@article {pmid42338648,
year = {2026},
author = {Riaz, R and Fatima, M and Ramzan, S and Rathi, D and Fatima, F and Farooq, M and Shaukat, A and Khaliq, N and Akilimali, A},
title = {FDA Approval of Donanemab-azbt: A New Dawn in Alzheimer's Disease Treatment.},
journal = {Health science reports},
volume = {9},
number = {6},
pages = {e72688},
pmid = {42338648},
issn = {2398-8835},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by the accumulation of beta-amyloid plaques and neurofibrillary tangles, leading to neuronal death and cognitive decline. Acetylcholinesterase inhibitors (AChEIs) such as donepezil, galantamine, and rivastigmine are commonly used to enhance cognitive function by increasing acetylcholine levels, but they can cause side effects like nausea, bradycardia, and headaches. NMDA receptor antagonists, like memantine, reduce glutamatergic activity and are used to manage symptoms, yet are also associated with adverse effects including dizziness and agitation. Recently, monoclonal antibodies such as aducanumab have been developed to target amyloid-beta aggregates, though they are associated with amyloid-related imaging abnormalities (ARIA).

AIMS: This article aims to summarize current pharmacological approaches to AD and to highlight the emerging role of Donanemab-azbt, an FDA-approved monoclonal antibody for early symptomatic AD, in reducing amyloid plaques and slowing cognitive decline.

METHODS: This overview synthesizes data from clinical trials and therapeutic experience with acetylcholinesterase inhibitors, NMDA receptor antagonists, and monoclonal antibodies, with a particular focus on Donanemab-azbt, its mechanism of targeting amyloid-beta aggregates, and its efficacy and safety profile in early symptomatic AD.

RESULTS: Donanemab-azbt has demonstrated efficacy in clinical trials, significantly reducing amyloid plaque burden and slowing cognitive decline in patients with early symptomatic AD. However, its use may result in ARIA and other adverse effects, necessitating careful clinical and radiological monitoring during treatment.

CONCLUSION: Despite the risks of ARIA and other adverse events, Donanemab-azbt represents a promising addition to AD therapy, offering the potential for improved outcomes in patients with early symptomatic disease and expanding the therapeutic options beyond traditional symptomatic treatments.},
}

@article {pmid42338764,
year = {2026},
author = {Li, N and Peng, X and Xiong, W and Yang, C and Wang, W},
title = {Neuroprotective effects of Ershiwuwei Shanhu pills on APP/PS1 mice through antioxidant enhancement, anti-apoptosis, and MAPK pathway regulation.},
journal = {Translational neuroscience},
volume = {17},
number = {1},
pages = {20250396},
pmid = {42338764},
issn = {2081-3856},
abstract = {OBJECTIVES: Alzheimer's disease (AD) involves cognitive impairment, neuronal degeneration, oxidative imbalance, and abnormal MAPK signaling. This study investigated the protective effects of Ershiwuwei Shanhu Pills (ESP) on cognition, oxidative stress, neuronal apoptosis, and MAPK pathway regulation in APP/PS1 mice.

METHODS: Sixty mice were used, including 50 APP/PS1 transgenic mice randomly assigned to five groups: untreated AD model, donepezil (0.5 mg/kg), and low- (100 mg/kg), medium- (200 mg/kg), or high-dose (400 mg/kg) ESP. Ten wild-type C57BL/6J mice served as normal controls. All treatments were administered orally for 60 days. Cognitive performance was assessed by the Morris water maze. Hippocampal pathology and apoptosis were evaluated by histology and TUNEL staining, while oxidative stress markers, AD-related proteins, and MAPK phosphorylation were measured via ELISA and Western blot.

RESULTS: ESP treatment improved learning and memory performance, reduced hippocampal neuronal damage, and decreased neuronal apoptosis. Antioxidant enzyme activities (SOD, CAT, GSH, GSH-PX) increased, whereas MDA and GSSG levels decreased. Circulating Aβ1-40, Aβ1-42, TAU181, and γ-secretase levels were reduced. ESP also downregulated phosphorylation of JNK, ERK, and p38. The medium-dose group showed therapeutic effects comparable to donepezil.

CONCLUSIONS: ESP exerts neuroprotective effects in APP/PS1 mice by alleviating oxidative stress, inhibiting neuronal apoptosis, and modulating MAPK signaling. These findings suggest ESP as a promising multi-target therapeutic strategy for AD.},
}

@article {pmid42338797,
year = {2026},
author = {Tang, WR and Chen, KQ},
title = {Mini-Review: Allicin as a Potential Neuroprotective Compound in Neurological Disorders.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {621474},
pmid = {42338797},
issn = {1176-6328},
abstract = {In recent years, allicin has received extensive attention in the field of neuroprotection. This mini-review summarizes the extraction, detection, synthesis, toxicity, novel drug delivery systems of allicin and its research progress in neurological diseases. We found that allicin can exert neuroprotective effects in Alzheimer's disease, Parkinson's disease, traumatic brain injury, cerebral ischemia-reperfusion injury, cerebral hemorrhage, and subarachnoid hemorrhage by inhibiting oxidative stress, neuroinflammation, and apoptosis, regulating mitochondrial function, and improving blood-brain barrier integrity. However, current studies are mostly limited to animal experiments and lack high-quality clinical research evidence. Additionally, the unstable chemical properties and low bioavailability of allicin have limited its clinical translation. In the future, more randomized controlled clinical trials should be conducted and new delivery systems should be developed to improve its stability and targeting. This mini-review aims to provide a theoretical basis for further research and application of allicin in neurological diseases.},
}

@article {pmid42339011,
year = {2026},
author = {Lin, YR and Chang, MC and Tung, YC and Lin, SC and Wang, WF and Jhang, KM},
title = {The Association of Hearing Impairment and Behavioral and Psychological Symptoms in Community-Dwelling Patients with Alzheimer's Disease.},
journal = {Psychology research and behavior management},
volume = {19},
number = {},
pages = {601819},
pmid = {42339011},
issn = {1179-1578},
abstract = {INTRODUCTION: This study aimed to investigate the relationship between hearing impairment and the longitudinal changes in behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease (AD).

MATERIALS AND METHODS: This case-control study enrolled 387 participants newly diagnosed with AD. Participants' hearing status was initially assessed based on their need for hearing assistance during neuropsychological tests. BPSD was evaluated using the Neuropsychiatric Inventory (NPI) at baseline and a 1-year follow-up visit. Multivariable logistic regression models were used to examine the association between hearing status and the presence of BPSD.

RESULTS: A higher percentage of participants in the hearing-impaired group exhibited moderate to severe apathy (26% vs. 14%, p=0.01) and sleep disturbance (24% vs. 14%, p=0.042) after 1 year. Hearing impairment was found to be an associated factor for the presence of sleep disturbance (odds ratio [OR] = 1.88; 95% confidence interval [CI] = 1.09-3.21) and moderate-to-severe apathy (OR=1.97; 95% CI=1.03-3.72) after 1 year. After adjusting for age, sex, education, baseline Clinical Dementia Rating (CDR) and baseline Neuropsychiatric Inventory (NPI) scores, hearing impairment remained an independent associated factor for the risk of worsening symptoms in apathy and sleep disturbance symptoms, with ORs of 2.06 (95% CI=1.13-3.70, p=0.016) and 2.13 (95% CI=1.18-3.80, p=0.012), respectively.

CONCLUSION: This study demonstrated that hearing impairment is associated with the longitudinal worsening of sleep and apathy symptoms in patients with AD over a 1-year follow-up period. Dementia care teams should place greater emphasis on these non-cognitive symptoms and provide appropriate management strategies.},
}

@article {pmid42339065,
year = {2026},
author = {Flores, S and Scott, J and Lu, R and Su, Y and Keefe, SJ and Smith, TH and Hornbeck, RC and McKay, NS and Strain, JF and Simmons, A and Dombrowski, K and Rizzo, J and Shimony, H and Bateman, RJ and Babulal, GM and Landau, SM and Jagust, W and Wolk, DA and Lah, J and Gleason, C and Johnson, S and Roberson, ED and Sperling, R and Johnson, K and Morris, JC and Xiong, C and Gordon, BA and Benzinger, TLS},
title = {Features predicting data exclusion in imaging studies of Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70389},
pmid = {42339065},
issn = {2352-8729},
abstract = {INTRODUCTION: Positron emission tomography (PET) without usable or accompanying magnetic resonance imaging (MRI) is typically excluded in quantitative analyses of Alzheimer's disease, potentially limiting study generalizability. We investigated participant features predicting data exclusion in magnetic resonance (MR)-dependent analyses and evaluated an existing MR-free PET pipeline to quantify these missing data.

METHODS: Imaging, clinical, cognitive, and sociodemographic data were analyzed for 2119 individuals in a multi-site cohort. Agreement between MR-dependent and MR-free Centiloids (CL) assessed using intra-class correlations and features predicting data exclusion were examined using logistic regressions.

RESULTS: MR-free and MR-dependent CLs generally agreed, but MR-free CLs underestimated MR-dependent cross-sectionally and longitudinally. Approximately 19.5% (n = 405) of our cohort would have been excluded in MR-dependent analyses. Age and cerebrovascular comorbidities were consistent exclusion features across multiple sites.

DISCUSSION: Data exclusion in imaging studies is not entirely random. Flexible quantification methods like MR-free PET could supplement traditional methods to improve generalizability in large, multi-site studies.},
}

@article {pmid42339066,
year = {2026},
author = {Wang, P and Song, YE and Lynn, A and Miskimen, K and Gulyayev, A and Prough, MB and Dorfsman, DA and Laux, RA and Fuzzell, SL and Hochstetler, SD and Zaman, AF and Adams, LD and Caywood, LJ and Clouse, JE and Herington, SD and Whitehead, P and Liu, Y and Moore, N and Ogrocki, P and Lerner, AJ and Griswold, AJ and Vance, JM and Cuccaro, ML and Scott, WK and Pericak-Vance, MA and Haines, JL},
title = {Heritability of Alzheimer's disease-related plasma biomarkers in the Amish population.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70388},
pmid = {42339066},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) hold promise for disease diagnosis and prediction, yet their genetic underpinnings remain under explored.

METHODS: We measured plasma amyloid beta (Aβ)40, Aβ42, Aβ42/Aβ40, total tau (t-tau), phosphorylated tau 181 (p-tau181), Aβ42/t-tau, Aβ42/p-tau181, neurofilament light chain, and glial fibrillary acidic protein in the Midwestern Amish. Pedigree-based heritability (h ped 2) was estimated from multigenerational pedigrees, and single nucleotide polymorphism (SNP)-based heritability (h SNP 2) was derived from SNPs.

RESULTS: Among all Amish individuals, additive genetic effects (h ped 2) explained 11.1% to 36.6% of biomarker variances. h SNP 2 estimates were consistently lower, ranging from 6.7% to 28.7%. The heritability of these biomarkers in subgroups of cognitively normal individuals and apolipoprotein E ε4 non-carriers yielded similar results.

DISCUSSION: Plasma biomarkers such as Aβ, t-tau, and p-tau181 are moderately heritable in the Amish, underscoring the impact of genetic determinants of plasma biomarkers associated with AD.},
}

@article {pmid42339067,
year = {2026},
author = {Lee, Y and Kang, S and Kim, YS and Kim, JS and Kim, HJ},
title = {Regional amyloid PET asymmetry and long-term clinical trajectory in mild cognitive impairment.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70394},
pmid = {42339067},
issn = {2352-8729},
abstract = {INTRODUCTION: Hemispheric amyloid positron emission tomography (PET) asymmetry may capture prognostic information beyond binary amyloid status in amnestic mild cognitive impairment (aMCI).

METHODS: We retrospectively studied 158 aMCI patients with baseline [18]F-florbetaben PET and magnetic resonance imaging acquired within 12 months and a mean follow-up of 6.89 ± 2.63 years. Participants were classified as amyloid beta (Aβ)- stable (n = 67), Aβ- progressor (n = 18), Aβ+ stable (n = 33), or Aβ+ progressor (n = 40). Vertex-wise cortical standardized uptake value ratio (SUVR) asymmetry (|AI|) was analyzed using surface-based general linear models adjusted for age, sex, education years, apolipoprotein E ε4 carrier status, global cortical SUVR, and clinical follow-up duration.

RESULTS: Aβ- MCI progressors showed higher |AI| in the lateral orbitofrontal cortex (790 vertices, cluster-wise p = 0.0002). Aβ+ MCI progressors showed lower |AI| in the lingual gyrus (478 vertices, cluster-wise p = 0.0001). No cross-status contrast yielded a significant cluster in the covariate-adjusted model.

DISCUSSION: Amyloid PET asymmetry reflects prognostic heterogeneity in aMCI, with distinct distributional patterns according to amyloid status.},
}

@article {pmid42339068,
year = {2026},
author = {La Joie, R and Blazhenets, G and Maiti, P and Chiotis, K and Eloyan, A and Kirby, K and Hammers, D and Koeppe, RA and Ackley, SF and Robison, J and Soleimani-Meigooni, DN and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and , },
title = {Identification of patients receiving amyloid-targeting therapies in observational studies using amyloid PET trajectories: Insights from LEADS.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70408},
pmid = {42339068},
issn = {2352-8729},
abstract = {INTRODUCTION: As amyloid-targeting therapies (ATTs) enter clinical care, observational cohorts must accurately ascertain ATT exposure. We developed an approach to flag mis/undocumented ATT in the Longitudinal Early-Onset Alzheimer's Disease Study using longitudinal amyloid positron emission tomography (PET).

METHODS: We analyzed 742 [[18]F]florbetaben PET from 270 participants with early-onset Alzheimer's disease. Using PET acquired before US Food and Drug Administration (FDA) approval of ATTs, we quantified Centiloid (CL) variability between two consecutive scans (PET "segments") to determine unusual CL decline thresholds that were then applied to post-FDA approval segments.

RESULTS: Pre-FDA approval segments increased by a median of 4.1 CL/year (whole cerebellum reference) and 3.6 CL/year (composite reference); unusual CL decline thresholds, defined as mean - 2 standard deviations of the pre-approval distributions were -15.8 and -9.4 CL/year, respectively. When applied to segments acquired post-FDA approval, extreme declines were observed in 59% to 78% of treated (n = 54) versus 4% to 8% of untreated segments (n = 344).

DISCUSSION: Longitudinal amyloid PET analyses can help identify ATT exposure in observational studies.},
}

@article {pmid42339151,
year = {2026},
author = {Lafrenière, A and Lina, JM and André, C and Martineau-Dussault, MÈ and Lorrain, D and Bastien, C and Hudon, C and Gosselin, N and Carrier, J},
title = {Altered rhythmic and arrhythmic electroencephalographic activity during non-rapid eye movement sleep in amnestic mild cognitive impairment.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag204},
pmid = {42339151},
issn = {2632-1297},
abstract = {Non-rapid eye movement sleep electroencephalographic activity has been proposed to provide helpful markers for the early detection of Alzheimer's disease. However, studies have produced mixed results regarding the impact of mild cognitive impairment-a prodromal stage-when using traditional spectral power analyses during this sleep phase. It is increasingly recognized that electrophysiological power spectra are composed of two components: a rhythmic part, which reflects oscillatory activity, and an arrhythmic part, which represents the balance of neuronal excitation and inhibition. In this cross-sectional study, our objective was thus to determine whether cognitive impairment is associated with the non-rapid eye movement sleep rhythmic and arrhythmic components in older adults. Fifty-six cognitively normal participants (68.3 ± 7.1 years old, 41% women) and 56 participants with amnestic mild cognitive impairment (69.9 ± 8.6 years old, 41% women) matched on multiple variables (age, sex, education, body mass index, apnoea-hypopnoea index) underwent a neuropsychological assessment and a night of polysomnography. Analyses focused on six channels of interest (F3, F4, C3, C4, P3 and P4). Significant between-group differences were observed for non-rapid eye movement sleep rhythmic and arrhythmic activity. Participants with amnestic mild cognitive impairment had lower rhythmic power in the fast-sigma/slow-beta range across all topographies investigated and higher gamma rhythmic power in the left parietal area. Participants with amnestic mild cognitive impairment also showed lower mean gamma aperiodic exponents-an arrhythmic activity measure-across all topographies. Frontal rhythmic power in the fast-sigma/slow-beta range predicted episodic memory in the amnestic mild cognitive impairment group. Our findings reveal alterations in both rhythmic and arrhythmic brain activity, indicating oscillatory changes and signs of hyperexcitability during non-rapid eye movement sleep in individuals with amnestic mild cognitive impairment.},
}

@article {pmid42339207,
year = {2026},
author = {Vavougios, GD and Hadjigeorgiou, G},
title = {The quantified immune-aging dysregulation index: a large-language model-powered method for annotating and quantifying systems-level dysregulation.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1732901},
pmid = {42339207},
issn = {2624-8212},
abstract = {BACKGROUND: Pathway enrichment analyses are widely used to interpret transcriptomic datasets; however, their outputs typically consist of lists of statistically enriched pathways that require qualitative interpretation and are difficult to compare across biological contexts. Methods of semantic classification that transform enrichment results into quantitative, mechanistically interpretable measures of system-level dysregulation remain underexplored.

METHODS: Here, we introduced TENSE (quanTifiEd immuNe-aging dySregulation index), a framework that summarizes pathway enrichment outputs into a quantitative estimate of immune-aging-associated dysregulation. Utilizing a Large Language Model classifier via a KNIME workflow, significantly enriched pathways are semantically classified into five mechanistic categories representing key processes implicated in immune aging, the DIRES scheme: DNA damage (D), DNA repair (R), epigenetic drift (E), inflammaging (I), and nucleic acid sensing (S). These pathway-derived signals are then aggregated into a normalized dysregulation score reflecting the magnitude (TENSE) and distribution (DIRES) of aging-associated processes across biological contexts.

RESULTS: Application of TENSE to transcriptional modules derived from neurodegenerative, radiation-response, and immune activation datasets revealed distinct dysregulation profiles. Alzheimer's disease-associated modules were primarily characterized by inflammaging signatures, particularly within microglial transcriptional programs, whereas radiation response datasets exhibited dominant DNA damage-related signals. Sepsis-associated gene signatures showed strong inflammatory contributions, producing the highest TENSE values observed. Robustness analysis demonstrated high reproducibility of pathway classification across repeated runs and close agreement between large language model-derived annotations and human consensus scores.

CONCLUSION: TENSE provides a reproducible and interpretable method for transforming pathway enrichment outputs into quantitative estimates of system-level immune-aging dysregulation. By bridging pathway enrichment analysis and mechanistic interpretation, the framework enables comparative analysis of aging-related biological processes across diverse datasets.},
}

@article {pmid42339361,
year = {2026},
author = {Chang, YJ and Kao, CL and Lan, KM},
title = {Association between low magnesium status and new-onset dementia in the general population: a propensity score-matched cohort study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1886820},
pmid = {42339361},
issn = {2296-861X},
abstract = {BACKGROUND: Low magnesium status has been linked to cerebrovascular conditions that overlap with pathways implicated in dementia, yet prior studies have relied on single magnesium measurements obtained in earlier population-based cohorts. Whether repeatedly documented low magnesium status is associated with incident dementia in real-world clinical populations is unclear.

METHODS: This retrospective propensity score-matched cohort study used data from the TriNetX Global Collaborative Network (2016-2023). Adults aged ≥50 years with two serum magnesium values <1.7 mg/dL within a 1-year window were compared with matched controls with two normal values (1.70-2.20 mg/dL). A 1-year landmark period was applied before the outcome ascertainment. The primary outcome was incident all-cause dementia. The secondary outcomes included dementia subtypes, stroke, and mortality. Prespecified positive and negative control outcomes, subgroup and sensitivity analyses, sequential multivariable Cox regression, and an exploratory analysis of high magnesium status were conducted.

RESULTS: After propensity score matching, 162,936 patients were included in each group. Low magnesium status was associated with incident all-cause dementia (HR 1.33; 95% CI, 1.26-1.40, p < 0.001), with the strongest association observed for vascular dementia (HR 1.63; 95% CI, 1.42-1.88, p < 0.001). Associations were also observed for stroke (HR 1.37, p < 0.001) and mortality (HR 1.52, p < 0.001). The results remained consistent across the sensitivity and multivariable analyses. High magnesium status was associated with all-cause dementia (HR 1.25, p < 0.001) and vascular dementia (HR 1.40, p < 0.001), but not Alzheimer's disease.

CONCLUSION: Repeatedly documented low magnesium status was associated with an increased risk of incident all-cause dementia, particularly vascular dementia, suggesting a potential role of magnesium homeostasis in long-term cognitive function.},
}

@article {pmid42339400,
year = {2026},
author = {Williams, T and Jang, SR and Lanctôt, KL and Kang, A and Bloudek, L and Wang, G},
title = {Simulation of long-term lecanemab treatment effect on Alzheimer's disease progression.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70274},
pmid = {42339400},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid therapies such as lecanemab have demonstrated statistically significant slowing of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in patients with early Alzheimer's disease (AD) in pivotal trials. Converting treatment differences on CDR-SB into time saved from disease progression may help convey clinical relevance for patients and caregivers more effectively.

METHODS: Disease progression models were developed using Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center data. A 37% treatment-related time delay, derived from the Clarity AD trial, was applied to estimate long-term efficacy of lecanemab.

RESULTS: Natural progression models estimated 11.5 to 13.7 years from mild cognitive impairment due to AD to severe AD. When starting treatment at CDR-SB 3.2, lecanemab delayed progression to severe AD by 2.5 to 3.7 years when assuming patients remained on treatment and 2.0 to 3.0 years when accounting for treatment discontinuation. Results were consistent across different datasets.

DISCUSSION: Projections suggest lecanemab substantially delays clinical progression of AD, preserving patients' time in earlier stages of AD.},
}

@article {pmid42339401,
year = {2026},
author = {Burke, J and Weerman, A and Hanson, M and Zhang, Q and Monfared, AAT and Mattke, S},
title = {Travel barriers to amyloid-targeting infusion access among older adults.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70282},
pmid = {42339401},
issn = {2352-8737},
abstract = {INTRODUCTION: Amyloid-targeting treatments (ATT) for Alzheimer's disease require regular infusions and caregiver accompaniment for approximately 80% of patients. Travel time to infusion sites and caregiver availability can therefore impede access to care, especially in rural and lower income populations.

METHODS: We conducted a survey in a nationally representative Internet panel with more than 2300 adults aged ≥65 years to estimate willingness to travel for bi-weekly infusion treatment, and access to an accompanying caregiver. Addresses of respondents and infusion sites were geocoded and driving times to the nearest infusion centers were calculated using Google Maps road network data. To estimate potential access gains under subcutaneous (SC) delivery, we estimated access by relaxing the travel and accompaniment requirements in a scenario analysis.

RESULTS: Median willingness-to-travel time was 97.5 minutes (interquartile range [IQR]: 67.5-187.5 minutes) one way for bi-weekly infusions over a 5-year period. Approximately 90% of respondents were willing to travel the required time to reach an infusion site. However, 18% indicated that it would be unlikely that they could identify someone to accompany them. When caregiver accompaniment was incorporated as a constraint, 75% met both the travel and caregiver criteria. In regression analysis, respondents with annual incomes above $60,000 and those residing in metropolitan areas were 9 and 19 percentage points more likely, respectively, to meet travel and caregiver criteria. In a scenario analysis, SC delivery increased overall access by up to 33%, in relative terms, with larger proportional gains for low income and rural respondents.

DISCUSSION: A meaningful number of individuals in a nationally representative sample live farther from their nearest site than they would be willing to travel, and obstacles to access worsen if individuals need a caregiver to accompany them, as is common among early-stage AD patients. Treatments that do not require infusion delivery could improve equitable access to care.},
}

@article {pmid42339433,
year = {2024},
author = {Jellinger, KA},
title = {Mild cognitive impairment in Parkinson's disease: current view.},
journal = {Frontiers in cognition},
volume = {3},
number = {},
pages = {1369538},
pmid = {42339433},
issn = {2813-4532},
abstract = {Parkinson's disease (PD), the most common motor movement disorder and second most common neurodegenerative disorder after Alzheimer's disease (AD), is often preceded by a period of mild cognitive impairment (MCI), which is associated with impairment of a variety of cognitive domains including executive function, attention, visuospatial abilities and memory. MCI, a risk factor for developing dementia, affects around 30% of de novo PD patients and can increase to 75% after more than 10 years. While 30-40% remain in the MCI state, up to 60% will convert to dementia. Characteristic findings are slowing of EEG rhythms, frontotemporal hypoperfusion, decreased functional connectivity in the default mode and attentional networks, prefrontal and basal-ganglia-cortical circuits, which often manifests prior to clinical symptoms and overt brain atrophy. The heterogeneity of cognitive phenotypes suggests that a common neurodegenerative process affects multiple functional neuronal networks and neuromodulatory systems that may be superimposed by Lewy body and Alzheimer's-related or other co-pathologies. Sparse neuropathological data for PD-MCI revealed a heterogenous picture with various morphological changes similar to MCI in other diseases. This review highlights the essential epidemiological, clinical, neuroimaging and morphological changes in PD-MCI, available biomarkers, and discusses the heterogenous pathobiological mechanisms involved in its development. In view of its complex pathogenesis, well-designed longitudinal clinico-pathological studies are warranted to clarify the alterations leading to MCI in PD, which may be supported by fluid and neuroimaging biomarkers as a basis for early diagnosis and future adequate treatment modalities of this debilitating disorder.},
}

@article {pmid42339484,
year = {2026},
author = {Annamneedi, A and Kesavan, R and Akgül, G and Vutukuri, R},
title = {Editorial: Cross-talk of synaptic proteins in neurological diseases.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1880392},
doi = {10.3389/fneur.2026.1880392},
pmid = {42339484},
issn = {1664-2295},
}

@article {pmid42339547,
year = {2026},
author = {Menéndez Soto Del Valle, R and Barry-Simonnet, C and Verjus, L and Crouzier, L and Peña Alcolea, S and Sablón Carrazana, M and Maurice, T and Rodríguez-Tanty, C},
title = {Enhanced cognitive protection through the combination of Amylovis-201, an anti-amyloidogenic agent with sigma-1 receptor agonist activity, and environmental enrichment in mice.},
journal = {Journal of psychopharmacology (Oxford, England)},
volume = {},
number = {},
pages = {2698811261458343},
doi = {10.1177/02698811261458343},
pmid = {42339547},
issn = {1461-7285},
abstract = {BACKGROUND: Amylovis-201 (CNEURO-201) shows strong neuroprotective activity in Alzheimer's disease (AD) models due to its anti-Aβ aggregating properties and sigma-1 receptors (S1R) agonist activity. The drug is neuroprotective in transgenic rodent models of AD that could translate into disease-modifying effects by both protecting neuronal and glial viability and actively decreasing amyloid aggregation. The individual vulnerability to the neurodegenerative process in AD is highly dependent on the "cognitive reserve," understood as the efficacy of brain plasticity throughout lifetime events.

AIMS: We aimed to determine whether Amylovis-201 efficacy in AD could be potentiated through stimulation of cognitive reserve. We combined Amylovis-201 administration with an experimental model of environmental enrichment (EE), using training on the Hamlet device. We analyzed the potentiating effects of the combination on brain plasticity and the development of resilience against memory deficits in a pharmacological AD model.

METHODS: We implemented a combined protocol with repeated per os (PO) administration of Amylovis-201 (0.1 and 1 mg/kg) and EE over 2 weeks (5 days/week), consisting of a 4-hour exploration of the Hamlet, a complex environment mimicking a small village with five functionalized houses.

RESULTS: The combination of EE and low dose (0.1 mg/kg PO) of Amylovis-201 had an additive effect on hippocampal neurogenesis. It also protected mice against scopolamine (0.5 mg/kg IP)-induced spatial working memory deficits in the Y-maze and, at 0.1 or 1 mg/kg PO, against Aβ25-35-induced memory deficits.

CONCLUSION: As EE is known to increase S1R expression, the combination of EE and Amylovis-201 had major effects on brain plasticity and neuroprotection.},
}

@article {pmid42339583,
year = {2026},
author = {Agbogbo, F and Dismuke, D},
title = {Status and future of recombinant adeno-associated virus vector manufacturing.},
journal = {Biotechnology progress},
volume = {},
number = {},
pages = {e88525},
doi = {10.1002/btpr.88525},
pmid = {42339583},
issn = {1520-6033},
abstract = {Sixty years of adeno-associated virus (AAV) research illustrates a trajectory marked by basic science exploration, iterative innovation, persistent challenges, a number of clinical setbacks, as well as commercial therapeutic triumphs. This continual evolution has led to recombinant AAV (rAAV) becoming a cornerstone of modern gene therapy. Significant advancements in molecular design, process development, and manufacturing have been made over the past three decades; these improvements are expected to significantly improve the safety, efficacy, and economics of rAAV gene therapies. Beyond rare disease, rAAV vectors have the potential to be used in prevalent conditions such as arthritis, heart failure, diabetes, Alzheimer's disease, and Parkinson's disease. Meeting the vector demands of these disease treatments will require continued innovations in rAAV manufacturing, including further improvements in process optimization and molecular engineering. In addition, the adoption of process intensification and automation strategies, pioneered in other biologics such as monoclonal antibody manufacturing, should prove pivotal in advancing the scale, robustness, and efficiency of rAAV production.},
}

@article {pmid42339607,
year = {2026},
author = {Chatterjee, A and Roy, R and Sarkar, S and Sarkar, S and Chaini, A and Roy, AN and Jana, B and Ethirajan, A and Pal, U and Barman, S and Ghosh, S and Das, A},
title = {Supramolecular Integration of 18-Crown-6 and an N-Capped Short Peptide Enables Multivalent Recognition and Modulation of Amyloid-β Proteotoxicity.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.6c03780},
pmid = {42339607},
issn = {1520-5126},
abstract = {Amyloid-β 42 (Aβ-42) misfolding and self-assembly drive proteostatic collapse in Alzheimer's disease, but chemically programmable systems enabling sequence-selective recognition and remodeling of the Aβ-42 aggregation pathway remain elusive. We report a rationally engineered supramolecular composite, 18C6-LV-PEG, that integrates benzo-18-crown-6 (18C6) to form a supramolecular inclusion complex with the ε-NH3[+] group on lysine, a short peptide sequence targeting the [17]LVFF[20] motif of Aβ-42, and a PEG appendage to enhance pharmacokinetics and blood-brain barrier permeability. Cooperative multivalent engagement of this motif, confirmed by [1]H-[15]N HSQC NMR, confers markedly enhanced affinity (Ka[ITC] ∼ 7.4 × 10[4] M[-1] toward monomeric Aβ-42) relative to individual components (≤10[2] M[-1]), demonstrating synergistic binding. Importantly, 18C6-LV-PEG not only blocks nucleation-dependent Aβ-42 aggregation but also effectively destabilizes soluble oligomers, as well as mature aggregates, revealing a mechanistically distinct supramolecular modulation of the Aβ-42 aggregation pathway relative to conventional inhibitors. The nontoxic conjugate mitigates oxidative stress, restores mitochondrial function, reinstates glial-neuronal connectivity, and improves cognition in an Alzheimer's model. More broadly, this work introduces a conceptual design principle that integrates precision Lys[16]-clamp by 18C6 with targeting of the aggregation-prone [17]LVFF[20] motif to enable chemically programmable, multivalent intervention in pathogenic protein assemblies.},
}

@article {pmid42339750,
year = {2026},
author = {Du, M and Wu, Y and Zhao, H and Sun, J},
title = {Subgroup Analysis of Interval-censored Failure Time Data With Application to Alzheimer's Disease.},
journal = {Statistics in medicine},
volume = {45},
number = {15-17},
pages = {e70613},
doi = {10.1002/sim.70613},
pmid = {42339750},
issn = {1097-0258},
support = {JJKH20261483KJ//Scientific Research Project of the Education Department of Jilin Province/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; Likelihood Functions ; Proportional Hazards Models ; Computer Simulation ; Algorithms ; },
abstract = {Subgroup analysis provides a useful tool for dealing with the heterogeneity in various situations, such as disease treatments, and has attracted a lot of attention in many areas, such as precision medicine. In this paper, we discuss the subgroup analysis for interval-censored failure time data under a heterogeneous Cox proportional hazards model, and a sieve penalized maximum likelihood estimation procedure is proposed. The proposed method can classify study subjects into different subgroups and determine the number of subgroups, the important predictors, and their estimated effects simultaneously. Also, the theoretical justification of the approach is provided, and an extensive simulation study is conducted to evaluate its empirical performance, which indicates that it works well in practical situations. In addition, the proposed methodology is applied to a set of real data on Alzheimer's Disease that motivated this study.},
}

Humans
*Alzheimer Disease/drug therapy/therapy
Likelihood Functions
Proportional Hazards Models
Computer Simulation
Algorithms

@article {pmid42339780,
year = {2026},
author = {Wuyart, A and Martinez, A and Oudart, JB and Mahmoudi, R and Millot, JM},
title = {Decreased Nonpolar Amino Acids in Cerebrospinal Fluid of Alzheimer's Disease Patients Revealed by Very High-Field NMR Spectroscopy.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.6c00294},
pmid = {42339780},
issn = {1535-3907},
abstract = {Alzheimer's disease (AD) is characterized by metabolic dysfunctions, making cerebrospinal fluid (CSF) an ideal biological matrix for characterizing brain metabolism. Very high-field 900 MHz nuclear magnetic resonance (NMR) spectroscopy was used to profile CSF metabolites from 47 patients (n = 27 AD, n = 20 non-AD). A total of forty-eight metabolites were identified and quantified. CSF concentrations of four nonpolar amino acids were reduced in AD: l-alanine (p = 0.001), l-valine (p = 0.02), l-leucine (p = 0.04), and l-phenylalanine (p = 0.04) (two-way ANOVA, pathology and sex as factors). No significant differences were observed for the other identified metabolites. A nonpolar amino acid factor (NAAF) was computed as the sum of these four metabolites (p < 0.001). Partial least-squares discriminant analysis (PLS-DA) based on the NAAF yielded moderate group separation (accuracy = 72%, Q[2] = 0.22, p = 0.006). Receiver operating characteristic (ROC) analysis demonstrated that the NAAF achieved the highest discriminatory performance over individual nonpolar amino acids (AUC = 0.83). l-Alanine correlated negatively with CSF tau markers (p-tau: r = -0.40, p = 0.005; t-tau: r = -0.42, p = 0.003); the NAAF displayed similar patterns (p-tau: r = -0.38, p = 0.009; t-tau: r = -0.40, p = 0.006). Very high-field NMR spectroscopy revealed a depletion of nonpolar amino acids in AD CSF, reflecting metabolic dysregulation in this neurodegenerative disease.},
}

@article {pmid42339820,
year = {2026},
author = {Foudah, AI and Ahmad, A and Bakht, MA and Jawaid, T and Alotaibi, F and Rehman, Z and Imran, M and Alam, A},
title = {Multiscale computational evaluation of marine fungal metabolites containing iminohydantoin-like scaffolds as anti-Alzheimer drug candidates.},
journal = {SAR and QSAR in environmental research},
volume = {37},
number = {6},
pages = {469-498},
doi = {10.1080/1062936X.2026.2685535},
pmid = {42339820},
issn = {1029-046X},
mesh = {*Alzheimer Disease/drug therapy ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Molecular Dynamics Simulation ; *Fungi/chemistry/metabolism ; *Quantitative Structure-Activity Relationship ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Molecular Docking Simulation ; *Hydantoins/chemistry/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-beta accumulation, neuroinflammation, and synaptic dysfunction, making beta-secretase 1 (BACE1) a promising therapeutic target. In the current investigation, we used an integrated computational approach, including virtual screening, machine learning, quantum-chemical analysis, molecular dynamics simulations, ADMET profiling, and network pharmacology, to identify marine fungal metabolites with potential BACE1-binding activity. A virtual chemical library consisting of 4,683 marine-derived compounds was virtually screened against the BACE1 catalytic subdomain to select 100 top compounds with docking energy ranging from -11.9 to -10.2 kcal/mol. The pharmacokinetic study showed promising CNS characteristics. CatBoost was identified as the most reliable model (r[2] = 0.243 ± 0.049), predicting pIC50 values of 7.51-7.95 for shortlisted marine fungal metabolites, suggesting potential BACE1 inhibitory activity. Density functional theory computations revealed good ligand reactivity and stability. Molecular dynamics simulation validated the stable ligand-protein interactions, and MM/GBSA analysis selected CMNPD7259 (ΔG_bind = -68.45 kcal/mol) as the most promising molecule. Network pharmacology further associated the metabolites with pathways involved in inflammation, apoptosis, immunological control, and neuronal function. Overall, the results indicate that metabolites from marine fungi are intriguing candidates for developing safer, more efficacious treatments for AD.},
}

*Alzheimer Disease/drug therapy
*Amyloid Precursor Protein Secretases/antagonists & inhibitors
Molecular Dynamics Simulation
*Fungi/chemistry/metabolism
*Quantitative Structure-Activity Relationship
Aspartic Acid Endopeptidases/antagonists & inhibitors
Molecular Docking Simulation
*Hydantoins/chemistry/pharmacology

@article {pmid42340126,
year = {2026},
author = {Thunell, J and Tysinger, B and Baumgart, M and Carrillo, M and Crimmins, E and Goldman, D and Heun-Johnson, H and Jacobson, M and Joyce, G and Leaf, D and Neumann, LTV and Zissimopoulos, J},
title = {The cost of dementia in the United States in 2026.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71480},
doi = {10.1002/alz.71480},
pmid = {42340126},
issn = {1552-5279},
support = {U01AG086827/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; United States ; *Dementia/economics/epidemiology ; *Cost of Illness ; Aged ; *Health Care Costs/statistics & numerical data ; Quality of Life ; Female ; Middle Aged ; Male ; Caregivers/economics ; Health Expenditures/statistics & numerical data ; },
abstract = {INTRODUCTION: Comprehensive cost measurement is essential for an effective policy response to societal dementia costs.

METHODS: Using dynamic microsimulation, the Health and Retirement Study, and other national data, we quantified the 2026 cost of dementia in the United States.

RESULTS: In 2026, 5.7 million (95% confidence interval [CI] [5.6, 6.0]) US adults aged 51 and older are living with dementia, supported by 5.2 million (95% CI [4.9, 5.5]) care partners. Total costs are $818 billion (B, 95% CI [759, 866]), driven by quality-of-life losses for persons with dementia ($320B, 95% CI [269, 363]) and care partners ($15B 95% CI [6, 25]). Unpaid care ($237B, 95% CI [220, 253]), earnings losses ($23B), and out-of-pocket costs combined with quality-of-life losses account for 80% of costs and are borne by families. Governments cover 70% of healthcare costs ($222B, 95% CI [209, 237]).

DISCUSSION: The costs of dementia fall on families, highlighting limited policy and work supports. Treatment innovation may increase medical costs but reduce caregiver burden and improve quality of life.

HIGHLIGHTS: The costs of dementia in the United States in 2026 are $818 billion. Quality-of-life losses are the largest driver of dementia's total burden. Individuals and families bear over three times the cost versus health systems. Methods enable analysis of treatment, care, and policy innovations on future costs.},
}

Humans
United States
*Dementia/economics/epidemiology
*Cost of Illness
Aged
*Health Care Costs/statistics & numerical data
Quality of Life
Female
Middle Aged
Male
Caregivers/economics
Health Expenditures/statistics & numerical data

@article {pmid42340145,
year = {2026},
author = {Tysinger, B and Heun-Johnson, H and Leaf, D and Thunell, J and Goldman, D and Zissimopoulos, J},
title = {A dynamic microsimulation method for estimating dementia costs in the United States.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71549},
doi = {10.1002/alz.71549},
pmid = {42340145},
issn = {1552-5279},
support = {#U01AG086827/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Dementia/economics/epidemiology ; United States/epidemiology ; Aged ; Quality of Life ; *Cost of Illness ; Female ; Male ; *Health Care Costs/statistics & numerical data ; Middle Aged ; Computer Simulation ; Caregivers/economics ; Medicare/economics ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Addressing dementia's substantial economic burden on individuals, families, health systems, governments, and payers, requires integrating national data and advanced analytic methods.

METHODS: We described data sources, measures, and simulation methods of a dynamic microsimulation model developed for quantifying dementia costs in the United States and for assessing impact of innovation and change over time. Model internal validation was assessed.

RESULTS: Using nationally representative Health and Retirement Study data on adults over age 50, Medicare and other national data, we produced estimates of individual-level health and economic outcomes over time. Estimates and simulation enabled measurement of population-level dementia prevalence, medical and long-term care costs, unpaid caregiving valuation, quality-of-life, and earnings for persons living with dementia and care partners. Counterfactual scenarios quantified dementia-related quality-of-life and earnings losses. Simulated outcomes aligned with observed data.

CONCLUSIONS: Transparent methods support replication, extension, and informed use of dementia cost estimates in research and policy.},
}

Humans
*Dementia/economics/epidemiology
United States/epidemiology
Aged
Quality of Life
*Cost of Illness
Female
Male
*Health Care Costs/statistics & numerical data
Middle Aged
Computer Simulation
Caregivers/economics
Medicare/economics
Aged, 80 and over

@article {pmid42340254,
year = {2026},
author = {Kremen, WS},
title = {A needed revision for the definition of subjective cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461255},
doi = {10.1177/13872877261461255},
pmid = {42340254},
issn = {1875-8908},
abstract = {Subjective cognitive decline (SCD) as defined by the SCD-initiative (2014/2020) is now nearly universally accepted. In this framework, conditions characterized by objective cognitive impairment are distinct from SCD, and SCD is not a diagnostic category. The criteria prevent the straightforward linguistic expression, 'subjective cognitive decline', from being applied to someone with objective cognitive impairment. However, individuals with objective impairment can, of course, experience of subjective decline. The definition thus operates as a quasi-diagnostic category, precluding description of subjective experience for some individuals. Here I propose a simple solution: preclinical and clinical SCD (P-SCD/C-SCD) for objectively unimpaired and impaired individuals, respectively.},
}

@article {pmid42340257,
year = {2026},
author = {Lopes Cardoso, D and Loizou, M and Fourla, DD and Woodman, C and Guille, MJ and Sharpe, C},
title = {Signaling through RXRb and its agonist, bexarotene, promotes neuron formation in Xenopus laevis embryos.},
journal = {Biology open},
volume = {},
number = {},
pages = {},
doi = {10.1242/bio.062675},
pmid = {42340257},
issn = {2046-6390},
support = {BBX018601/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Retinoic acid, acting through RAR/RXR nuclear receptors, is required for neuronal differentiation in Xenopus laevis. Bexarotene, characterised as a pan-RXR agonist, reduces the symptoms of Alzheimer's disease (AD) in mouse models by clearing amyloid plaque and by promoting neurogenesis. In this paper, we show that RXR-initiated bexarotene signalling generates additional neurons both during normal Xenopus laevis development and in ectodermal explants in which BMP signalling is inhibited. Differential gene expression between ectodermal explants taken from uninjected and embryos co-injected with mRNA that expresses Noggin, a BMP antagonist, and RXRb identifies genes mediating change from an epidermal to a neural fate. The explants express genes associated with an anterior neural, but not neuronal fate. The addition of bexarotene to equivalent co-injected explants activates genes that promote neuronal differentiation and posterior character, including genes of the canonical Wnt signalling pathway. Xenopus ectodermal explants therefore provide a simple and efficient tool to identify novel retinoid agonists that promote neuronal differentiation. The genes expressed in response to bexarotene are consistent with a pathway to neuronal differentiation allied to standard retinoid signalling.},
}

@article {pmid42340301,
year = {2026},
author = {Dharmapuri, A and Chaudhuri, S and Contreras, JA and Hayes, CA and , },
title = {Interleukin-6 is associated with white matter hyperintensities and cognition independent of Alzheimer's disease plasma biomarkers-HABS-HD.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458367},
doi = {10.1177/13872877261458367},
pmid = {42340301},
issn = {1875-8908},
abstract = {BackgroundChronic inflammation contributes to neurodegeneration and cerebrovascular injury, yet it remains unclear whether inflammatory biomarkers influence white matter hyperintensity (WMH) volume and cognition independent of Alzheimer's disease (AD) plasma biomarkers.ObjectiveThis study examined whether inflammatory biomarkers were associated with WMH volume and multidomain cognitive performance independent of AD plasma biomarkers, and whether WMH volume mediated associations between IL-6 and cognition.MethodsUsing data from 1806 participants in the Health and Aging Brain Study-Health Disparities (HABS-HD), we examined associations between log transformed plasma inflammatory biomarkers (IL-10, TNF-α, IL-6, and IL-5) and WMH volume and cognitive performance (memory, executive function, processing speed, language). Multivariable linear regression models adjusted for demographic and vascular risk factors were repeated with additional adjustment for AD biomarkers (p-Tau181, NfL, total tau, Aβ42/40). Mediation analyses were included to test whether WMH meditated the association between IL-6 and cognitive domains.ResultsHigher IL-6 levels were consistently associated with increased WMH volume in base and AD-adjusted regression models. Increased levels of IL-6 were also associated with poorer performance in all cognitive domains, but these associations did not survive multiple comparisons correction. WMH partially mediated the association between IL-6 and memory (23%) and processing speed (19%).ConclusionsElevated IL-6 is independently linked to cerebrovascular injury and poorer cognition beyond classical AD biomarkers, supporting a vascular-inflammatory pathway distinct from amyloid and tau pathology. These findings underscore the importance of integrating inflammatory and neurodegenerative markers to elucidate heterogeneous mechanisms of brain aging across diverse populations.},
}

@article {pmid42340305,
year = {2026},
author = {Royall, DR and Palmer, RF and , },
title = {Biomarker affliction classes contribute additively to observed dementia severity and prospective conversion risk.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458678},
doi = {10.1177/13872877261458678},
pmid = {42340305},
issn = {1875-8908},
abstract = {BackgroundDementia is likely to be overdetermined by the independent contributions of its biomarkers, of which Alzheimer's disease (AD)-specific biomarkers are a subset.ObjectiveTo assess the impact of affliction by multiple biomarkers on dementia severity.MethodsUsing previously validated algorithms, N = 988 PET (+) subjects of the Alzheimer's Disease Neuroimaging Initiative (ADNI) were assigned to groups "afflicted by" or "resilient against" the effects of central nervous system amyloid-β (Aβ), plasma adipokines, and/or neurodegeneration and tested against Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and time to dementia conversion.ResultsCDR-SB rose as a function of the number of afflicting biomarkers in both demented and non-demented cases. 327/988 (33.1%) were afflicted by a single biomarker. That biomarker was Aβ in only 19.88% of these PET (+) subjects. 221/988 (22.4%) were afflicted by all three. Only 124/988 (12.6%) were resilient to all three. Affliction by adipokines had the strongest effect (r = 0.33, p < 0.001). Affliction by Aβ was weakest (r = 0.18, p < 0.001). The number of afflicting biomarkers explained 25.2% of CDR variance and significantly impacted conversion risk over 48 months (by χ2 (df = 3) = 56.69, p < 0.001) independently of baseline CDR-SB (by Cox Proportional Hazards Wald χ2 (df = 3) = 26.24, p < 0.001).ConclusionsThe biomarkers that determine dementia severity in PET (+) subjects may ultimately comprise ad hoc combinations and do not necessarily include Aβ. These findings have implications for A/T/N diagnoses.},
}

@article {pmid42340306,
year = {2026},
author = {Brookman, R and Christensen, J and Maurice, OR and Aghaei, M and Cass, A and Monzaviyan, S and Shatnawi, E and Carter, M and Tran, J and McIlwain, N and Garrido, S and Siette, J and Strutt, P and Harris, CB},
title = {Measures used to evaluate psychosocial interventions in dementia care: A narrative review and synthesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261459125},
doi = {10.1177/13872877261459125},
pmid = {42340306},
issn = {1875-8908},
abstract = {Psychosocial interventions are widely used in dementia care, yet standardized outcome measurement remains highly variable, and recent frameworks emphasize outcomes prioritized by people living with dementia and their care partners. This narrative, measurement-focused review does not appraise or synthesize treatment effects. Instead, it aims to map outcome measures to the International Consortium for Health Outcomes Measurement (ICHOM) dementia set plus an additional carer-wellbeing domain, to organize them into a taxonomy of wellbeing domains that highlights patterns and gaps in measurement practice. Eligible studies included participants with Alzheimer's disease and related dementias, evaluated a psychosocial intervention, and reported standardized pre- and post-intervention outcome measures at short and/or long-term follow-up. A total of 136 studies met inclusion criteria. Interventions encompassed arts and creative therapies, cognitive and reminiscence approaches, education and psychosocial support, physical and movement-based therapies, sensory and relaxation therapies, environmental and daily living support, and animal/robot-assisted programs. Outcome measures clustered on neuropsychiatric symptoms (205 instances) and cognitive functioning (146 instances), with fewer measures of social functioning (22 instances) and health-related quality of life (13 instances). Measurement approaches were highly variable (43 distinct neuropsychiatric measures, 47 cognitive measures, 14 social functioning measures). Outcomes were predominantly assessed using short-term measures, with some long-term follow-up, and few observational in-the-moment measures capturing engagement, enjoyment, reciprocity or mastery. This review presents a taxonomy of outcome measures that highlights the mismatch between current evaluation practices and person-centered psychosocial priorities in dementia care, and guides more purposeful measure selection.},
}

@article {pmid42340309,
year = {2026},
author = {Read, S and Brimblecombe, N and Hicks, B and Hu, B and King, D and Wittenberg, R},
title = {Functional difficulties, receipt of help, and unmet needs among people with newly diagnosed dementia: Results from the DETERMIND project.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261459015},
doi = {10.1177/13872877261459015},
pmid = {42340309},
issn = {1875-8908},
abstract = {BackgroundNewly diagnosed people with dementia and Alzheimer's disease may have varying levels of functional difficulties in which help is required. Little is known about how their needs are met, the associations of needs with care dyad background characteristics and how these characteristics are associated with each other.ObjectiveWe investigated the pathways between background characteristics, functional difficulties (need) and receipt of help.MethodsThe sample included 672 newly diagnosed people with dementia and their carers. Four activities of daily living (ADLs), three instrumental activities of daily living (IADLs) and receipt of help in these activities were used to define needs and unmet needs. Receipt of adequate support from health and social care services was also reported. Regression and path models explored the associations with background characteristics.ResultsMost people with dementia had at least one ADL (42%) or IADL (83%) difficulty. Among those who had a difficulty, 50% and 31% had at least one unmet ADL or IADL need, respectively. Support from health and social care services was reported as inadequate by 29%. Many background characteristics (age, gender, education, homeownership, urban-rural location, area deprivation) were associated with receipt of help through functional limitations and/or whether the carer was spouse or coresident.ConclusionsAlthough people newly diagnosed with dementia had fewer ADL than IADL difficulties, unmet need was proportionally higher for ADLs than IADLs. The findings point to possible barriers to receiving help shaped by complex pathways through sociodemographic factors, current levels of functioning and carer characteristics.},
}

@article {pmid42340312,
year = {2026},
author = {Yap, EYA and Chia, DB and Lee, JJ and Choo, MH and Cheng, HK and Shankar, R},
title = {The effectiveness of psychoeducational interventions for family caregivers of people with dementia in Asia: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461174},
doi = {10.1177/13872877261461174},
pmid = {42340312},
issn = {1875-8908},
abstract = {BackgroundDementia is a growing health challenge in the Asia-Pacific region, where family caregivers experience substantial burden shaped by cultural expectations of filial piety. Psychoeducational interventions are recommended non-pharmacological strategies to support caregivers; however, no systematic review has evaluated their effectiveness specifically within Asian populations. Understanding their effectiveness is critical given cultural factors influencing caregiving experiences in Alzheimer's disease and other dementias.ObjectiveTo synthesize the effectiveness of psychoeducational interventions in reducing caregiver burden among Asian family caregivers of people with dementia, describe intervention characteristics, and identify factors influencing effectiveness.MethodsThis systematic review followed PRISMA 2020 guidelines. CINAHL, Cochrane, Embase, PubMed, PsycINFO, Scopus, and Web of Science were searched for studies published between 1 January 2012 and 1 November 2025. Two investigators independently conducted study selection, quality appraisal using the Joanna Briggs Institute critical appraisal tool, and data extraction. A narrative synthesis was conducted due to study heterogeneity.ResultsTen randomized controlled trials were included. Interventions varied in conceptual theories, delivery mode, format, and duration. Six studies reported significant reductions in caregiver burden. More effective interventions were delivered via telephone, provided individually, and implemented over three months. Some studies also reported improvements in self-efficacy, depression, perceived stress, and distress. None incorporated gender-sensitive approaches in intervention design or evaluation.ConclusionsPsychoeducational interventions show promise in alleviating burden among Asian family caregivers of people with dementia, including those with Alzheimer's disease. Tailoring delivery mode, format, and duration may optimize effectiveness. Future research should include diverse Asian populations and incorporate gender-sensitive approaches.},
}

@article {pmid42340330,
year = {2026},
author = {Wang, Q and Bai, Y and Shin, BS and Kim, KW},
title = {Perceptual-phase eye-tracking during figure copying is associated with amyloid-β PET positivity in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461540},
doi = {10.1177/13872877261461540},
pmid = {42340330},
issn = {1875-8908},
abstract = {BackgroundAmyloid-β (Aβ) pathology is a core feature of Alzheimer's disease (AD) and may be present in mild cognitive impairment (MCI). Accessible, non-invasive markers of early Aβ-related cognitive change are needed.ObjectiveTo investigate whether perceptual-phase eye-tracking metrics during figure copying are associated with Aβ-PET positivity in MCI.MethodsIn this cross-sectional study, 59 patients with MCI underwent [18]F-flutemetamol PET and were classified as Aβ-PET positive (n = 34) or Aβ-PET negative (n = 25). Participants completed a simplified Rey-Osterrieth Complex Figure Test while wearing eye-tracking glasses. The display was then divided into perceptual and working areas of interest (AOIs), and metrics were extracted for each AOI. A matched-pair sensitivity analysis (n = 28) was performed to reduce differences in age, education, and Mini-Mental State Examination scores. Binary logistic regression was used to examine the association between Aβ-PET positivity and fixation duration in the perceptual AOI.ResultsThe Aβ-PET positive group showed significantly longer fixation duration in the perceptual AOI (p = 0.027, r = 0.296), whereas no significant group differences were observed in the working AOI. Exploratory analyses showed higher fixation count, visit duration, visit count, and saccade count in the perceptual AOI of the Aβ-PET-positive group. Longer fixation duration in the perceptual AOI was independently associated with Aβ positivity (OR per second = 1.18, 95% CI 1.03-1.36, p = 0.021).ConclusionsAβ-PET positivity in MCI was associated with greater perceptual-phase gaze inefficiency during figure copying. Perceptual-phase eye-tracking metrics may serve as potential markers of amyloid-related visuospatial alteration in MCI.},
}

@article {pmid42340458,
year = {2026},
author = {de Los Ángeles Fernández-Ceballos, M and Prieto-González, JM and Agís-Balboa, RC},
title = {Plasma Biomarkers for Alzheimer's Disease Across the Continuum: A Systematic Review of SIMOA-Based Studies.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01752-4},
pmid = {42340458},
issn = {1573-6830},
support = {IN606A-2024/016//Axencia Galega de Innovación/ ; PID2022-138936OB-C31//Ministerio de Ciencia e Innovación/ ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, and its overall incidence is rising as the proportion of older individuals in the population increases. Traditional diagnostic methods, such as lumbar puncture and neuroimaging, are costly and invasive, driving the search for blood-based biomarkers (BBB) for early diagnosis. The quantification of these biomarkers requires ultrasensitive techniques, such as the single-molecule array (SIMOA) platform. This systematic review synthesizes the available evidence on the biomarkers β-amyloid (Aβ42, Aβ40, and their ratio), tau protein (t-Tau, p-Tau181, p-Tau231, p-Tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in studies analyzing their blood concentrations using SIMOA, regardless of the platform model (SR-X, HD-1, HD-X). Findings support the potential of plasma biomarkers as an alternative or complement to invasive methods, although further validation is required before clinical implementation.},
}

@article {pmid42340466,
year = {2026},
author = {Pereira, HR and Diogo, VS and Fonseca, JM and Ferreira, HA and Prata, DP},
title = {Real-World Generalizability of Alzheimer's Volumetric MRI Machine-Learning Models: External Validation with British Data.},
journal = {Clinical neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00062-026-01688-8},
pmid = {42340466},
issn = {1869-1447},
abstract = {PURPOSE: Assessing generalizability and performance of machine learning models in clinical settings is crucial. In this study, we aimed to test our models' performance on an external validation real-world clinical dataset and to evaluate the impact of magnetic field strength and brain volume normalization on the classification.

METHODS: We validated two previously published models trained on public datasets (Alzheimer's disease [AD], mild cognitive impairment [MCI] and cognitively normal [CN] subjects) on a real-world clinical dataset from UK memory clinics (SLaM-BRC: 255 non-AD [subjects without cognitive complaints], 281 MCI and 711 AD).

RESULTS: Our 'CN vs. AD' model showed similar performance when tested at different magnetic fields (1.5T vs. 3.0T: 87.1% of 93 subjects had the same class assignment). The volume-normalized 'CN vs. AD' model (87.7% balanced accuracy [BAC]) led to decreased performance in the SLaM-BRC (81.5% BAC) due to misclassifications of non-AD subjects with evidence of hippocampal atrophy. The non-normalized 'CN vs. MCI vs. AD' model's performance (initially 55.3% BAC) remained similar in the SLaM-BRC cohort (BAC: SLaM-BRC = 54.6%).

CONCLUSION: Volumes normalized to the estimated total intracranial volume led to a smaller difference in performance between internal and external datasets than non-normalized volumes. Our 'CN vs. MCI vs. AD' model performance remained the same, denoting robustness. These findings suggest that dataset and disease/diagnostic heterogeneities, magnetic field, and brain volume normalization may affect models' performance.},
}

@article {pmid42340476,
year = {2026},
author = {Zhu, J and Huang, YR and Chen, F and Wang, MQ and Yu, XL and Zhang, GF and Liu, RT},
title = {An Engineered Multifunctional Fusion Protein Targeting Aβ Oligomers, Microglia and Autophagy Ameliorates Cognitive Deficits and Amyloid Pathology in Alzheimer's Disease Mice.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01753-3},
pmid = {42340476},
issn = {1573-6830},
support = {82401674//National Natural Science Foundation of China/ ; 2025ZD1801300//Innovative Drug Research and Development National Science and Technology Major Project/ ; },
abstract = {In Alzheimer's disease (AD), Amyloid-β (Aβ) oligomers function as key neurotoxic agents that underpin the disease's progression. A diverse array of therapeutic entities, including peptides, single-chain variable fragments (scFvs), and small molecules, have demonstrated the ability to interact with Aβ oligomers, thereby suppressing their aggregation and associated neurotoxicity. Despite these advances, such agents frequently struggle to promote the phagocytosis and subsequent breakdown of aggregated Aβ by microglia. Moreover, the dense accumulation of Aβ oligomers may resist enzymatic hydrolysis within the acidic lysosomal lumen, contributing to lysosomal stress and dysfunction. To overcome these problems, we engineered a multifunctional fusion protein, p62-LIR-W20-Tuftsin (W20-LT), consisting of an oligomer-specific scFv, a microglia-targeting Tuftsin peptide, and a p62-LIR peptide to activate autophagy. In vitro assays demonstrated that W20-LT significantly outperformed the parental W20 by promoting the rapid microglial uptake of Aβ oligomers and enhancing their intracellular clearance through an autophagy-associated pathway. In APPswe/PS1dE9 (APP/PS1) mice, a low-dose regimen (0.5 µg, every 3 days) of W20-LT, but not W20, significantly ameliorated cognitive deficits and reduced amyloid pathology. Mechanistically, W20-LT was associated with enhanced autophagy-lysosomal pathway activity, as indicated by increased LC3B-II and reduced p62 levels, together with downregulated CatD and LAMP1 levels, thereby mitigating neuroinflammation. In summary, our findings suggest that W20-LT represents a promising proof-of-concept therapeutic strategy that combines scFv-based Aβ oligomer recognition with enhanced autophagy-associated clearance, thereby mitigating AD pathology.},
}

@article {pmid42340485,
year = {2026},
author = {Kac, PR and Cousins, KAQ and Szadziewska, A and Shaw, LM and Turton, M and Van Deerlin, VM and Harrison, P and Zetterberg, H and Wolk, DA and McMillan, CT and Galasko, D and Hanrieder, J and Lee, EB and Kvartsberg, H and Irwin, DJ and Blennow, K},
title = {Tau368 improves p-tau diagnostic accuracy for FTLD-tau from FTLD-TDP.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42340485},
issn = {1432-0533},
support = {#2023-00356, #2022-01018 and #2019-02397//Vetenskapsrådet/ ; #2022-00732//Vetenskapsrådet/ ; 101053962//HORIZON EUROPE European Research Council/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer's Drug Discovery Foundation/ ; (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; NEuroBioStand, #22HLT07//the European Partnership on Metrology, co-financed from the European Union's Horizon Europe Research and Innovation Programme and by the Participating States/ ; #FO2022-0270//Hjärnfonden/ ; #FO2024-0048-TK-130 and FO2024-0048-HK-24//Hjärnfonden/ ; No 860197 (MIRIADE)//the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute/ ; P01-AG-066597, P30-AG-072979, P01-AG084497, R01-AG087258, R01AG090414, R01-NS109260/NH/NIH HHS/United States ; #AF-994551//Swedish Alzheimer Foundation/ ; #ALFGBG-1006418//Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/cerebrospinal fluid/diagnosis/pathology ; Male ; Phosphorylation ; Female ; Aged ; Middle Aged ; *Frontotemporal Dementia/cerebrospinal fluid/diagnosis/pathology ; Alzheimer Disease/cerebrospinal fluid/pathology/diagnosis ; Tauopathies/cerebrospinal fluid ; alpha-Synuclein/cerebrospinal fluid ; Brain/pathology ; },
abstract = {Across tauopathies-Alzheimer's disease (AD), frontotemporal lobar degeneration due to tau (FTLD-tau)-we compared cerebrospinal fluid (CSF) biomarkers of phosphorylated-tau (p-tau) p-tau181, p-tau212, tau368, total tau (t-tau), and the tau368/t-tau ratio, and tested differentiation from non-tau (FTLD-TDP, neuronal α-synuclein disease (αSyn), and controls). In AD, CSF p-tau181 and p-tau212 were significantly higher than in all other groups, including FTLD-tau, while tau368/t-tau was significantly lower. With the aim to combine tau phosphorylation biomarkers (p-tau181 and p-tau212) with biomarkers for severity of tau pathology (tau368), we made ratios between these biomarkers and examined their diagnostic accuracy in FTLD after excluding high/intermediate AD neuropathologic change (ADNC). CSF p-tau181 and p-tau212, as well as p-tau181/tau368 and p-tau212/tau368, were higher in FTLD-tau compared with non-tau groups, and the diagnostic accuracy to discriminate FTLD-tau from FTLD-TDP improved. Levels of the ratios were increased in behavioral and primary progressive aphasia variants of tauopathies when compared to FTLD-TDP. Furthermore, the biomarkers showed significant correlation with both FTLD-tau and AD tau burden at autopsy across brain regions. These results suggest unique patterns of increased relative levels of p-tau epitopes in CSF among ADNC and FTLD-tau could improve the diagnosis of tauopathies and inform inclusion criteria in clinical trial design.},
}

Humans
*tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
*Frontotemporal Lobar Degeneration/cerebrospinal fluid/diagnosis/pathology
Male
Phosphorylation
Female
Aged
Middle Aged
*Frontotemporal Dementia/cerebrospinal fluid/diagnosis/pathology
Alzheimer Disease/cerebrospinal fluid/pathology/diagnosis
Tauopathies/cerebrospinal fluid
alpha-Synuclein/cerebrospinal fluid
Brain/pathology

@article {pmid42340575,
year = {2026},
author = {Carpi, M and De Bartolo, M and Henao Isaza, V and Noce, G and Del Percio, C and Lopez, S and Carducci, F and Lizio, R and Afragola, AP and Bölükbaş, B and Fiorentino, F and Barone, A and Cappiello, A and Di Filippo, F and Riemma, D and Costanzo, G and Biundo, R and Cauzzo, S and Fiorenzato, E and Vianello, F and Spoa, M and Stocchi, F and Coletti, C and Vacca, L and Infarinato, F and Romano, P and Radicati, F and De Pandis, MF and Marziali, S and Giubilei, F and Narda, L and Ziccardi, L and Antonini, A and Barone, P and Babiloni, C},
title = {Associations of daily step counts with cognitive, clinical, and resting-state electroencephalographic measures in patients with cognitive decline due to Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42340575},
issn = {2509-2723},
abstract = {Sedentary behavior is a recognized and modifiable risk factor for cognitive decline and dementia across neurodegenerative conditions. This study used a smartwatch-based telemonitoring procedure combined with ecological cognitive assessment to examine whether step counts can capture sedentary behavior and its association with cognitive functioning in patients with mild cognitive impairment (ADMCI) and dementia (ADD) due to Alzheimer's disease. Then, 19 ADD, 28 ADMCI, and 23 cognitively unimpaired older adults (Nold) were consecutively recruited. Participants underwent clinical assessment, resting-state electroencephalography (rsEEG), and neuropsychological testing. They were then monitored at home for approximately one week using Samsung Galaxy Watch 4-6 devices recording step counts (total, purposeful, and incidental) and activity intensity (peak 30-min cadence), together with the unsupervised SmartMe&You-TELEMAIA serious videogame battery administered on a commercial tablet for cognitive assessment. The ADD group showed reduced step counts and lower peak cadence than both ADMCI and Nold participants, whereas rsEEG markers and cognitive measures discriminated the three groups with a graded pattern. Within the AD sample, smartwatch-derived activity metrics were associated with cognitive functioning as assessed by conventional neuropsychological testing and ecological serious videogame performance, but showed limited associations with rsEEG rhythms. EEG delta and alpha rhythms were also more abnormal in the ADD group than in the ADMCI group. Home-based daytime activity monitoring with commercial smartwatches indicated that step volume and intensity are associated with cognitive status in patients with ADMCI and ADD. These findings suggest that smartwatch-derived activity metrics may provide feasible and cost-effective markers of everyday functioning in Alzheimer's disease.},
}

@article {pmid42340775,
year = {2026},
author = {Madhurya, M and Sudha, K and Sowndarya, K and Dushyanth, B},
title = {Cognitive and Memory Decline in Thyroid Disorders: A Biomarker Based Cross Sectional Study in Aging Adults.},
journal = {La Clinica terapeutica},
volume = {177},
number = {4},
pages = {760-765},
doi = {10.7417/CT.2026.2068},
pmid = {42340775},
issn = {1972-6007},
mesh = {Humans ; Female ; Biomarkers/blood ; Male ; Cross-Sectional Studies ; Brain-Derived Neurotrophic Factor/blood ; Aged ; *Memory Disorders/etiology/blood ; Amyloid beta-Peptides/blood ; Acetylcholinesterase/blood ; *Hypothyroidism/blood/complications ; Alzheimer Disease/etiology/blood ; Aging/blood ; *Thyroid Diseases/complications/blood ; *Cognitive Dysfunction/etiology/blood ; Peptide Fragments/blood ; *Hyperthyroidism/blood/complications ; Calcium/blood ; Glutathione/blood ; Middle Aged ; },
abstract = {BACKGROUND: The pathophysiology of Alzheimer's disease (AD) involves a complex interplay of several factors like oxidative stress, hypercalcemia, decreased acetylcholine, which may act independently or synergistically to drive cognitive decline. The accumulation of Aβ42 fragments derived from amyloid precursor protein is hall mark of AD. Epidemiologic studies suggest that thyroid dysfunction may increase the risk of early-onset AD. This study aims to provide the potential mechanisms linking thyroid dysfunction and AD, both common in older adults by evaluating serum memory and cognitive biomarkers in aging patients with thyroid disorders.

MATERIALS AND METHODS: Serum levels of Aβ42, acetylcholinesterase (AChE), brain-derived neurotrophic factor (BDNF), GSH, and calcium were measured in 45 patients each with hyperthyroidism and hypothyroidism, and compared with 30 age- and sex-matched healthy controls. Serum Aβ42 and BDNF were quantified using sandwich ELISA. AChE, GSH, and calcium were measured spectrophotometrically.

RESULTS: Aβ42 levels were significantly elevated in both hyperthyroid (p=0.000) and hypothyroid patients (p=0.043) compared to controls.BDNF and AChE levels were significantly elevated in both thyroid disorder groups versus healthy individuals (p=0.000).These elevations were relatively more pronounced in hypothyroid patients compared to hyperthyroid patients (BDNF: p=0.036; AChE: p=0.034). Serum calcium levels were significantly increased in both hyperthyroid and hypothyroid patients compared to controls (p=0.000). GSH levels were significantly elevated in hyperthyroid patients compared to both hypothyroid patients and healthy controls (p=0.000).

CONCLUSION: Elevated Aβ42, AChE, and calcium levels may contribute to persistent cognitive and memory impairment in thyroid disorders, underscoring the need to evaluate memory markers to reduce the risk of dementia.},
}

Humans
Female
Biomarkers/blood
Male
Cross-Sectional Studies
Brain-Derived Neurotrophic Factor/blood
Aged
*Memory Disorders/etiology/blood
Amyloid beta-Peptides/blood
Acetylcholinesterase/blood
*Hypothyroidism/blood/complications
Alzheimer Disease/etiology/blood
Aging/blood
*Thyroid Diseases/complications/blood
*Cognitive Dysfunction/etiology/blood
Peptide Fragments/blood
*Hyperthyroidism/blood/complications
Calcium/blood
Glutathione/blood
Middle Aged

@article {pmid42340807,
year = {2026},
author = {Rudolf, MA and Ng, YT and Lieberman, AP},
title = {Sleep fragmentation correlates with amyloid beta deposition at brain autopsy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71616},
doi = {10.1002/alz.71616},
pmid = {42340807},
issn = {1552-5279},
mesh = {Humans ; Female ; *Brain/pathology/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Autopsy ; Aged, 80 and over ; *Sleep Deprivation/pathology ; Actigraphy ; Longitudinal Studies ; *Alzheimer Disease/pathology ; Aged ; Neuropsychological Tests ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: Poor sleep is a symptom and candidate risk factor for Alzheimer's disease (AD). We investigated whether objective and subjective longitudinal sleep measures correlated with AD pathology at brain autopsy.

METHODS: Rush Memory and Aging Project (MAP) participants (n = 798; Meanage at baseline = 81.72) underwent annual evaluation with actigraphy along with sleep questionnaires and cognitive assessment. Brain autopsy provided quantitative neuropathologic data.

RESULTS: Objective sleep fragmentation was associated with higher amyloid density. This association was only observed among individuals with low AD neuropathologic change or no/mild cognitive impairment. Last-measured sleep fragmentation had a stronger association with amyloid density than did mean sleep fragmentation across the study. Poorer subjective sleep quality was paradoxically linked to lower AD-related neuropathologic burden.

DISCUSSION: These findings provide histopathologic evidence linking objectively measured sleep fragmentation to cerebral amyloid deposition and suggest that sleep disruption may be most relevant during earlier stages of AD pathogenesis.},
}

Humans
Female
*Brain/pathology/metabolism
*Amyloid beta-Peptides/metabolism
Male
Autopsy
Aged, 80 and over
*Sleep Deprivation/pathology
Actigraphy
Longitudinal Studies
*Alzheimer Disease/pathology
Aged
Neuropsychological Tests
Surveys and Questionnaires

@article {pmid42103282,
year = {2026},
author = {Cissé, M and Moullé, V and Brossaud, R and Oullier, T and Neunlist, M},
title = {Microbiota-Gut-Brain Axis in Neurodegenerative Diseases: The Role of Bacterial Amyloids.},
journal = {Cellular and molecular gastroenterology and hepatology},
volume = {20},
number = {8},
pages = {101802},
doi = {10.1016/j.jcmgh.2026.101802},
pmid = {42103282},
issn = {2352-345X},
abstract = {Neurodegenerative diseases are proteinopathies, characterized by misfolded protein aggregation in the brain that drives neuronal dysfunctions. Neurodegenerative diseases are also increasingly recognized as multi-organ disorders in which the gut plays a pivotal role. Indeed, recent advances in the research field of neurodegenerative diseases suggest that the gut is not merely a passive bystander, given the high prevalence of gastrointestinal symptoms, but a critical contributor to disease etiology, with evidence supporting a direct role in initiating and driving disease progression. Among environmental factors increasingly recognized as modulators of neurodegenerative disease progression, the gut microbiota has gained prominence. Beyond the impact of altered bacterial metabolites, growing evidence indicate a potential role of gut microbiota-derived amyloids in neurodegenerative diseases. For instance, gut microbial amyloids such as curli can cross-seed host proteins like α-synuclein and β-amyloid promoting aggregation, gut-to-brain propagation, and exacerbating neurodegeneration, revealing a novel mechanism linking the microbiome to neurodegenerative diseases. This conceptual shift opens promising avenues for strategies targeting the gut microbiota, including therapeutic and preventive interventions aimed at reshaping microbial communities or limiting exposure to pathogenic amyloids to reduce risk of neurodegenerative diseases. Here, we review recent discoveries to elucidate the complex interplay between gut microbiota and host amyloids, offering insights for enhancing gut and brain health and potentially preventing or reversing neurodegenerative disease progression.},
}

@article {pmid42330851,
year = {2026},
author = {Mlakić, M and Talić, S and Odak, I and Roca, S and Šagud, I and Barić, D and Škorić, I},
title = {Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110096},
doi = {10.1016/j.bioorg.2026.110096},
pmid = {42330851},
issn = {1090-2120},
abstract = {This study reports the design, synthesis, and biological evaluation of novel resveratrol-inspired thieno-benzimidazole and thieno-oxazole derivatives as potential therapeutics for Alzheimer's disease. The research is grounded in the cholinergic hypothesis, which links cognitive decline to reduced acetylcholine levels due to enzymatic degradation by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Given the increasing relevance of BChE in later disease stages, the focus was placed on developing selective BChE inhibitors. A series of 14 compounds was synthesized using multi-step organic reactions, including Wittig reactions, Vilsmeier formylation, and cyclization strategies. Structural confirmation was achieved through NMR and mass spectrometry. The studied acetylated derivatives exhibit photochemical instability due to efficient trans-cis isomerization and subsequent secondary processes under UV irradiation, necessitating strict light protection during handling, storage, and application. Biological evaluation revealed that all compounds selectively inhibited BChE, with no significant AChE inhibition observed. Among them, carbamate-oxazole derivative 14 exhibited the highest potency (IC50 = 0.248 μM), outperforming the reference drug rivastigmine. Several other derivatives showed moderate to strong activity, with oxazole-based compounds generally outperforming benzimidazole analogs. In addition to enzyme inhibition, antioxidant activity was assessed using the DPPH and CUPRAC assays. Compound 8 exhibited the strongest radical-scavenging activity, comparable to that of Trolox. Molecular docking and dynamics simulations provided insight into binding interactions, highlighting key π-π stacking and hydrogen bonding within the BChE active site. Furthermore, in silico genotoxicity analysis indicated that the most active compounds lack mutagenic potential. Overall, the study identifies promising multifunctional candidates combining selective BChE inhibition, antioxidant properties, and favorable safety profiles, supporting their potential as lead compounds for Alzheimer's disease therapy.},
}

@article {pmid42330959,
year = {2026},
author = {Du, Y and Sun, C and Wu, L and Wu, Z and Tong, Y and Tian, H and Mao, Y and Shi, X and Ding, H and Xie, W and Yao, W and Chen, S and Gao, X},
title = {Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.},
journal = {Cell metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cmet.2026.05.014},
pmid = {42330959},
issn = {1932-7420},
abstract = {Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.},
}

@article {pmid42331016,
year = {2026},
author = {Steinhorst, K and Lakatos, P and Hohberger, B},
title = {Imbalanced Trace Elements as Risk Factors in the Pathogenesis of Glaucoma.},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2805-1399},
pmid = {42331016},
issn = {1439-3999},
support = {01EP2108A//German Federal Ministry of Education and Research/ ; 01EP2108A//German Federal Ministry of Education and Research/ ; },
abstract = {Glaucoma, a neurodegenerative disease, is characterised by ocular pathogenic patterns, yet also by cerebral pathologies, particularly within the visual pathway. Oxidative stress is involved in glaucoma pathogenesis, similar to other neurodegenerative diseases, such as Alzheimer's disease. Trace elements can intervene within these molecular processes (e. g., via enzymes) and in the event of imbalances, also cause pathological changes. This review aims to provide an overview of the common features of glaucoma and other neurodegenerative diseases, focusing on the influence of imbalanced trace elements such as zinc, copper, iron and selenium, and oxidative stress.},
}

@article {pmid42331020,
year = {2026},
author = {Feng, H and Hao, Y and Li, Y and Chen, J and Zhao, R and Huang, Y},
title = {Targeting Membrane Lipid and Curvature Signatures for Neuronal Exosome Capture and Protein Profiling as a Liquid Biopsy for Cognitive Impairment.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00397},
pmid = {42331020},
issn = {1520-6882},
abstract = {Selective isolation and analysis of brain-derived exosomes are essential for understanding and clinical management of neurodegeneration diseases. Herein, inspired by the unique lipidomic features of the central nervous system and lipid packing signature of exosomal membranes, we report a high-performance exosome capture platform, Exo-RTrap, developed through screening of the molecular interactions between an arginine-rich peptide (R9) and main lipids. Different from conventional view of nonspecific electrostatic association, we demonstrate highly selective and high-affinity binding of R9 toward phosphatidylserine (PS) over other anionic lipids, accompanied by spontaneous assembly into nanoscale vesicular complexes. Notably, R9 exhibits 370-fold stronger affinity for PS-containing liposomes than PS-free ones and recognizes membrane curvature in a PS-dependent manner, with sensitivity regulated by PS lateral density. Guided by these mechanistic insights, Exo-RTrap with dual-mode recognition coupling PS targeting with curvature responsiveness enabled rapid and selective isolation of exosomes from complex medium and biofluids, with purity and antifouling ability exceeding ultracentrifugation and precipitation methods. The capability of Exo-RTrap to selectively enrich disease-relevant neuronal exosomes was demonstrated by its accurate discrimination of serum samples from patients with Alzheimer's disease and mild cognitive impairment, whereas exosomes isolated by ultracentrifugation failed to achieve comparable performance. Moreover, integration with mass spectrometry-based proteomics further identified differentially expressed proteins as potential biomarkers for staging cognitive impairment. By defining the molecular rules governing R9-lipid interactions, this work presents a promising peptide-based exosome isolation platform for early detection and monitoring of neurodegenerative disorders.},
}

@article {pmid42331203,
year = {2026},
author = {Li, D and Zhang, Z and Lu, L and Liu, J and Cai, W and Hou, J and Lu, Y and Yu, G},
title = {Neuroinflammation-centered pathophysiology and therapeutic strategy design in Alzheimer's disease: Cutting-edge developments.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112689},
doi = {10.1016/j.cellsig.2026.112689},
pmid = {42331203},
issn = {1873-3913},
abstract = {Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder characterized by complex interactions among amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, metal dyshomeostasis, and impaired autophagy. Increasing evidence positions neuroinflammation not merely as a secondary response but as a central driver of disease progression, dynamically interacting with amyloid and tau protein pathology and contributing to synaptic dysfunction and neuronal loss. Among inflammatory mechanisms, microglial activation pathways-particularly TREM2 signaling, NLRP3 inflammasome activation, and complement cascade dysregulation-are currently the most clinically actionable targets, supported by genetic, biomarker, and therapeutic evidence. Emerging data suggest that modulation of innate immune pathways is most likely to confer benefit during the prodromal and early symptomatic stages of AD, when neuroinflammatory responses remain partially adaptive and neuronal networks retain functional reserve. Despite decades of drug development, many candidates have failed due to limited efficacy or safety concerns. Recent FDA approvals of anti-amyloid monoclonal antibodies, including aducanumab and lecanemab, represent important advances toward disease-modifying therapy, although their long-term clinical impact and safety profiles remain under evaluation. These developments underscore the importance of biomarker-guided patient selection, disease-stage stratification, and vigilant safety monitoring, particularly regarding amyloid-related imaging abnormalities. Therapeutic strategies are increasingly shifting toward multi-target approaches that integrate amyloid modulation, tau protein-directed interventions, and attenuation of maladaptive neuroinflammatory responses. Concurrently, inflammatory mediators and peripheral metabolic biomarkers are gaining recognition as tools for early detection, risk stratification, and therapeutic response monitoring, potentially enabling precision-based intervention. This review synthesizes current understanding of AD pathogenesis through an inflammation-centered framework, highlighting clinically actionable immune pathways and stage-specific therapeutic windows. By integrating mechanistic insights with biomarker-driven strategies, we aim to delineate translational paths toward more precise, safe, and clinically meaningful disease modification.},
}

@article {pmid42331250,
year = {2026},
author = {Fahmy, MI and Rizk, NI and Eitah, HE and Arab, HH and Alsufyani, SE and Arafa, EA and Azzam, HN},
title = {Resveratrol alleviates neurological disorders and motor dysfunction in 3-NP induced- Huntington Disease in rats: Role of activating AMPK/SIRT1/ULK1 autophagy pathway.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {111084},
doi = {10.1016/j.neuropharm.2026.111084},
pmid = {42331250},
issn = {1873-7064},
abstract = {Huntington's disease (HD) is a genetic neurodegenerative disease characterized by striatum damage, which results in a number of uncontrollable muscle movements alongside intellectual and cognitive impairment. The progression of HD is accompanied by neuroinflammation, oxidative stress, and neuronal apoptosis. Resveratrol (RESV) is a naturally occurring compound known for its potent antioxidant and anti-inflammatory effects. RESV showed promising neuroprotective effects against Alzheimer's and Parkinson's disease. The current research aims to study the neuroprotective effects of RESV against 3-nitropropionic acid (3-NP)-induced HD. Forty adult male rats were divided equally into four groups as follows: Group 1- normal control group. Group 2- RESV (25 mg/kg/day, p.o) - treated rats. Group 3- rats treated with 3-NP (10 mg/kg/day, i.p). Group 4- rats treated with 3-NP (10 mg/kg/day, i.p) +RESV (25 mg/kg/day, p.o). The results showed that RESV alleviated the behavioral deficits observed in 3-NP treated rats. In addition, the histopathological images showed obvious improvement in RESV-treated rats. RESV activated the AMP-activated protein kinase (AMPK)-related autophagy pathway that resulted in neuroprotection and cell survival. Moreover, RESV showed anti-inflammatory and antioxidant effects by decreasing levels of inflammatory biomarkers including tumor necrosis factor (TNF)-α, nuclear factor kappa (NF-κ)-B, and interleukin (IL)-1β, alongside increasing neuronal antioxidant capacity by stimulating reduced glutathione (GSH), superoxide dismutase (SOD), and preventing lipid peroxidation. In conclusion, our study showed that RESV has a potent neuroprotective effect as evidenced by its ability to significantly alleviate biochemical and behavioral hallmarks of HD.},
}

@article {pmid42331352,
year = {2026},
author = {Salgado, KDCB and de Albuquerque, ALS and Pedrosa, TCF and Cota, AAB and Talvani, A and Oliveira, LAM and Nogueira, KOPC},
title = {Cannabidiol Limits Early Aβ-Induced Glial Activation and Preserves Synaptic Integrity in Primary Mouse Hippocampal Neuron-Glia Cultures.},
journal = {The European journal of neuroscience},
volume = {63},
number = {12},
pages = {e70588},
doi = {10.1111/ejn.70588},
pmid = {42331352},
issn = {1460-9568},
mesh = {Animals ; *Cannabidiol/pharmacology ; *Hippocampus/drug effects/cytology/metabolism ; *Neurons/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Neuroglia/drug effects/metabolism ; *Synapses/drug effects/metabolism ; Cells, Cultured ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Coculture Techniques ; },
abstract = {Alzheimer's disease (AD) initiates with subtle neuroimmune alterations that precede overt synaptic loss and neuronal death, yet the early sequence linking Aβ exposure to glial activation remains incompletely understood. To capture early neuroimmune dynamics with greater physiological relevance, we employed primary mixed neuron-glia cultures derived from the hippocampi of postnatal day 1 (P1) mice. Unlike conventional coculture systems, these hippocampal mixed cultures preserve intrinsic neuron-astrocyte-microglia communication and recapitulate key features of the in vivo hippocampal microenvironment. Using this model, we investigated whether cannabidiol (CBD) modulates the initial pathogenic events triggered by Aβ25-35 during a 24h simultaneous cotreatment in cell culture. Aβ exposure induced robust hippocampal glial activation, oxidative stress, and elevated levels of proinflammatory mediators, particularly IL-1β, IL-6, and TNF-α. Notably, hippocampal synaptic and neurogenic markers (5HT1A, Gria1, GRIN1, DCX, PSD-95) remained largely unaltered at this early stage, revealing a temporal dissociation in which glial-driven inflammation precedes synaptic dysfunction. CBD significantly attenuated inflammatory and oxidative responses and prevented Aβ-induced cellular damage, indicating engagement of endocannabinoid-related mechanisms that constrain early hippocampal glial reactivity. Although CBD did not fully normalize all glial alterations, it preserved hippocampal synaptic integrity and halted progression toward neuronal dysfunction. Together, these findings identify early hippocampal glial inflammation as a primary target of CBD and provide mechanistic insight into the temporal sequence linking Aβ exposure to neuroimmune activation. These results highlight early glial responses as a critical window for therapeutic intervention and support cannabinoid-based strategies to modulate the initial stages of Alzheimer's disease pathogenesis.},
}

Animals
*Cannabidiol/pharmacology
*Hippocampus/drug effects/cytology/metabolism
*Neurons/drug effects/metabolism
*Amyloid beta-Peptides/toxicity
Mice
*Neuroglia/drug effects/metabolism
*Synapses/drug effects/metabolism
Cells, Cultured
Mice, Inbred C57BL
Oxidative Stress/drug effects
Coculture Techniques

@article {pmid42331506,
year = {2026},
author = {Hu, J and Lu, S and Zhang, Q and Qian, K and Rehman, H and Zhu, C and Farrell, J and Castrillon-Candas, JE and Au, R and Farrer, LA and Qiu, WQ and Chen, J and Zhang, X},
title = {Alzheimer's disease risk prediction from clinical and social determinants of health: a machine learning cohort study in UK Biobank.},
journal = {BMJ health & care informatics},
volume = {33},
number = {1},
pages = {},
doi = {10.1136/bmjhci-2025-101803},
pmid = {42331506},
issn = {2632-1009},
mesh = {Humans ; *Social Determinants of Health/statistics & numerical data ; United Kingdom/epidemiology ; Female ; *Alzheimer Disease/epidemiology/diagnosis ; Male ; Aged ; *Machine Learning ; UK Biobank ; Risk Assessment/methods ; Predictive Learning Models ; Risk Factors ; Cohort Studies ; Classification Algorithms ; Middle Aged ; Prediction Algorithms ; Biological Specimen Banks ; },
abstract = {OBJECTIVES: Social determinants of health (SDOH) may improve Alzheimer's disease (AD) risk prediction by capturing upstream contextual risk beyond routinely measured clinical variables. We aimed to develop and validate an accurate, interpretable machine-learning pipeline for AD risk prediction in UK Biobank using routinely collected data.

METHODS: Using data from 13 076 participants in the UK Biobank, we developed an automated machine-learning pipeline for AD risk prediction with feature selection and a C5.0 boosted-tree classifier. Data were split into training, development and test sets (7:2:1); missing values were imputed in the training data only, and feature selection, tuning and threshold calibration were performed using the training/development data, with final evaluation on the independent test set. Internal validation used repeated subsampling without replacement.

RESULTS: During up to 16 years of follow-up, 927 participants developed AD. Feature selection reduced 3590 variables to 26 predictors spanning age, APOE4, SDOH, medical history and routine clinical measures. The final model showed good discrimination (area under the precision-recall curve 0.89) and adequate calibration (Hosmer-Lemeshow p=0.71), with stable performance under repeated subsampling. Sex-stratified models showed similar patterns.

DISCUSSION: SDOH contributed useful predictive information, but their associations should be interpreted as predictive rather than causal and may reflect socioeconomic confounding and healthcare access.

CONCLUSIONS: This model could support scalable AD risk screening using routinely collected data, but external validation and recalibration in non-UK populations are needed before broader application.},
}

Humans
*Social Determinants of Health/statistics & numerical data
United Kingdom/epidemiology
Female
*Alzheimer Disease/epidemiology/diagnosis
Male
Aged
*Machine Learning
UK Biobank
Risk Assessment/methods
Predictive Learning Models
Risk Factors
Cohort Studies
Classification Algorithms
Middle Aged
Prediction Algorithms
Biological Specimen Banks

@article {pmid42331512,
year = {2026},
author = {Si, S and Deng, S and Zhang, Y and Wang, X and Yue, G and Sun, Y and Lu, H and Li, J and Tao, F and Lin, M and Dong, Z and Zhuo, B and Li, L and Pang, B and Jin, X and Meng, Z and Shi, J},
title = {Impact of ambient fine particulate matter (PM2.5) pollution on disease burden in BRICS from 1990 to 2023: evidence from the Global Burden of Disease Study 2023.},
journal = {BMJ global health},
volume = {11},
number = {6},
pages = {},
doi = {10.1136/bmjgh-2026-023674},
pmid = {42331512},
issn = {2059-7908},
mesh = {Humans ; *Global Burden of Disease/trends ; *Particulate Matter/adverse effects ; India/epidemiology ; China/epidemiology ; Brazil/epidemiology ; Russia/epidemiology ; Disability-Adjusted Life Years ; South Africa/epidemiology ; *Air Pollution/adverse effects ; *Environmental Exposure/adverse effects ; },
abstract = {BACKGROUND: Ambient fine particulate matter (PM2.5) pollution (APMP) is a leading global mortality risk factor. Its long-term trends, drivers and future burden trajectories in emerging economies remain inadequately understood. This study provides the first systematic assessment of spatiotemporal patterns, key drivers and projections to 2050 of APMP-attributable health loss in BRICS countries (Brazil, Russia, India, China and South Africa) from 1990 to 2023, benchmarked against global and Group of Seven (G7) trends.

METHODS: Using Global Burden of Disease 2023 data, this study analysed APMP-attributable deaths and disability-adjusted life years (DALYs) via absolute numbers and age-standardised rates. The multidimensional framework included joinpoint regression, age-period-cohort (APC) modelling, Das Gupta decomposition, disease spectrum ranking and Bayesian-APC projection.

RESULTS: In 2023, APMP caused 2.955 million deaths in BRICS (59% of the global total). Age-standardised mortality and DALY rates remained higher than global averages and increased since 1990, contrasting with sustained declines in the G7. Substantial heterogeneity existed: India's burden was heaviest and growing, China's remained high but stabilised, while Brazil and Russia achieved marked reductions. APC modelling revealed pronounced mortality increases in older ages (especially 95+ years in China and India). Decomposition identified population ageing as the key driver in BRICS, especially China; population growth and deteriorating epidemiological conditions under high exposure drove increases in India and South Africa. Leading APMP-attributable burdens in BRICS were ischaemic heart disease, chronic obstructive pulmonary disease and intracerebral haemorrhage, unlike in the G7 where Alzheimer's disease and other dementias ranked first. Projections indicate the BRICS burden will remain above the global average by 2050, with China and India continuing to bear severe burdens.

CONCLUSION: BRICS is the epicentre of global APMP-attributable burden. The widening gap with the G7 underscores divergent environmental health governance paradigms. Findings call for differentiated strategies within BRICS and enhanced transnational collaboration to curb APMP burden rises and bridge global environmental health equity gaps.},
}

Humans
*Global Burden of Disease/trends
*Particulate Matter/adverse effects
India/epidemiology
China/epidemiology
Brazil/epidemiology
Russia/epidemiology
Disability-Adjusted Life Years
South Africa/epidemiology
*Air Pollution/adverse effects
*Environmental Exposure/adverse effects

@article {pmid42331642,
year = {2026},
author = {Guedj, E and Verger, A and Horowitz, T},
title = {Brain [18F]FDG PET in Subjective Cognitive Complaints: From Diagnostic Gap to Neurobiological Insight.},
journal = {PET clinics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cpet.2026.05.004},
pmid = {42331642},
issn = {1879-9809},
abstract = {Subjective cognitive complaints are heterogeneous and may occur with normal, subtle, or objectively abnormal cognitive testing. Fluorodeoxyglucose (FDG) PET can help explore their metabolic substrate, particularly in subjective cognitive decline within the Alzheimer's disease continuum. In mild traumatic brain injury and long coronavirus disease (COVID), available studies suggest possible metabolic-network abnormalities but involve more heterogeneous populations and should be interpreted cautiously within multimodal, clinically characterized frameworks.},
}

@article {pmid42331677,
year = {2026},
author = {Gildengers, A and Wang, Y and Hughes, TF and Jacobsen, E and Karikari, TK and Snitz, B and Zeng, X and Chang, CH and Ganguli, M},
title = {Loneliness and Plasma Biomarkers of Neurodegeneration in Community-Dwelling Older Adults: Cross-Sectional and Longitudinal Analyses.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.05.012},
pmid = {42331677},
issn = {1545-7214},
abstract = {BACKGROUND/OBJECTIVE: Loneliness has been linked with cognitive decline and dementia. Studies show relationships between loneliness and neurodegeneration, amyloid, and tau burden. We investigated whether loneliness relates to plasma biomarkers of neurodegenerative processes among cognitively normal or mildly impaired older adults at the population level.

SETTING/PARTICIPANTS: A population-based cohort (n = 884) in southwestern Pennsylvania.

MEASUREMENTS: Demographics; loneliness and social isolation composite scores, depression symptoms, Clinical Dementia Rating, plasma amyloid beta (Aβ) 42, Aβ40, p-tau181, p-tau217, NfL, GFAP.

DESIGN: We examined the associations of loneliness with plasma biomarkers using regression analyses in both cross-sectional and longitudinal models. For cross-sectional analysis, we used data from 884 dementia-free participants at the closest wave to biomarker testing (within 180 days). For longitudinal analysis, we first derived loneliness trajectories from 514 participants with repeated annual loneliness measurements for up to 15 years prior to biomarker testing, then used these trajectories as predictors in regression models examining their associations with plasma biomarkers.

RESULTS: Compared with the stable loneliness trajectory, the increasing loneliness trajectory showed nominally higher p-tau181 levels (β = 0.305 log-transformed, 95% CI: 0.022, 0.587; t_476 = 2.112; p = 0.035, uncorrected; multiple comparison-adjusted p = 0.211), adjusting for age, sex, education, social isolation, and depression symptoms.

CONCLUSIONS: This exploratory analysis found a nominal association between increasing loneliness and p-tau181 that did not survive correction for multiple comparisons. Findings should be considered hypothesis-generating. If confirmed through replication in larger samples, associations between loneliness patterns and tau pathology could inform understanding of psychosocial contributions to neurodegeneration.},
}

@article {pmid42331740,
year = {2026},
author = {Xu, K and Salaiza, JA and Adeoye, H and Bhowmik, S and El Sayed, T and Rana, M and Mirica, LM},
title = {Pharmacokinetic Studies of Amyloid-Targeting Bis(styryl)benzene Agents for Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00361},
pmid = {42331740},
issn = {1948-7193},
abstract = {The pharmacokinetics (PK) and biodistribution of radiolabeled amyloid-β (Aβ)-targeting probes have been extensively characterized in the context of Alzheimer's disease (AD), whereas the corresponding nonradiolabeled scaffolds remain largely unexplored in vivo. Herein, we report in vivo PK studies of the widely used amyloid probe methoxy-X04 (MeX04) in transgenic 5xFAD and wild-type (WT) mice. In plasma, MeX04 shows comparable exposure between 5xFAD and WT mice, indicating no major genotype-dependent differences in systemic clearance. In contrast, brain exposure was markedly increased in 5xFAD mice, with higher brain Cmax and AUC parameters and slower washout, consistent with Aβ-dependent sequestration and retention in the AD brain tissue. Notably, fluorescence microscopy revealed that the fluorescence intensity of amyloid plaque-bound MeX04 closely mirrored the total brain concentration, and we employed ex vivo fluorescence intensity quantification to evaluate the PK of a related bis(styryl)benzene compound, LS-4, which is proposed to exhibit increased affinity for soluble Aβ aggregates. We then performed age-dependent ex vivo staining of compound-bound Aβ aggregates in 5xFAD brains, and LS-4 exhibits appreciable amyloid-bound fluorescence intensity in younger 5xFAD mice, consistent with its higher affinity for Aβ oligomers, whereas MeX04 exhibited stronger fluorescence intensity in older mice. Consequently, we propose an efficient approach to track temporal changes in the PK of Aβ-binding compounds by ex vivo evaluation of their amyloid-bound fluorescence intensity, providing a rapid assessment of the general PK trends of newly developed amyloid-binding probes.},
}

@article {pmid42331779,
year = {2026},
author = {Gao, TL and Geng, S and Chen, J and Yang, L and Nie, YJ and Yu, H and Chai, GS},
title = {Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04199-9},
pmid = {42331779},
issn = {2158-3188},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8[ + ]T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.},
}

@article {pmid42331820,
year = {2026},
author = {Gonzalez-Kozlova, E and Tichkule, S and Nose, Y and Chen, TY and Reznik, E and Santiago, JV and Korrapati, A and Soleymani, T and Kosoy, R and Figueiredo, I and Lee, D and Hoffman, GE and Kyprianou, N and Gordon, RE and Cordon-Cardo, C and Rangaraju, S and Seyfried, NT and Haroutunian, V and Fullard, JF and Roussos, P and Dogra, N},
title = {SECmeres outperform extracellular vesicles as potential blood RNA biomarkers for Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42331820},
issn = {2041-1723},
support = {NIH R21 AGO78848//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/genetics/diagnosis ; *Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *RNA/blood ; Brain/metabolism/pathology ; Female ; Male ; Blood-Brain Barrier/metabolism ; Aged, 80 and over ; Aged ; },
abstract = {Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or 'SECmeres'. We discovered that RNAs associated with SECmeres discriminated AD cases from controls with higher significance than small EVs, large EVs showed no differences. Discriminating RNAs were enriched in small EVs (Synaptotagmin, Alpha-synuclein, MAPT) or SECmeres (L1CAM, Syntaxin, Neurogranin), indicating distinct brain-derived signatures. Single-cell RNAseq deconvolution shows small EVs contain RNAs from diverse brain cells, whereas SECmeres enrich brain endothelial transcripts, lining cerebral blood vessels and forming the blood-brain barrier (BBB). These findings challenge the prevailing view that small EVs are the primary carriers of biomarkers. Collectively, our study shows that blood EVPs carry brain-specific information for liquid biopsy, pending validation in larger blinded clinical trials.},
}

Humans
*Alzheimer Disease/blood/genetics/diagnosis
*Biomarkers/blood
*Extracellular Vesicles/metabolism/genetics
*RNA/blood
Brain/metabolism/pathology
Female
Male
Blood-Brain Barrier/metabolism
Aged, 80 and over
Aged

@article {pmid42332025,
year = {2026},
author = {Korukonda, A and Weinshenker, D},
title = {A new hope: locus coeruleus-norepinephrine system at the nexus of neuropsychiatric symptoms.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42332025},
issn = {1476-5578},
support = {AG079199//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG062581//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG081046//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066511//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {The earliest stages of Alzheimer's disease (AD) are frequently characterized by neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, compulsivity, appetite dysregulation, and sleep disturbances, often preceding measurable cognitive decline. Evidence from clinical and animal studies implicates hyperactivity of the locus coeruleus-norepinephrine (LC-NE) system as a mechanistic driver of these behaviors. Here, we review noradrenergic circuits that can potentially underlie psychiatric disturbances to identify therapeutic targets for preventing and delaying onset of AD. Given that this system influences attention, arousal, mood, and stress responses, LC-NE hyperactivity across circuitry involving amygdala, thalamus, hypothalamus, anterior cingulate cortex, prefrontal cortex, and olfactory areas can contribute to NPS features in early AD. Advances in neuroimaging and physiological measures of noradrenergic function have enabled in vivo tracking of LC integrity and NE transmission, offering the opportunity to detect LC-NE dysfunction early in disease progression and potentially implement targeted pharmacologic and neuromodulatory interventions to restore optimal LC-NE tone. Overall, dissection of LC-NE circuitry and its clinical translation hold promise for developing biomarker-driven, stage-specific interventions to reduce NPS burden and enhance the efficacy of disease-modifying therapies in AD.},
}

@article {pmid42332177,
year = {2026},
author = {Tang, M and Fleming, E and Gu, J and Shi, H and Xu, Y and Gong, X},
title = {Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {42332177},
issn = {1559-0720},
support = {Grant No. SH2023078//the Zhenjiang Science and Technology Plan Project/ ; Grant No. JDYY2023009//the Medical Education Collaborative Innovation Fund of Jiangsu University/ ; Grant No. 32002235//the National Natural Science Foundation of China/ ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.},
}

@article {pmid42332290,
year = {2026},
author = {Zheng, M and Fang, Y and Na, L and Zhao, Q},
title = {Predicting piRNA-Disease Associations Based on Dual-View Learning and Multi-head Self-Attention Mechanism Fusion.},
journal = {Interdisciplinary sciences, computational life sciences},
volume = {},
number = {},
pages = {},
pmid = {42332290},
issn = {1867-1462},
support = {2025-MSLH-351//Science and Technology Plan Project of Liaoning Province/ ; LJ212410146026//Fundamental Research Funds for the Liaoning Universities/ ; },
abstract = {PIWI-interacting RNAs (piRNAs) are an important class of non-coding RNA molecules in epigenetic regulation. It plays a crucial role in maintaining genomic stability and inhibiting transposable elements, and have been proven to participate in various diseases by regulating gene expression and influencing signaling pathways. Traditional biological experimental methods have limitations such as low throughput, long cycles, and high costs, making them difficult to meet the requirements of large-scale systematic screening. In this study, we develop a predictive framework named PiDA-DVLSA. We integrate autoencoder, dual graph transformer, and multi-head self-attention mechanisms, and construct an end-to-end multimodal deep learning system. We use autoencoder to perform nonlinear dimensionality reduction and denoising on piRNA sequence features and disease phenotype semantic features, and extract potential representations with strong discriminative ability. Then, we use graph transformers to model the high-order topological relationships between nodes in isomorphic similar graphs, and input heterogeneous graph transformers to learn complex cross-entity interaction patterns in heterogeneous networks. Finally, we achieve adaptive fusion of multi-source information through multi-head self-attention mechanisms. PiDA-DVLSA performs excellently on the benchmark dataset, with AUC and AUPR reach 0.9437 and 0.9195, respectively, significantly outperform eight mainstream algorithms. In independent case validations for breast cancer, clioblastoma, and Alzheimer disease, our model successfully predicts multiple biologically significant potential associations, further confirming its practicality and effectiveness in real scientific research scenarios and providing a solid computational basis for future precision diagnostic and therapeutic applications. PiDA-DVLSA is freely available at https://github.com/zhaoqi106/PiDA-DVLSA .},
}

@article {pmid42332435,
year = {2026},
author = {He, W and Zhang, K and Jia, X and Lv, Y and Cheng, T and Han, L and Xia, Y and Zhang, X and Zhai, W and Yang, F and Wang, S and Jin, L},
title = {Design, Biological Characterization, and Discovery of the Brain-Penetrant NLRP3 Inhibitor Based on a [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold for the Treatment of Central Nervous System Diseases.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00839},
pmid = {42332435},
issn = {1520-4804},
abstract = {NLRP3 inflammasome is a critical cytosolic multiprotein complex central to the innate immune response. Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC; this scaffold recruits and activates pro-caspase-1. Active caspase-1 catalyzes the proteolytic maturation and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, and induces a programmed cell death called pyroptosis. Dysregulated or chronic NLRP3 inflammasome activation is a major driver of pathogenesis in a wide spectrum of peripheral inflammatory diseases, including gout, pericarditis, atherosclerosis, nonalcoholic steatohepatitis, and NLRP3 gain-of-function autoinflammatory disorders known as CAPS, as well as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein we described the discovery of NLRP3 inhibitors based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. Represented by compound 25, this scaffold exhibited exceptional potency, favorable physicochemical properties, and desirable pharmacokinetic profiles, including good brain penetration. Compound 25 showed potential as a candidate for the treatment of Parkinson's disease.},
}

@article {pmid42332490,
year = {2026},
author = {Wei, Y and Yang, B and Wang, J and Zhao, W and Dai, W and Xie, R and Zhang, L},
title = {Optimizing cardiovascular health to mitigate cognitive decline: Physical activity as a primary modifiable target.},
journal = {Medicine},
volume = {105},
number = {25},
pages = {e49246},
doi = {10.1097/MD.0000000000049246},
pmid = {42332490},
issn = {1536-5964},
support = {JSDW202233//Jiangsu Provincial Medical Key Discipline Cultivation Unit/ ; LKM2023044//Elderly Health Foundation of Jiangsu Province/ ; },
mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Aged ; *Exercise/physiology ; *Cardiovascular Diseases/complications/epidemiology/prevention & control ; Nutrition Surveys ; United States/epidemiology ; Neuropsychological Tests ; *Cognitive Dysfunction/prevention & control ; Cognition/physiology ; Middle Aged ; },
abstract = {Cardiovascular disease has been consistently associated with cognitive impairment; however, the relationship between Life's Essential 8 (LE8), a novel composite metric of cardiovascular health (CVH), and cognitive function in older adults remains inadequately characterized. This study aimed to investigate the cross-sectional association between LE8 scores and cognitive function among United States older adults and identify the relative contributions of individual LE8 components. We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey 2011 to 2014 cycles. A total of 2108 participants aged ≥ 60 years with complete cognitive assessment and LE8 data were included. Cognitive function was evaluated using 4 validated neuropsychological tests: Consortium to Establish a Registry for Alzheimer Disease Word Learning and Delayed Recall, animal fluency test, and Digit Symbol Substitution Test. Composite and domain-specific z-scores were computed. Weighted multiple linear regression models were employed to examine LE8-cognition associations, adjusting for demographic and clinical covariates. Weighted quantile sum regression was applied to determine the relative contribution weights of individual LE8 components. In fully adjusted models, each 10-point increment in LE8 score was associated with a 0.09-unit increase in composite cognitive z-score (95% confidence intervals: 0.04-0.14, P < .001). Compared with low CVH (LE8 < 50), high CVH (LE8 ≥ 80) demonstrated significantly higher cognitive z-scores (β = 0.41, 95% confidence intervals: 0.25-0.57, P < .001). Weighted quantile sum regression identified moderate physical activity as the predominant contributor (weight = 0.56) to cognitive performance, followed by blood glucose (0.19) and blood pressure (0.14). Higher LE8 scores are significantly associated with better cognitive function in older adults, with moderate physical activity emerging as the most influential modifiable factor. These findings underscore the potential of integrated CVH optimization as a strategy for cognitive preservation in aging populations.},
}

Humans
Female
Male
Cross-Sectional Studies
Aged
*Exercise/physiology
*Cardiovascular Diseases/complications/epidemiology/prevention & control
Nutrition Surveys
United States/epidemiology
Neuropsychological Tests
*Cognitive Dysfunction/prevention & control
Cognition/physiology
Middle Aged

@article {pmid42332537,
year = {2026},
author = {Ni, P and Zhao, B and Xv, H},
title = {Study on diagnostic genes and immune microenvironment disorder in comorbid atherosclerosis and Alzheimer disease.},
journal = {Medicine},
volume = {105},
number = {25},
pages = {e49470},
doi = {10.1097/MD.0000000000049470},
pmid = {42332537},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/genetics/immunology/diagnosis/epidemiology ; *Atherosclerosis/genetics/immunology/diagnosis/epidemiology ; Biomarkers ; Mendelian Randomization Analysis ; Early Growth Response Protein 2/genetics ; Machine Learning ; Protein Interaction Maps/genetics ; MicroRNAs/genetics ; Computational Biology ; Gene Expression Profiling ; Membrane Proteins/genetics ; },
abstract = {Atherosclerosis (AS) and Alzheimer disease (AD) are globally prevalent chronic diseases with challenges of difficult early diagnosis and a lack of effective combined therapies. This study explored their shared molecular mechanisms, potential diagnostic biomarkers, and immune microenvironment disorders. Using AS dataset GSE100927 and AD dataset GSE97760, key differentially expressed genes (key DEGs) were identified via bioinformatics (differential expression analysis, protein-protein interaction network, machine learning). A risk prediction model was built and validated with receiver operating characteristic/area under the curve. Immune infiltration was compared between patient and control groups; miRNA-transcription factor-mRNA and key DEGs-chemical networks were predicted, and key DEGs-AS/AD causal relationships verified by Mendelian randomization. Venn analysis found 89 common DEGs (enriched in lipid metabolism, Wnt pathway, etc). Four key DEGs (early growth response 2 [EGR2], leukocyte-specific transcript 1 [LST1], membrane-spanning 4-domains subfamily A member 7 [MS4A7], and 2'-5'-oligoadenylate synthetase like [OASL]) were confirmed. The model had high accuracy (C-index = 0.982, area under the curve > 0.9). Mendelian randomization showed EGR2 was an AS risk/AD protective factor; LST1 an AS risk factor; MS4A7 an AD risk factor; no clear OASL-AD causality. EGR2, LST1, MS4A7, and OASL are novel diagnostic biomarkers and potential therapeutic targets for comorbid AS and AD.},
}

Humans
*Alzheimer Disease/genetics/immunology/diagnosis/epidemiology
*Atherosclerosis/genetics/immunology/diagnosis/epidemiology
Biomarkers
Mendelian Randomization Analysis
Early Growth Response Protein 2/genetics
Machine Learning
Protein Interaction Maps/genetics
MicroRNAs/genetics
Computational Biology
Gene Expression Profiling
Membrane Proteins/genetics

@article {pmid42332710,
year = {2026},
author = {Liu, Y and Dai, Y and Pan, Y and Yang, X and Zhu, M and Diao, X and Ma, J and Huang, X and Zheng, F},
title = {Dynamic dementia risk before and after incident diabetes mellitus: a combined case-control and cohort study.},
journal = {BMC public health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12889-026-28216-0},
pmid = {42332710},
issn = {1471-2458},
support = {82373665//National Natural Science Foundation of China/ ; 2021-RC330-001//Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences/ ; },
abstract = {BACKGROUND: Evidence on the temporal dynamics of dementia risk before incident diabetes remains limited. We aimed to investigate the temporal pattern of dementia risk before and after incident diabetes, compared with matched controls.

METHODS: Case-control and cohort analyses were conducted by using data from the UK Biobank. Propensity score matching was performed to match participants with and without diabetes. Conditional logistic regression was adopted in case-control analysis to estimate dementia risk before incident diabetes. Cox proportional-hazard regression models were adopted in cohort analysis to estimate dementia risk following a diabetes diagnosis.

RESULTS: A total of 44,166 participants with diabetes and 132,498 matched diabetes-free participants were included. During the 10-year period before diabetes, dementia occurred in 344 (0.78%) participants who later had diabetes and 530 (0.40%) diabetes-free participants. Compared to participants without diabetes, the dementia risk was significantly higher in participants with diabetes (Odds Ratio [OR]: 2.14, 95% Confidence Interval [CI]: 1.83-2.50), with the ORs gradually increasing as the time approached the diagnosis date. The adjusted OR was 3.86 (95% CI: 3.11-4.80) for dementia in the 2 years before diabetes. After a diabetes diagnosis, a higher risk for dementia remained in participants with incident diabetes (Hazard Ratio [HR]: 1.82, 95%CI: 1.68-1.97). Similar results were found for Alzheimer's disease and vascular dementia (VD), with VD showing a risk of over 6-fold.

CONCLUSIONS: Dementia risk starts to increase 10 years before diabetes, and the 2-year period preceding diagnosis might represent a high-risk period that calls for closer cognitive monitoring for vulnerable individuals.},
}

@article {pmid42332766,
year = {2026},
author = {Bodde, HE and Poos, JM and Kolman, GHPR and Bosman, A and Willemsen, SP and Peetoom, K and Pijnenburg, YAL and Koopmans, R and Verhey, FRJ and de Vugt, ME and Bakker, C and , and Papma, JM},
title = {The prevalence and incidence of young onset dementia in the Netherlands: a prospective study in two catchment areas.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02120-6},
pmid = {42332766},
issn = {1758-9193},
support = {WE.09-2017-09//Gieskes-Strijbis Foundation/ ; WE.09-2017-09//Alzheimer Netherlands/ ; WE.09-2017-09//Dutch Young‑Onset Dementia Knowledge Centre/ ; 10510032120002/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Young-onset dementia (YOD), defined as dementia with symptom onset before the age of 65, is associated with distinct and often complex care needs that differ from those with late-onset dementia. Current national data on YOD incidence, prevalence, and demographic characteristics are limited, underscoring the importance of prospective studies to inform policy and tailored care services.

METHODS: We conducted two prospective one-year prevalence and incidence studies using active case-finding in two Dutch catchment areas, one urban and one more rural region, between 2020 and 2022. Individuals with YOD making use of care services were registered in an online database. Data on dementia subtype, living situation, and migration background were collected to explore regional variation.

RESULTS: We identified 372 individuals with YOD in the urban Rotterdam area, and 209 in the more rural Eindhoven-De Kempen area. Age-standardized prevalence per 100,000 individuals, standardized to the Dutch population, was 77.3 in the Rotterdam region, and 66.1 in the Eindhoven-De Kempen region for ages 30-69 years, and 46.3 and 36,9, respectively, for ages 30-64 years. Corresponding age-standardized incidence rates were 24.2 and 23.5 for ages 30-69 years, and 13.9 in both regions for ages 30-64 years. Alzheimer's disease was the most common diagnosis in both areas. Compared with Eindhoven-De Kempen, the Rotterdam region had significantly more vascular dementia cases (p < 0.05 for incidence, and p < 0.001 for prevalence) and longer diagnostic delays (2.2 vs. 1.3 years between first GP consultation and diagnosis). Most individuals lived at home (76.4% and 85.4% resp. in Rotterdam and Eindhoven-De Kempen) and 30.8% in Rotterdam and 12.5% in Eindhoven-De Kempen had a migration background. Extrapolation of incidence figures suggests that between 14,655 and 20,340 individuals were living with YOD in the Netherlands in 2021.

CONCLUSIONS: This study estimates the number of people living with YOD in the Netherlands. In addition, our findings show regional variation in dementia subtypes, a high proportion of people with YOD living at home, and a substantial proportion of people with YOD with a migration background. These insights underline the importance of region‑specific, person‑centered, culture sensitive YOD care at home.},
}