@article {pmid40571023,
year = {2025},
author = {Fu, J and Liang, Z and Chen, Z and Chen, W and Zhou, Y and Xiong, F and Meng, L and Liang, Q and Gao, H},
title = {Mechanism of Dendrobium officinale polysaccharide in alleviating Alzheimer's disease: Insights from metabolomics, lipidomics, and proteomics analysis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {145531},
doi = {10.1016/j.ijbiomac.2025.145531},
pmid = {40571023},
issn = {1879-0003},
abstract = {Dendrobium officinale, a traditional edible and medicinal plant, possesses significant medicinal and nutritional value. Specifically, the neuroprotective effect of Dendrobium officinale polysaccharide (DOP) has been increasingly recognized. However, the precise mechanism through which DOP exerts its neuroprotective effects remains incompletely elucidated. Accordingly, the present study integrated pharmacodynamics, serum metabolomics, lipidomics and hippocampal proteomics analyses to investigate the therapeutic effects of DOP and elucidate its underlying mechanisms in AD mice. Results showed that DOP significantly ameliorated cognitive impairment and hippocampal pathological damage in AD mice. Metabolomic and proteomic analyses revealed that DOP effectively reversed 43 differential metabolites (polar metabolites and lipids) and 137 different proteins. Joint analysis combined with Western blot validation suggests that the GnRH signaling pathway may function as a predominant neuroprotective mechanism associated with DOP. Collectively, this study provides novel evidence for DOP as a potential drug candidate for treating AD.},
}

@article {pmid40571020,
year = {2025},
author = {Hajipour, MJ and Rezvantalab, S and Mohammad-Beigi, H and Maleki, R and Ghezelbashan, G and Alyami, EM and Ramamoorthy, A and Maurizi, L},
title = {cis and trans isomers of phospho-tubulin-associated unit proteins differently affect amyloid aggregation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {145500},
doi = {10.1016/j.ijbiomac.2025.145500},
pmid = {40571020},
issn = {1879-0003},
abstract = {The co-localization of phospho-tau proteins (p-tau) and amyloid beta (Aβ) or alpha-synuclein (α-Syn) aggregates and their combined pathological impacts have been recognized in the brains of both human and animal models of Alzheimer's disease (AD) and Parkinson's disease (PD). The fibrillation of amyloidogenic proteins is a dynamic process that can be affected by the presence of other proteins and therefore, it's essential to reveal how the cross-interaction between Aβ or α-Syn with p-tau affects their amyloidogenesis. Using simulation studies, we showed that cis and trans conformations of phosphorylated tau (phosphorylated at Thr231) show different affinities to Aβ and α-Syn. Trans p-tau showed more favorable and stronger interaction with Aβ and α-Syn and accelerated their aggregation. Consistently, the experimental approaches demonstrated that trans p-tau considerably enhances the fibrillation of both Aβ (from ~7 h to ~30 min) and α-Syn (from ~10 h to ~1 h) in a concentration-dependent manner, whereas cis p-tau, a neurotoxic isomer and early driver of tauopathy, exhibited a less pronounced acceleratory effect on amyloid aggregation (from 7 h to 5 h for Aβ and from 7 h to 5 h for α-Syn).},
}

@article {pmid40570982,
year = {2025},
author = {Liu, XM and Liu, XD and Zhang, YQ and Liu, YT and Lv, LW and Wang, MH and Ren, Q and Liu, Y and Wu, MZ and Shi, YX and Zhang, YX and Li, B},
title = {Deciphering the Anti-senescent Effects of Clioquinol: Lifespan Prolongation, Metabolic Homeostasis, and Phenotypic Rehabilitation in Drosophila melanogaster.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.06.046},
pmid = {40570982},
issn = {1873-4596},
abstract = {Clioquinol (CQ), a halogenated 8-hydroxyquinoline, was once an oral antiparasitic for intestinal amoebiasis in the 1950s-1970s but was withdrawn due to neurotoxicity. Lately, it shows activities beyond antimicrobials, like in osteoarthritis and neurodegenerative diseases, yet its anti-aging effects are unclear. This study used Drosophila melanogaster to test CQ's effects on healthy aging and age-related diseases. Results showed CQ extended lifespan in normal or high-fat diet flies, enhanced stress resistance and glycolipid metabolism, improved motility, and prevented intestinal inflammation and obesity, and alleviated age-related digestive decline. In addition, CQ also prolonged lifespan and improved motor activity in Alzheimer's flies. Gene-deficient lifespan experiments and transcriptomic analysis revealed CQ's anti-aging mechanisms involving multiple signaling pathways, such as differential gene expression in HIF-1 signaling, Notch signaling, P53 signaling, JAK-STAT signaling, FOXO signaling, and IL-17 signaling pathway, activated TNF signaling and PI3K-Akt signaling pathway, and inhibited mTOR signaling pathway. Overall, CQ shows promise as a candidate for anti-aging interventions and treating aging-related diseases.},
}

@article {pmid40570808,
year = {2025},
author = {Fu, J and Zheng, Y and Dey, N and Ferreira, D and Moreno, R},
title = {Synthesizing individualized aging brains in health and disease with generative models and parallel transport.},
journal = {Medical image analysis},
volume = {105},
number = {},
pages = {103669},
doi = {10.1016/j.media.2025.103669},
pmid = {40570808},
issn = {1361-8423},
abstract = {Simulating prospective magnetic resonance imaging (MRI) scans from a given individual brain image is challenging, as it requires accounting for canonical changes in aging and/or disease progression while also considering the individual brain's current status and unique characteristics. While current deep generative models can produce high-resolution anatomically accurate templates for population-wide studies, their ability to predict future aging trajectories for individuals remains limited, particularly in capturing subject-specific neuroanatomical variations over time. In this study, we introduce Individualized Brain Synthesis (InBrainSyn), a framework for synthesizing high-resolution subject-specific longitudinal MRI scans that simulate neurodegeneration in both Alzheimer's disease (AD) and normal aging. InBrainSyn uses a parallel transport algorithm to adapt the population-level aging trajectories learned by a generative deep template network, enabling individualized aging synthesis. As InBrainSyn uses diffeomorphic transformations to simulate aging, the synthesized images are topologically consistent with the original anatomy by design. We evaluated InBrainSyn both quantitatively and qualitatively on AD and healthy control cohorts from the Open Access Series of Imaging Studies - version 3 dataset. Experimentally, InBrainSyn can also model neuroanatomical transitions between normal aging and AD. An evaluation of an external set supports its generalizability. Overall, with only a single baseline scan, InBrainSyn synthesizes realistic 3D spatiotemporal T1w MRI scans, producing personalized longitudinal aging trajectories. The code for InBrainSyn is available at https://github.com/Fjr9516/InBrainSyn.},
}

@article {pmid40570779,
year = {2025},
author = {Tolbatov, I and Marzo, T and Peana, M and Medici, S and Zoroddu, MA and La Mendola, D and Marrone, A},
title = {The binding of kojic acid dimer and its Zn(II) and Cu(II) complexes at the beta-amyloid peptide: A DFT-based computational assessment.},
journal = {Journal of inorganic biochemistry},
volume = {271},
number = {},
pages = {112979},
doi = {10.1016/j.jinorgbio.2025.112979},
pmid = {40570779},
issn = {1873-3344},
abstract = {The increasing number of people afflicted by Alzheimer's disease in the world requires a constant intensification of the efforts to seek for new agents capable of dismantling the molecular mechanisms underlying the onset and development of this neurodegenerative disorder. In this study, the binding of kojic acid dimer (KAD), and its adducts with Zn(II) and Cu(II) to the beta-amyloid peptide (Aβ) have been investigated by means of density functional theory-based computational approaches. We envisioned that the capability of KAD to inhibit the amyloid cascade may be exerted in concomitance and/or supported by the coordination of either Zn(II) or Cu(II). Thus, the structure and binding features of KAD-Zn and KAD-Cu metal complexes were computationally assessed to gain an atomistic insight of the possible Aβ inhibition. Our calculations evidenced that Zn(II), but not Cu(II), might act in concert with KAD in the binding of the Aβ peptide. Furthermore, we identified the Aβ13-20 region as a plausible binding site for KAD and KAD-Zn complexes, emphasizing its relevance for future experimental studies.},
}

@article {pmid40570412,
year = {2025},
author = {Melo, L and Silva, AMS and Albuquerque, HMT},
title = {The role of quinoline in the development of near-infrared fluorescent probes for diagnosis of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {296},
number = {},
pages = {117874},
doi = {10.1016/j.ejmech.2025.117874},
pmid = {40570412},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder, having some negative impacts, affecting memory and other cognitive abilities, caused by injuries in brain cells. It is widely accepted that early diagnosis is essential for the successful management of AD. Since the current diagnosing strategies for imaging Aβ and tau proteins face limitations, near-infrared fluorescence (NIRF) has been pursued as alternative for in vivo applications. As described in recent dedicated literature, quinoline (and its analogues) is a valuable scaffold for creating new fluorescent probes due to its compact molecular size, the presence of a nitrogen atom in its ring which enhances coordination properties, and its capacity to form hydrogen bonds, as well as the easy chemical manipulation to tune several properties. In recent years, numerous fluorescent probes incorporating this moiety have been developed. This review focuses on the quinoline moiety as key component of several fluorescent probes, highlighting their design strategies, optical characteristics, and in vitro and in vivo performance, based on their distinct detection mode such as aggregation induced emission (AIE), intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT).},
}

@article {pmid40570368,
year = {2025},
author = {Hung, C and Llorian, M and Pal, K and Livesey, FJ and Choudhary, J and Roumeliotis, TI and Patani, R},
title = {Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia.},
journal = {Cell reports},
volume = {44},
number = {7},
pages = {115867},
doi = {10.1016/j.celrep.2025.115867},
pmid = {40570368},
issn = {2211-1247},
abstract = {Nucleocytoplasmic transport defects are observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD. We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally observe the redistribution of mitochondria-related transcripts across AD and FTD neurons. The significantly increased mitochondrial RNA (mtRNA) in the cytosol of AD and FTD mutant neurons raised the possibility of leakage, which motivated us to investigate mtDNA leakage. We reveal abnormal cytoplasmic accumulation of mtDNA in AD and FTD cortical neurons together with evidence of mitochondrial aberrance. Importantly, mislocalisation of nucleic acids, mitochondrial dysfunction and cGAS-STING activation can be ameliorated through VCP D2 ATPase inhibition.},
}

@article {pmid40570367,
year = {2025},
author = {Podleśny-Drabiniok, A and Romero-Molina, C and Patel, T and See, WY and Liu, Y and Marcora, E and Goate, AM},
title = {Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.},
journal = {Cell reports},
volume = {44},
number = {7},
pages = {115909},
doi = {10.1016/j.celrep.2025.115909},
pmid = {40570367},
issn = {2211-1247},
abstract = {Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1 macrophages toward a transcriptional state reminiscent of disease-associated microglia and lipid-associated macrophages (LAM), collectively referred to as DLAM. Transcriptome profiling reveals gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing shows an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrate alterations in cell motility, phagocytosis, lysosomal activity, and metabolic profiles. These findings provide insights into cytokine-mediated reprogramming of macrophages toward disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.},
}

@article {pmid40570084,
year = {2025},
author = {Tosun, S and Karalı, FS and Eskioğlu, Eİ and Çınar, N and Macoir, J},
title = {Turkish Version of the Video-Naming Test for Assessing Verb Anomia (DVAQ-30): Normative Data for the Adult Turkish Population and Validation Study in Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {International journal of language & communication disorders},
volume = {60},
number = {4},
pages = {e70068},
doi = {10.1111/1460-6984.70068},
pmid = {40570084},
issn = {1460-6984},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/psychology/diagnosis/complications ; Turkey ; *Alzheimer Disease/psychology/diagnosis/complications ; Middle Aged ; Adult ; Reproducibility of Results ; Aged, 80 and over ; Reference Values ; *Anomia/diagnosis/psychology ; Psychometrics ; *Language Tests/standards ; *Neuropsychological Tests/standards ; Young Adult ; },
abstract = {OBJECTIVE: Compared to nouns, the impairment of the capacity of retrieving verbs in spoken production is much less documented. In the clinical field, there are also very few tests that have been developed specifically for verb anomia. Clinicians and researchers lack a concise and practical naming test to assess verb anomia, a condition that can occur in adults and the elderly due to various factors. The aim of this study was to adapt the Quebec Action Video Naming Test-30 items (DVAQ-30) into Turkish, establish its validity and develop normative data adapted to the Turkish population.

METHOD: This research consists of three studies. In Study 1, the DVAQ-30 was linguistically and culturally adapted to the Turkish language, resulting in the DVAQ-TR. In Study 2, a group of adults and older Turkish-speaking people were assessed with the DVAQ-TR to obtain normative data. In Study 3, the psychometric properties of the DVAQ-TR (known-group discriminant validity and convergent validity) were investigated by comparing the performance of healthy individuals and patients with mild cognitive impairment (MCI) or with Alzheimer's disease (AD).

RESULTS: Normative data were obtained based on the performance of 424 participants aged between 18 and 81 years. The percentiles were stratified according to the sociodemographic influencing variables of age, sex and level of education. The DVAQ-TR had good convergent validity and distinguished the performance of healthy participants from that of participants with MCI or AD.

CONCLUSIONS: The DVAQ-TR fills an important gap and has the capacity to assist clinicians and researchers in more accurately identifying acquired verb anomia, including in people with MCI or AD.

WHAT THIS PAPER ADDS: What is already known on this subject Verb anomia is a frequent symptom in various neurocognitive disorders, yet it remains under-assessed in clinical settings, especially compared to noun naming. Existing tools in Turkish primarily focus on object naming and often rely on static images, which may not effectively capture action concepts. Recent studies suggest that video-based assessments provide a more ecologically valid approach to verb naming evaluation. What this study adds to existing knowledge This study presents the Turkish adaptation and validation of the DVAQ-30, a video-based verb naming test, offering culturally and linguistically appropriate normative data for Turkish-speaking adults and elderly individuals. It also demonstrates that the DVAQ-TR successfully differentiates between healthy controls and individuals with MCI or Alzheimer's disease and shows good convergent validity with the Boston Naming Test. These findings highlight the clinical utility of the DVAQ-TR in detecting verb anomia in Turkish-speaking populations. What are the clinical implications of this study? The DVAQ-TR provides clinicians with a quick, valid, and culturally sensitive tool for assessing verb anomia in adults with suspected neurocognitive impairments. It enhances diagnostic accuracy and may inform tailored language intervention strategies in individuals with MCI and Alzheimer's disease. The availability of Turkish normative data ensures accurate interpretation of test results across different age, sex, and education groups.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/psychology/diagnosis/complications
Turkey
*Alzheimer Disease/psychology/diagnosis/complications
Middle Aged
Adult
Reproducibility of Results
Aged, 80 and over
Reference Values
*Anomia/diagnosis/psychology
Psychometrics
*Language Tests/standards
*Neuropsychological Tests/standards
Young Adult

@article {pmid40570073,
year = {2025},
author = {Buneeva, OA and Kapitsa, IG and Zavyalova, MG and Kaloshina, SA and Zgoda, VG and Medvedev, AE},
title = {The delayed effect of the neuroprotector fabomotizole on the brain proteome in rats with the rotenone model of parkinsonism.},
journal = {Biomeditsinskaia khimiia},
volume = {71},
number = {3},
pages = {217-226},
doi = {10.18097/PBMCR1586},
pmid = {40570073},
issn = {2310-6972},
mesh = {Animals ; Rotenone/toxicity ; Rats ; *Proteome/metabolism ; *Brain/metabolism/drug effects/pathology ; *Neuroprotective Agents/pharmacology ; Male ; Disease Models, Animal ; Rats, Wistar ; *Parkinsonian Disorders/metabolism/chemically induced/drug therapy ; *Nerve Tissue Proteins/metabolism ; *Parkinson Disease, Secondary/chemically induced/metabolism/drug therapy ; Benzimidazoles ; Morpholines ; },
abstract = {Fabomotizole is an original anxiolytic agent developed at the Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies that acts on a number of important receptor systems of the brain. In a model of Parkinson's disease induced in rats by a course of rotenone administration, fabomotizole attenuated manifestations of behavioral impairments and influenced the profile and relative content of brain proteins. Five days after the last administration of rotenone, the fabomotizole effect on the behavioral reactions of rats persisted. According to the proteomic study, the profile of brain proteins and changes in their relative content differed significantly from the results obtained immediately after the last administration of rotenone, as well as rotenone in combination with fabomotizole. Changes in the relative content of almost all proteins detected immediately after the last administration of rotenone or rotenone with fabomotizole were not detectable five days later. However, at this time point, there were changes in the relative content of other proteins associated with neurodegeneration in Parkinson's and Alzheimer's diseases. Such dynamics suggests a wave-like change in the content of pathogenetically important brain proteins involved in the mechanisms of neurodegeneration and neuroprotection.},
}

Animals
Rotenone/toxicity
Rats
*Proteome/metabolism
*Brain/metabolism/drug effects/pathology
*Neuroprotective Agents/pharmacology
Male
Disease Models, Animal
Rats, Wistar
*Parkinsonian Disorders/metabolism/chemically induced/drug therapy
*Nerve Tissue Proteins/metabolism
*Parkinson Disease, Secondary/chemically induced/metabolism/drug therapy
Benzimidazoles
Morpholines

@article {pmid40570023,
year = {2025},
author = {Scarmeas, N and Noriega De La Colina, A},
title = {The duality of disease: the Alzheimer's disease dilemma through the lens of nosos and asthenia.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf239},
pmid = {40570023},
issn = {1460-2156},
}

@article {pmid40569027,
year = {2025},
author = {Kumari, P and Kumar, D and Chopade, S and Karati, D},
title = {Exploring prodrug approaches for Alzheimer's treatment: an overview.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17582024.2025.2514990},
pmid = {40569027},
issn = {1758-2032},
abstract = {Alzheimer's disease (AD) is the largest global health burden among age-related conditions; it involves inflammation, plaque buildup, and oxidative stress combined with tangles that lead to brain atrophy and a decline in cognitive function. Though intensive research efforts have been focused on identifying the etiology of AD, its causative factors, especially concerning therapeutic interventions that can make a significant impact in this regard, are relatively vague due to several impediments such as the blood-brain barrier (BBB). Prodrugs and nanomedicine deliver new promising alternatives for drug administration over the BBB with better therapeutic results. This paper documents several prodrugs created for AD along with in vitro techniques for analyzing prodrug kinetics and recently developed nanotechnology-based delivery systems. The innovations discussed herein aim to enhance the bioavailability, stability, and activity of drugs toward offering better treatment opportunities as well as new research avenues against AD.},
}

@article {pmid40568877,
year = {2025},
author = {Li, N and Wang, S and Li, H and Liu, Z and Mo, H and Luan, J and Guo, N and Gou, X and Wu, Y and Li, Z},
title = {Gut Microbiota-Driven Metabolic Alterations Reveal the Gut-Brain Communication of Ergothioneine in Ameliorating Cognitive Impairment in APP/PS1 Mice.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c02557},
pmid = {40568877},
issn = {1520-5118},
abstract = {The pathogenesis of Alzheimer's disease (AD) is complex, and there are currently no effective therapeutic drugs available. Growing evidence suggested that dietary factors may play a vital role in the prevention and mitigation of AD. In this study, we investigated the effects of ergothioneine (ET), administered through drinking water for 6 months, on cognitive impairment in APPswe/PS 1dE9 (APP/PS1) mice. Treatment with ET (40 mg/kg) significantly enhanced cognitive function, reduced neuronal damage, decreased Aβ accumulation, suppressed microglial overactivation, and lowered TNF-α expression in the mouse brain. Moreover, ET treatment partially restored neurotransmitter and chemokine homeostasis in the brain. Notably, ET administration reshaped the gut microbiota of APP/PS1 mice, including increased abundance of Alistipes, Clostridiales_unclassified, and Peptococcaceae_unclassified. ET also enhanced the formation of butyric acid, isobutyric acid, and valeric acid. Serum metabolomic analysis revealed distinct metabolic profiles of APP/PS1 from wild-type (WT) mice, with sphingolipids and glycerophospholipids identified as the most enriched pathways influenced by ET treatment. Correlation analysis elucidated the alterations in gut microbiota networks, contributions of the gut microbiota to short-chain fatty acids and serum metabolic profiles, and mediatory roles of metabolites between the gut microbiota and AD. Altogether, this study elucidated the protective effects of ET on the gut-brain axis in AD, underscoring its potential as an early dietary intervention to improve memory function and alleviate AD symptoms. These findings provide a foundational and theoretical basis for the development of ET-based dietary strategies for AD prevention.},
}

@article {pmid40568677,
year = {2025},
author = {Shade, LM and Sharifitabar, M and Beiser, A and Satizabal, CL and Mosley, TH and Curran, JE and Bressler, J and Heckbert, SR and Hughes, TM and Austin, TR and Nasrallah, IM and Launer, LJ and Yanek, LR and Bis, JC and Doddapaneni, H and Gibbs, RA and Gabriel, S and Gupta, N and Viaud-Martinez, KA and Smith, AV and Opsasnick, LA and Ammous, F and Smith, JA and Arnett, DK and Kardia, SLR and Psaty, BM and Longstreth, WT and Mathias, RA and Nyquist, P and Rich, SS and Rotter, JI and Boerwinkle, E and DeCarli, CS and Glahn, DC and Blangero, J and Fornage, M and Fardo, DW and Seshadri, S and Sarnowski, C},
title = {Whole genome sequence association analysis of brain structural volume measures in the NHLBI TOPMed Program highlights novel loci in diverse participants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.11.25329426},
pmid = {40568677},
abstract = {Brain structural volumes are highly heritable and are linked to multiple neuropsychological outcomes, including Alzheimer's disease (AD). Genome-wide association studies have successfully identified genetic variants associated with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), and lateral ventricular volume (LVV). However, these studies mostly focused on common genetic variants with minor allele frequencies (MAF) > 1%, and individuals included in most of these studies were of predominantly European ancestry. Here, we performed whole-genome sequence (WGS) association studies of MRI brain volumes in 7,674 individuals of diverse race and ethnicity from the Trans-Omics for Precision Medicine (TOPMed) program. We identified novel genetic loci on chromosomes 13 and 16 near LINC00598 and CACNG3 associated with HV and TBV, respectively (lead variants rs115674829, P -value = 1.7×10 [-9] in pooled analysis and rs150440001, P -value = 6.6×10 [-9] in black participants). Both lead variant minor A alleles are rarer in white participants (MAF = 0.14% and 0.03%) and in Hispanic participants (MAF = 1.5% and 0.17%) but more common in black participants (MAF = 13% and 1.5%). Rare variant aggregated analyses identified RIPK1, a gene encoding a kinase involved in neuroinflammation and promising target for AD treatment, suggestively associated with LVV (P -value=5×10 [-6]). This study provides new insights into the genetic correlates of brain structural volumes and illustrates the importance of leveraging WGS data and cohorts of diverse race and ethnicity to better characterize the genetic architecture of complex polygenic traits.},
}

@article {pmid40568668,
year = {2025},
author = {Mendez, JS and Queme, B and Fu, Y and Morrison, J and Lewinger, JP and Kawaguchi, E and Mi, H and Obón-Santacana, M and Moratalla-Navarro, F and Martín, V and Moreno, V and Lin, Y and Bien, SA and Qu, C and Su, YR and White, E and Harrison, TA and Huyghe, JR and Tangen, CM and Newcomb, PA and Phipps, AI and Thomas, CE and Conti, DV and Wang, J and Platz, EA and Keku, TO and Newton, CC and Um, CY and Kundaje, A and Shcherbina, A and Murphy, N and Gunter, MJ and Dimou, N and Papadimitriou, N and Bézieau, S and van Duijnhoven, FJ and Männistö, S and Rennert, G and Wolk, A and Hoffmeister, M and Brenner, H and Chang-Claude, J and Tian, Y and Le Marchand, L and Cotterchio, M and Tsilidis, KK and Bishop, DT and Melaku, YA and Lynch, BM and Buchanan, DD and Ulrich, CM and Ose, J and Peoples, AR and Pellatt, AJ and Li, L and Devall, MA and Campbell, PT and Albanes, D and Weinstein, SJ and Berndt, SI and Gruber, SB and Ruiz-Narvaez, E and Song, M and Joshi, AD and Drew, DA and Petrick, JL and Chan, AT and Giannakis, M and Hsu, L and Peters, U and Gauderman, WJ and Stern, MC},
title = {Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.13.25329599},
pmid = {40568668},
abstract = {BACKGROUND: High intake of red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported 204 variants (G) associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways and constructed pathway-based Polygenic Risk Scores (pPRS) to model pPRS x environment (E) interactions.

METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls of European ancestry from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. The 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red or processed meat intake in relation to CRC risk.

RESULTS: A total of 30 variants were overrepresented in four pathways: Alzheimer disease-presenilin, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF- β signaling. We found a significant interaction between TGF- β -pPRS and red meat intake (p = 0.003). When variants in the TGF- β pathway were assessed, significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5 , Chr6) (p = 0.013 & 0.011, respectively) were observed. We did not find evidence of pPRS x red meat interactions for other pathways or with processed meat.

CONCLUSIONS: This pathway-based interaction analysis revealed a significant interaction between variants in the TGF- β pathway and red meat consumption that impacts CRC risk.

IMPACT: These findings shed light into the possible mechanistic link between CRC risk and red meat consumption.

IMPACT STATEMENT: In this work, we developed pathway-based Polygenic Risk Scores, which for the first time suggested, that red meat intake interacts with variants overrepresented in TGF- β signaling pathway to increase colorectal cancer risk.},
}

@article {pmid40568661,
year = {2025},
author = {Mansel, CO and Ghisays, V and Mahnken, JD and Swerdlow, RH and Reiman, EM and Karnes, JH and Denny, JC and Veatch, OJ},
title = {Downward bias in the association between APOE and Alzheimer's Disease using prevalent and by-proxy disease sampling in the All of Us Research Program.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.22.25328175},
pmid = {40568661},
abstract = {BACKGROUND: Recent genome-wide association studies (GWAS) for Alzheimer's Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by 1) including non-age-matched controls and prevalent cases, and/or 2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example.

METHODS: Participants in the All of Us Research Program over the age of 49 at enrollment (n=258,693) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). Dementia diagnoses were determined using available Electronic Health Records (EHR) and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression.

RESULTS: The mean age of the cohort was 67±10 years, and it was 58% female; 63% clustered predominantly with European genetic reference populations. Among the participants, 3,107 (1.2%) had prevalent ADRD, 301 (0.1%) had incident ADRD, and 19,910 (7.7%) reported a family history of ADRD (proxy ADRD). Both prevalent and proxy ADRD had attenuated associations with APOE genotype compared to incident ADRD. The adjusted generalized ratio (95% CI) (AGR) for incident ADRD for APOE ε4 heterozygotes was 2.95 (2.31-3.74) compared to 2.10 (1.96-2.24) and 1.42 (1.32-1.55) for proxy and prevalent ADRD, respectively. For APOE ε4 homozygotes, the effect sizes were even more different. Furthermore, APOE association effect sizes increased when restricting the control (no ADRD) group to older age brackets.

CONCLUSIONS: Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us , with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.},
}

@article {pmid40568659,
year = {2025},
author = {Ramsden, CE and Horowitz, MS and Zamora, D and Beach, TG and Serrano, GE and Arce, RA and Sedlock, A and Nagle, S and Shou, RQ and Indig, FE and Davis, JM and Maric, D},
title = {Evidence for ApoE receptor 2-Disabled homolog-1 pathway disruption in the amygdala in sporadic Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.13.25329511},
pmid = {40568659},
abstract = {INTRODUCTION: The ApoE receptor 2-Disabled homolog-1 (ApoER2-Dab1) pathway suppresses Tau phosphorylation as part of a multi-arm pathway that regulates cytoskeletal and synaptic integrity. We previously showed that multiple ApoER2-Dab1 pathway components accumulate in regions affected in early Alzheimer's disease (AD). Since the amygdala is a hub for emotional regulation and fear memory, we hypothesized that accumulation of ApoER2-Dab1 components in amygdala may correlate with cognitive or neuropsychiatric manifestations of AD.

METHODS: We used single-marker and multiplex immunohistochemistry to label ApoER2-Dab1 components in amygdala from 32 cases spanning the clinicopathological spectrum of AD.

RESULTS: Seven ApoER2-Dab1 pathway components accumulated in amygdala and correlated with histological progression and cognitive or neurobehavioral deficits in AD. ApoER2-Dab1 components accumulated within ApoER2-expressing neurons and dystrophic neurites surrounding ApoE-enriched extracellular plaques.

DISCUSSION: Findings add to growing evidence implicating ApoER2-Dab1 disruption in neurodegeneration and suggest that ApoER2-Dab1 disruption in amygdala may contribute to neuropsychiatric manifestations of AD.},
}

@article {pmid40568416,
year = {2025},
author = {Zhao, S and Scholcz, A and Rouse, MA and Klar, VS and Ganse-Dumrath, A and Toniolo, S and Broulidakis, MJ and Lambon Ralph, MA and Rowe, JB and Garrard, P and Thompson, S and Irani, SR and Manohar, SG and Husain, M},
title = {Self- versus caregiver-reported apathy across neurological disorders.},
journal = {Brain communications},
volume = {7},
number = {3},
pages = {fcaf235},
pmid = {40568416},
issn = {2632-1297},
abstract = {Apathy is a prevalent and persistent neuropsychiatric syndrome across many neurological disorders, significantly impacting both patients and caregivers. We systematically quantified discrepancies between self- and caregiver-reported apathy in 335 patients with a variety of diagnoses, such as frontotemporal dementia (behavioural variant and semantic dementia subtypes), Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Alzheimer's disease dementia, mild cognitive impairment, small vessel cerebrovascular disease, subjective cognitive decline and autoimmune encephalitis. Using the Apathy Motivation Index (AMI) and its analogous caregiver version (AMI-CG), we found that caregiver-reported apathy consistently exceeded self-reported levels across all conditions. Moreover, self-reported apathy accounted for only 14.1% of the variance in caregiver ratings. This apathy reporting discrepancy was most pronounced in conditions associated with impaired insight, such as behavioural variant frontotemporal dementia, and was significantly correlated with cognitive impairment. Deficits in memory and fluency explained an additional 11.2% of the variance in caregiver-reported apathy. Specifically, executive function deficits (e.g. indexed by fluency) and memory impairments may contribute to behavioural inertia or recall of it. These findings highlight the need to integrate patient and caregiver perspectives in apathy assessments, especially for conditions with prominent cognitive impairment. To improve diagnostic accuracy and deepen our understanding of apathy across neurological disorders, we highlight the need for adapted apathy assessment strategies that account for cognitive impairment particularly in individuals with insight or memory deficits. Understanding the cognitive mechanisms underpinning discordant apathy reporting in dementia might help inform targeted clinical interventions and reduce caregiver burden.},
}

@article {pmid40568304,
year = {2025},
author = {Blanc, F and Bouteloup, V and Paquet, C and Chupin, M and Pasquier, F and Gabelle, A and Ceccaldi, M and de Sousa, PL and Krolak-Salmon, P and David, R and Fischer, C and Dartigues, JF and Wallon, D and Moreaud, O and Sauvée, M and Belin, C and Roubaud Baudron, C and Botzung, A and Ravier, A and Demuynck, C and Namer, I and Habert, MO and Bousiges, O and Schorr, B and Muller, C and Philippi, N and Chêne, G and Cretin, B and Mangin, JF and Dufouil, C},
title = {Faster decline of very prodromal dementia with Lewy bodies when amyloid positive.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {2},
pages = {e70141},
pmid = {40568304},
issn = {2352-8729},
abstract = {INTRODUCTION: The cognitive and neuroimaging evolution during dementia with Lewy bodies (DLB) from the prodromal phase (Pro-DLB; subjective cognitive impairment [SCI] to mild cognitive impairment [MCI]) according to amyloid beta (Aβ) status is poorly understood.

METHODS: The decline of Lewy-Memento patients with SCI or MCI was compared according to Aβ status across four groups: Pro-DLB, prodromal Alzheimer's disease (Pro-AD), Pro-DLB+AD, and a group without prodromal DLB and AD (no symptoms [NS]). We observed the evolution of cognitive, functional, quality of life measures, brain volumetry, and metabolism on fluorodeoxyglucose positron emission tomography.

RESULTS: In the Pro-DLB and Pro-DLB+AD groups, Aβ+ patients had more cognitive and functional decline than the Aβ- patients. In the Pro-AD and NS groups, Aβ+ patients had more functional decline. Aβ+ Pro-AD showed a greater volume decline of the brain (left insula).

DISCUSSION: The presence of amyloid lesions worsens very prodromal DLB patients over time, both cognitively and functionally, but without increasing atrophy.

HIGHLIGHTS: Patients at a very prodromal stage, subjective cognitive impairment or mild cognitive impairment, had a clinical diagnosis of either prodromal Alzheimer's disease (Pro-AD), prodromal dementia with Lewy bodies (Pro-DLB), Pro-DLB+AD, or no diagnosis.Amyloid beta positive (Aβ+) patients had more functional decline, whatever the group.Aβ+ DLB patients (Pro-DLB and Pro-DLB+AD) had more global cognitive (Mini-Mental State Examination) decline.Aβ+ Pro-AD patients showed a greater volume decline of the left insula.},
}

@article {pmid40568182,
year = {2025},
author = {Maboudi, M and Soleymani, E and Banimostafavi, ES and Kordi, S and Adelani, M and Zakariaei, Z and Fakhar, M},
title = {Coexistence of Tuberculosis and Lophomoniasis in a Patient With Alzheimer's Disease.},
journal = {Respirology case reports},
volume = {13},
number = {6},
pages = {e70248},
pmid = {40568182},
issn = {2051-3380},
abstract = {The coexistence of lophomoniasis and tuberculosis (TB), both airborne diseases, is relatively uncommon. Co-infections like these can complicate treatment strategies due to overlapping symptoms and potential drug interactions. We report a rare case of comorbidity involving two pulmonary diseases, lophomoniasis and TB, in an 82-year-old woman with Alzheimer's disease (AD) from northern Iran. Her primary symptoms included weakness, lethargy, dyspnea, sputum production, night sweats, and significant weight loss. Both TB and lophomoniasis can compromise the immune system, potentially worsening the progression or severity of AD by increasing susceptibility to infections or enhancing neuroinflammation. Following the prescription of appropriate drug regimens for both diseases, the patient was discharged from the hospital in stable condition. Overall, it is crucial to consider lophomoniasis in the differential diagnosis of patients with pulmonary tuberculosis, especially in endemic areas where both infections are prevalent, to ensure timely diagnosis and effective management.},
}

@article {pmid40568171,
year = {2025},
author = {Reineke, LC and Zhu, PJ and Dalwadi, U and Dooling, SW and Liu, Y and Wang, IC and Young-Baird, S and Okoh, J and Kuncha, SK and Zhou, H and Kannan, A and Park, H and Debeaubien, NA and Croll, T and Lee, DJ and Arthur, C and Dever, TE and Walter, P and Chen, J and Frost, A and Costa-Mattioli, M},
title = {Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.28.640897},
pmid = {40568171},
issn = {2692-8205},
abstract = {The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B [R658C] genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in Ppp1r15b [R658C] mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions-including Down syndrome, Alzheimer's disease and aging-but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.},
}

@article {pmid40568106,
year = {2025},
author = {Xiao, L and Sharma, P and Yang, X and Abebe, D and Loh, YP},
title = {Neurotrophic Factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's Disease mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.04.657876},
pmid = {40568106},
issn = {2692-8205},
abstract = {BACKGROUND: The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic Factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology AD mouse models However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

METHODS: AAV-human NF-α1/CPE and a non-enzymatic form, NF-α1/CPE -E342Q were delivered into hippocampus of 3xTg-AD mice and effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of hippocampus of 3xTg-AD mice with and without AAV-NF-α1/CPE treatment was carried out.

RESULTS: Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and increase in activated microglia in 3xTg-AD mice, indicating its action is independent of its enzymatic activity. Quantitative proteomic analysis of hippocampus of 3xTg-AD mice that underwent NF-α1/CPE gene therapy revealed differential expression of >2000 proteins involving many metabolic pathways. Of these, two new proteins down-regulated by NF-α1/CPE: Nexin4 (SNX4) and Trim28 which increase Aβ production and tau levels, respectively were identified. Western blot analysis verified that they were reduced in AAV-NF-α1/CPE treated 3xTg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as top signaling pathway altered as a response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3xTg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple proteins known to be markers of autophagy were down-regulated in 3xTg-AD mice, accounting for impaired autophagy. Expression of these proteins were upregulated in 3xTg-AD mice with NF-α1/CPE gene therapy, thereby reversing autophagic impairment.

CONCLUSIONS: This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3xTg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment.},
}

@article {pmid40568088,
year = {2025},
author = {Klaisner, S and Hao, Y and Beilina, A and Park, JH and Li, Z and Iba, M and Tindall, C and Jin, B and Epstein, J and Kowal, I and Pantazis, CB and Carmiol, N and Jarreau, P and Washecka, N and Weller, C and Nalls, MA and Van Keuren-Jensen, K and Singleton, AB and Cookson, MR and Qi, YA},
title = {Large-scale HLA immunopeptidome and interactome profiling in microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.23.650327},
pmid = {40568088},
issn = {2692-8205},
abstract = {Microglia are immune cells of the brain and act as major antigen presenting cells. Antigen presentation involves the human leukocyte antigen (HLA) complex, which is implicated in genetic risk of multiple neurodegenerative diseases. How HLA affects the function of microglia in the context of neurodegenerative disease remains unclear. Here, we investigated the HLA epitopes and their protein interactome in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGLs) using systematic mass spectrometry (MS)-based immunopeptidomics, whole-cell proteomics, affinity purification, and prediction algorithms. Our results revealed the presence of almost 7,000 peptides presented by HLA class I and II within microglia. We further showed that the immunopeptidome landscapes of iPSCs, iMGLs and interferon-gamma (IFNγ) stimulated iMGLs are all readily distinguishable. Furthermore, HLA interacts with different groups of proteins in iPSCs compared to iMGLs which involve proteins in immune response. Importantly, we detected 25 HLA epitopes derived from 15 genes associated with Alzheimer's and related dementias such as Tau, PLD3 (Alzheimer's disease), TDP-43, FUS (Frontotemporal dementia), and PARK7, VPS35 (Lewy Body dementia). We predicted 31 mutant epitopes derived from these ADRD genes that could be presented with strong interaction to HLA molecules. Along with these epitopes, we observed an enrichment of immune-related interaction proteins in microglia treated with IFNγ. These results provide evidence that aggregated and mutated proteins can interact with HLA alleles and be presented on the cell surface by microglia cells. This study sheds light on the antigen presenting and adaptive immunity mechanism within the central nervous system and its possible effects on neurodegenerative diseases.},
}

@article {pmid40567948,
year = {2025},
author = {Pozzi, FE and Falco, A and Gotti, G and Fiamingo, G and Remoli, G and Appollonio, I and Ferrarese, C and Tremolizzo, L},
title = {Neurological soft signs in neurodegenerative dementias: Results of the DemeNSS study.},
journal = {PCN reports : psychiatry and clinical neurosciences},
volume = {4},
number = {2},
pages = {e70143},
pmid = {40567948},
issn = {2769-2558},
abstract = {AIM: Neurological soft signs (NSSs) encompass subtle neurological abnormalities, often indicative of impaired motor and sensory integration, observed in various neuropsychiatric conditions. NSSs have been recently investigated as potential diagnostic markers in neurodegenerative dementias. We aimed to confirm an NSS increase in subjects with cognitive decline and evaluate them in the differential diagnosis of neurodegenerative dementias.

METHODS: A sample of 93 subjects with dementia (34 with Alzheimer's disease [AD], 29 with frontotemporal dementia [FTD], 16 with Lewy body disease [LBD], and 14 with corticobasal syndrome [CBS]) and 93 healthy controls (HCs) were assessed using the 16-item Heidelberg NSS Scale.

RESULTS: Subjects with neurodegenerative dementias exhibited significantly higher NSS scores than HCs (20.4 ± 7.9 vs. 5.7 ± 4.2, p < 0.01). Notably, those with CBS/LBD showed markedly elevated NSSs compared to those with AD and FTD (26.2 ± 6.7 vs. 18.4 ± 7.1 and 16.6 ± 6.5, respectively, p < 0.01). Diagnosis, Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and anticholinergic burden were significant predictors of NSS expression in subjects with dementia. In HCs, only age and MMSE were significant predictors. A reduced Neurological Soft Signs (rNSS) Scale, including only five items that can be administered in less than a minute, demonstrated diagnostic performances comparable to the full NSS Scale.

CONCLUSION: NSSs are increased across neurodegenerative dementia subtypes, particularly in CBS and LBD. The Heidelberg NSS Scale, as well as its variant rNSS, may serve as quick and informative tools to be added to the visits in memory clinics.},
}

@article {pmid40567913,
year = {2025},
author = {Paulsen, AJ and Driscoll, I and Breidenbach, BM and Glittenberg, M and Lose, SR and Ma, Y and Sager, MA and Carlsson, CM and Gallagher, CL and Hermann, BP and Blennow, K and Zetterberg, H and Asthana, S and Johnson, SC and Betthauser, TJ and Christian, BT and Cook, DB and Okonkwo, OC},
title = {The impact of estimated cardiorespiratory fitness on Alzheimer's disease biomarkers and their relationships with cognitive decline.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70122},
pmid = {40567913},
issn = {2352-8737},
abstract = {INTRODUCTION: The accumulation of core Alzheimer's disease (AD) pathology contributes to cognitive decline. Cardiorespiratory fitness (CRF) influences AD pathological progression resulting in improvement or maintenance of cognitive function with age. CRF-related differences in accumulation rates or risk of reaching clinically relevant AD biomarker levels, and potentially interactive effects of core AD pathology and CRF on cognitive decline, remain largely unknown.

METHODS: Participants (N = 533; MeanAGE = 65, 70% female) from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention underwent serial blood draws, and cognitive and imaging assessments (MeanFollow-up = 6.0 years). Positron emission tomography (PET) imaging of amyloid beta (Aβ) and tau (T) and plasma phosphorylated tau-217 (p-tau217) were used to determine biomarker status (±). Sex-specific estimated CRF (eCRF) tertiles were created using a validated equation. Kaplan-Meier survival curves and Cox proportional hazards examined the risk of becoming biomarker-positive. Linear mixed-effects models, stratified by biomarker status, estimated associations between baseline eCRF and core AD biomarker accumulation, and whether eCRF modified relationships between biomarker accumulation and cognitive decline.

RESULTS: There were no significant relationships between eCRF and biomarker trajectories. However, those in high eCRF group who were Aβ- at baseline had a significantly lower risk of becoming biomarker-positive (Aβ-PET: HR, 95% confidence interval [CI] = 0.42, 0.20-0.88; p-tau-217: 0.45, 0.21-0.97) compared to the low eCRF group. The detrimental relationship between Aβ accumulation and cognitive decline was significantly attenuated for Aβ+/T+ with high eCRF.

DISCUSSION: Although eCRF did not influence core AD biomarker accumulation trajectories, high eCRF seems protective against becoming biomarker-positive and attenuates the known deleterious relationship between biomarker accumulation and cognitive decline in Aβ+/T+.

HIGHLIGHTS: High estimated cardiorespiratory fitness (eCRF) is associated with a lesser likelihood of becoming AD biomarker positive.High eCRF did not alter biomarker accumulation in those positive for Alzheimer's disease (AD) pathology.High eCRF attenuated the relationship between AD biomarkers and cognitive decline.Innovative methods: Stratifying analyses by amyloid beta and tau status.},
}

@article {pmid40567815,
year = {2025},
author = {Wang, Y and Zhu, T and Cheng, Q and Cui, X and Zhang, P and Lu, Z and , },
title = {Predicting brain health in community-dwelling elderly populations by integrating Gaussian mixture model and plasma biomarkers.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251331110},
pmid = {40567815},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, and early screening is crucial for intervention.

OBJECTIVE: Currently, early screening for older adults without dementia primarily rely on cognitive scale. This study aims to explore a more feasible approach.

METHODS: Plasma biomarkers (Aβ42/40, p-tau181 and p-tau217) and Gaussian mixture models (GMM) were utilized for stratifying risk levels in older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative. Linear mixed effects model was employed to compare subsequent pathological and cognitive changes, alongside a comparison with traditional scale-based screening methods. Cox regression model was used to assess the risk of progression to dementia across different biomarker status groups.

RESULTS: Plasma Aβ42/40 and p-tau217 effectively predicted Aβ PET pathological progression, while p-tau217 also predicted tau PET changes. All three biomarkers could forecast the progression of FDG PET and cognitive function. P-tau217 and p-tau181 significantly modulated pathology-related cognitive impairment. All three biomarkers could predict dementia risk. The screening method combining GMM with plasma biomarkers demonstrates superior predictive ability compared to traditional scale-based approaches.

CONCLUSIONS: Our study indicated that the combination of GMM and plasma biomarkers for community screening shows promising potential in monitoring brain health among older adults without dementia. P-tau217 exhibited the best predictive value among the three plasma biomarkers.},
}

@article {pmid40567814,
year = {2025},
author = {Du, L and Li, G and Wei, Y and Han, G},
title = {γ-secretase targeting in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251349529},
pmid = {40567814},
issn = {2542-4823},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and is characterized by memory loss and cognitive decline. The amyloid cascade hypothesis posits that the pathogenesis of AD is initiated by the oligomerization and accumulation of toxic amyloid-β (Aβ) peptides within the brain. The aspartic protease γ-secretase, which catalyzes the final step in the cellular production of Aβ peptides, has been identified as a potential target for anti-amyloid intervention strategies. This target has attracted increasing attention in recent years, and novel small molecules have been developed as selective γ-secretase inhibitors and γ-secretase modulators. This review aims to discuss the role of γ-secretase protein hydrolysis activity in the pathogenesis of AD and to review the molecular mechanisms and prospects for the future development of strategies that target γ-secretase to intervene in AD development, which is expected to provide new ideas for the treatment of AD.},
}

@article {pmid40567778,
year = {2025},
author = {Li, J and Liu, J and Su, Y and Chang, J and Ye, M},
title = {Classification of the stages of Alzheimer's disease based on three-dimensional lightweight neural networks.},
journal = {PeerJ. Computer science},
volume = {11},
number = {},
pages = {e2897},
pmid = {40567778},
issn = {2376-5992},
abstract = {Alzheimer's disease is a neurodegenerative disease that seriously threatens the life and health of the elderly. This study used three-dimensional lightweight neural networks to classify the stages of Alzheimer's disease and explore the relationship between the stages and the variations of brain tissue. The study used CAT12 to preprocess magnetic resonance images of the brain and got three kinds of preprocessed images: standardized images, segmented standardized gray matter images, and segmented standardized white matter images. The three kinds of images were used to train four kinds of three-dimensional lightweight neural networks respectively, and the evaluation metrics of the neural networks are calculated. The accuracies of the neural networks for classifying the stages of Alzheimer's disease (cognitively normal, mild cognitive impairment, Alzheimer's disease) in the study are above 96%, and the precisions and recalls of classifying the three stages are above 94%. The study found that for the classification of cognitively normal, the best classification results can be obtained by training with the segmented standardized gray matter images, and for mild cognitive impairment and Alzheimer's disease, the best classification results can be obtained by training with the standardized images. The study analyzed that in the process of cognitively normal to mild cognitive impairment, variations in the segmented standardized gray matter images are more obvious at the beginning, while variations in the segmented standardized white matter images are not obvious. As the disease progresses, variations in the segmented standardized white matter images tend to become more significant, and variations in the segmented standardized gray matter images and white matter images are both significant in the development of Alzheimer's disease.},
}

@article {pmid40567454,
year = {2025},
author = {Sawada, Y and Satoh, T and Saba, H and Kato, Y and Kuwada, T and Shima, S and Murakami, K and Sasaki, M and Abe, Y and Harano, K},
title = {Assessment of localized brain regions correlated with MMSE using VBM analysis of structural MRI in a Japanese sample.},
journal = {Neuroimage. Reports},
volume = {5},
number = {2},
pages = {100264},
pmid = {40567454},
issn = {2666-9560},
abstract = {The global aging population has led to a significant rise in dementia and cognitive decline, with Alzheimer's disease as the primary cause. Early detection of mild cognitive impairment (MCI), a prodromal stage of dementia, is critical for timely intervention. The Mini-Mental State Examination (MMSE) is commonly used for cognitive screening, yet its limitations-such as ceiling effects and educational biases-may hinder the early identification of subtle cognitive impairments. This cross-sectional study employed voxel-based morphometry (VBM) analysis of structural magnetic resonance imaging (MRI) to explore brain regions positively correlated with MMSE scores in a cohort of 510 participants. Significant gray matter volume (GMV) reductions were observed in the bilateral lateral frontal lobes, left medial frontal lobe, left hippocampus, left anterior cingulate cortex (ACC), and bilateral inferior temporal gyri in association with lower MMSE scores. Participants were classified into three groups-Normal Cognition (NC), MCI, and Dementia (D)-based on MMSE cutoff values. Compared to the NC group, the MCI group exhibited significant GMV reductions in the left hippocampus, left parahippocampal gyrus, left ACC, and right ventromedial prefrontal cortex (vmPFC). The D group showed further GMV reductions in the bilateral hippocampus and left inferior temporal gyrus compared to the MCI group. These findings highlight the clinical utility of VBM-based structural MRI in assessing localized brain atrophy associated with cognitive decline, supporting its potential role in early diagnosis and intervention for MCI. Further research integrating longitudinal studies and multimodal biomarkers is warranted to enhance diagnostic accuracy.},
}

@article {pmid40567448,
year = {2025},
author = {Blujus, JK and Cole, MW and Festa, EK and Buka, SL and Salloway, SP and Heindel, WC and Oh, H and , },
title = {Functional redundancy of the posterior hippocampi is selectively disrupted in non-demented older adults with β-amyloid deposition.},
journal = {Neuroimage. Reports},
volume = {5},
number = {2},
pages = {100255},
pmid = {40567448},
issn = {2666-9560},
abstract = {Several neural mechanisms underlying resilience to Alzheimer's disease (AD) have been proposed, including redundant neural connections between the posterior hippocampi and all other brain regions, and global functional connectivity of the left frontal cortex (LFC). Here, we investigated if functional redundancy of the hippocampus (HC) and LFC underscores neural resilience in the presence of early AD pathologies. From the ADNI database, cognitively normal older adults (CN) (N = 220; 36 % Aβ+) and patients with Mild Cognitive Impairment (MCI) (N = 143; 51 % Aβ+) were utilized. Functional redundancy was calculated from resting state fMRI data using a graph theoretical approach by summing the direct and indirect paths (path lengths = 1-4) between each region of interest and its 263 functional connections. Posterior HC, but not anterior HC or LFC, redundancy was significantly lower in Aβ+ than Aβ-groups, regardless of diagnosis. Posterior HC redundancy related to higher education and better episodic memory, but it did not moderate the Aβ-cognition relationships across the diagnostic groups. Together, these findings suggest that posterior HC redundancy captures network disruption that parallels selective vulnerability to Aβ deposition. Further, our findings indicate that functional redundancy may underscore a network metric different from global functional connectivity of the LFC.},
}

@article {pmid40567363,
year = {2025},
author = {Adnan, M and Siddiqui, AJ and Bardakci, F and Surti, M and Badraoui, R and Patel, M},
title = {Neuroprotective potential of quercetin in Alzheimer's disease: targeting oxidative stress, mitochondrial dysfunction, and amyloid-β aggregation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1593264},
pmid = {40567363},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) peptide accumulation, oxidative stress, mitochondrial dysfunction and cholinergic deficits, all of which contribute to neuronal damage and cognitive decline.

METHODS: This study investigated the neuroprotective potential of quercetin, a natural flavonoid, in human neuroblastoma SH-SY5Y cells exposed to Aβ-induced toxicity. Various assays were conducted to evaluate cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), acetylcholinesterase (AChE) activity and Aβ aggregation.

RESULTS: Quercetin significantly enhanced cell viability and reduced oxidative stress by lowering intracellular ROS levels. It preserved mitochondrial integrity by stabilizing ΔΨm and inhibited AChE activity, thereby supporting cholinergic function. Additionally, quercetin reduced Aβ aggregation and the formation of toxic amyloid fibrils.

DISCUSSION: These findings suggest that quercetin confers neuroprotection by targeting multiple pathological mechanisms involved in AD, including oxidative stress, mitochondrial dysfunction, AChE activity and Aβ aggregation. Quercetin demonstrates promise as a natural therapeutic agent for the treatment of AD. However, further in-vivo investigations and clinical studies are warranted to validate these findings and explore its translational potential.},
}

@article {pmid40567342,
year = {2025},
author = {Kelechi Wisdom, E and Soyemi, T and Mayowa, S and Ede, NS and Ubalaeze Solomon, E and Iloanusi, CA and Agbo, CE and Suzan Idogen, O and Augustine Ikechukwu, C and Clinton Ifeanyi, O and Akpowowo, CK and Oyebola, FG and Nndoumele, C and Olabisi Promise, L},
title = {Building healthcare capacity for neurodegenerative disease management in Nigeria: Challenges and opportunities.},
journal = {Journal of public health research},
volume = {14},
number = {2},
pages = {22799036251350957},
pmid = {40567342},
issn = {2279-9028},
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are growing public health concerns worldwide, and their burden is particularly severe in low- and middle-income countries, including Nigeria. This perspective highlights the urgent need for tailored public health strategies to address the rising prevalence of these diseases, focusing on prevention, early detection, and management in the Nigerian context. With an aging population and limited healthcare infrastructure, Nigeria faces unique challenges in diagnosing and treating NDs. Cultural factors, such as stigma and misconceptions about cognitive decline, further complicate timely intervention. The paper explores the current public health strategies implemented to combat these diseases, including lifestyle modifications, national policy development, and public-private partnerships. It emphasizes the need for community-based programs, the integration of primary healthcare and neurology, and increased awareness to reduce the societal burden of NDs. Additionally, the manuscript discusses the essential role of training healthcare providers and the integration of traditional and modern medicine in enhancing care. It calls for a coordinated, culturally relevant approach to addressing the rising tide of neurodegenerative diseases in Nigeria, with recommendations for policy reform, healthcare system strengthening, and greater research investment.},
}

@article {pmid40567202,
year = {2025},
author = {Iverson, GL and Jamshidi, P and Deep-Soboslay, A and Hyde, TM and Kleinman, JE and Hazrati, LN and Castellani, RJ},
title = {Postmortem tau in the CA2 region of the hippocampus in older adult men who participated in youth amateur American-style football.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251351524},
doi = {10.1177/13872877251351524},
pmid = {40567202},
issn = {1875-8908},
abstract = {BackgroundResearchers have reported that hyperphosphorylated tau (p-tau) accumulates in the Cornu Ammonis 2 subfield (CA2) of the hippocampus with age, preferentially in primary age-related tau astrogliopathy, in association with early Alzheimer's disease, and preferentially in chronic traumatic encephalopathy neuropathologic change.ObjectiveExamine the possible association between preferential p-tau in the CA2 region of the hippocampus and history of playing high school American-style football.MethodsPostmortem brain tissue samples were obtained from the Lieber Institute for Brain Development for 174 men (median age at death = 65 years; range = 50-96). There were 126 with no known history of participation in contact or collision sports and 48 (27.6%) who participated in football.ResultsApproximately half were rated modified Braak stage I (47.1%) and modified CERAD stage 0 (52.0%). Preferential CA2 p-tau was present in 29.9%. The average age for those with versus without preferential CA2 p-tau was 75 and 63, respectively (Cohen's d = -1.27, large effect).The sport history groups did not differ in age (p = 0.607). In both univariate and multivariate logistic regressions, older age groups (odds ratio [OR] = 3.42 and 3.23) and those with greater modified CERAD scores (OR = 1.78 and 1.48) were significantly more likely to have preferential CA2 p-tau. There was not a significant association between football participation and preferential CA2 p-tau.ConclusionsThere was not a significant association between participation in high school football and preferential CA2 p-tau identified after death. These results support other theories in the literature-that preferential CA2 p-tau is associated with aging and with Alzheimer's disease neuropathologic change.},
}

@article {pmid40567106,
year = {2025},
author = {Popp, ZT and Ang, TFA and Hwang, PH and Au, R and Chen, J},
title = {Association between education and rate of cognitive decline among individuals with Alzheimer's disease: A multi-national European observational study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352216},
doi = {10.1177/13872877251352216},
pmid = {40567106},
issn = {1875-8908},
abstract = {BackgroundThe cognitive reserve (CR) hypothesis presumes higher tolerance of Alzheimer's disease (AD)-related pathology without functional decline for those with high education and more rapid decline after AD onset. Evidence supporting the second part of the hypothesis has been largely confined to U.S.-based studies.ObjectiveTo assess the relationship between education and cognitive decline in a multi-national European cohort of older adults living with AD.MethodsWe analyzed data from participants recruited into the GERAS-EU cohort study from AD clinics in the United Kingdom, Germany, and France. Linear mixed models were employed to assess the relationship between education (dichotomized using a 12-year cutoff) and cognitive decline measured by Mini-Mental State Examination (MMSE) scores during 1.5 to 3 years of follow-up, adjusting for age, sex, time from formal diagnosis, country, comorbidities, and AD treatment.ResultsA total of 1313 participants were analyzed, with mean age of 77.3 years (SD = 7.6), 715 (54.5%) females, and 378 (28.8%) with high education (≥12 years). Participants with high education experienced a 0.19-point greater decline (versus low education group) in MMSE scores every 6 months during follow-up (95% Confidence Interval: 0.03-0.35, p = 0.02). The secondary analyses (stratified by disease severity, sex, or country) showed a consistent direction of the association, although only significant in the severe AD group (p = 0.01).ConclusionsOur findings provide partial support for the CR hypothesis. Delayed AD diagnosis in individuals with high education may contribute to faster decline after diagnosis, highlighting the importance of sensitive screening for early signs of cognitive impairment.},
}

@article {pmid40567104,
year = {2025},
author = {Wadley, VG and Zhang, Y and Bull, T and Barba, C and Bolaji, Y and Bryan, RN and Crowe, M and Desiderio, L and Erus, G and Geldmacher, DS and Go, R and Lassen-Greene, CL and Mamaeva, OA and Marson, DC and McLaughlin, M and Nasrallah, IM and Owsley, C and Passler, J and Perry, RT and Pilonieta, G and Steward, KA and Wood, A and Kennedy, RE},
title = {Daily function outcomes in adults with mild cognitive impairment due to Alzheimer's disease after two years of processing speed training versus a control training protocol.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251351341},
doi = {10.1177/13872877251351341},
pmid = {40567104},
issn = {1875-8908},
abstract = {BackgroundCognitive processing speed is integral to everyday activities and can be improved with training in persons with mild cognitive impairment (MCI). However, whether this training maintains everyday abilities is not known.ObjectiveWe aimed to determine whether everyday functions key to independence could be preserved with two years of processing speed training.MethodsIn a randomized controlled trial, we objectively evaluated a processing speed training protocol compared to a control training protocol, in 103 persons with MCI (n = 90) or very mild dementia (n = 13) due to Alzheimer's disease (AD). Each protocol involved serial assessments, laboratory training, and home training over a two-year period. We accounted for APOE ε4 carrier status and MRI-based neurodegeneration conducted at baseline. Outcomes were longitudinal changes in performance-based Instrumental Activities of Daily Living (IADLs), community mobility, and on-road driving. We used linear mixed models to evaluate changes in these outcomes over time.ResultsChanges in IADL function, driving, and community mobility did not differ by training assignment. Greater baseline neurodegeneration predicted larger declines in all functional outcomes (p values < 0.001).ConclusionsIn persons with MCI or very mild dementia, processing speed training was no more effective for maintaining everyday functions than training involving common computer activities and games that do not target processing speed. Greater baseline neurodegeneration predicted worse performance over time on all measures of function.},
}

@article {pmid40567076,
year = {2025},
author = {Zhang, L},
title = {Exosomal microRNA-22-3p influences oxidative stress injury and neuronal apoptosis in Alzheimer's disease via targeting KDM6B.},
journal = {General physiology and biophysics},
volume = {44},
number = {4},
pages = {337-348},
doi = {10.4149/gpb_2025009},
pmid = {40567076},
issn = {0231-5882},
mesh = {*MicroRNAs/metabolism/genetics ; *Oxidative Stress ; *Apoptosis ; *Alzheimer Disease/metabolism/pathology/genetics ; *Exosomes/metabolism/genetics ; *Neurons/metabolism/pathology ; *Jumonji Domain-Containing Histone Demethylases/metabolism/genetics ; Animals ; Mice ; Humans ; Cell Line ; Amyloid beta-Peptides ; },
abstract = {This research was intended to unravel the effects of exosomal microRNA-22-3p (miR-22-3p) secreted from bone marrow mesenchymal stem cells (BMSCs) on oxidative stress damage and neuronal apoptosis in Alzheimer's disease (AD) via KDM6B. BMSCs and BMSCs-derived exosomes (BMSCs-Exos) were obtained and identified. An in vitro AD model was established. The levels of miR-22-3p and KDM6B were tested. Cell viability, ROS levels, MDA content and SOD levels, as well as apoptosis levels, were evaluated. The targeting relationship between miR-22-3p and KDM6B was validated. BMSC-Exos, miR-22-3p mimic and KDM6B siRNA advanced the cell viability, attenuated cell apoptosis, and ameliorated the oxidative stress injury of Aβ1-42-induced HT22 cells, including the decrease in the content of ROS and MDA and the increase in SOD activity. miR-22-3p inhibitor and KDM6B overexpression lentivirus advanced the decrease of cell viability, aggravated cell apoptosis, and promoted oxidative stress injury in Aβ1-42-induced HT22 cells, including the increase of ROS and MDA content and the decrease of SOD activity. miR-22-3p mimic combined with oe-KDM6B reversed the effects caused by miR-22-3p mimic alone. miR-22-3p targeted KDM6B. BMSC-Exos-derived miR-22-3p suppresses KDM6B expression to alleviate oxidative stress damage and apoptosis in AD neurons.},
}

*MicroRNAs/metabolism/genetics
*Oxidative Stress
*Apoptosis
*Alzheimer Disease/metabolism/pathology/genetics
*Exosomes/metabolism/genetics
*Neurons/metabolism/pathology
*Jumonji Domain-Containing Histone Demethylases/metabolism/genetics
Animals
Mice
Humans
Cell Line
Amyloid beta-Peptides

@article {pmid40567069,
year = {2025},
author = {Xia, X and Duffner, LA and Bintener, C and Bradshaw, A and Lamirel, D and Jönsson, L},
title = {Diagnostic and prognostic multimodal prediction models in Alzheimer's disease: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251351630},
doi = {10.1177/13872877251351630},
pmid = {40567069},
issn = {1875-8908},
abstract = {BackgroundMultimodal prediction models for Alzheimer's disease (AD) are emerging as promising tools for improving detection and informing prognosis.ObjectiveTo summarize the predictive objectives, constituting predictors and algorithms, and performance of existing multimodal prediction models.MethodsWe performed a systematic literature search in Medline, Embase, and Web of Science up to January 15, 2024, to identify prediction models covering the full spectrum of AD, from the preclinical stage to subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia. The predictors, algorithms, and model performance of prediction models were summarized narratively by their predictive objectives. The review protocol was registered with the Open Science Framework (osf.io/zkw6g).ResultsPredicting the future progression from MCI to AD dementia was the most common objective of prediction models for AD. The second most common objective was to classify AD stages (SCD versus MCI versus AD dementia), followed by detecting the presence of amyloid, tau, or neurodegeneration. More than half of the prediction models reported an area under the receiver operating characteristic curve exceeding 0.8 and an accuracy exceeding 70%. However, 66.7% of the prediction models were developed using data from the ADNI study, and only 10.1% of the models went through external validation.ConclusionsExisting multimodal prediction models have mainly focused on the prediction of current or future AD stages and reported good performance. However, these models need to be validated using data other than the data used for model training before being considered for practical applications.},
}

@article {pmid40567064,
year = {2025},
author = {Lee, JK and Johnson, L and Hall, JR and Bateman, JR and O'Bryant, S and Mielke, MM},
title = {Associations of chronic stress and social support with cognition: The role of gender and race/ethnicity in the HABS-HD study cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352110},
doi = {10.1177/13872877251352110},
pmid = {40567064},
issn = {1875-8908},
abstract = {BackgroundFew studies have examined whether chronic stress and social support are potential modifiable risk factors for Alzheimer's disease and related dementias.ObjectiveTo examine the associations of chronic stress and social support with domain-specific cognitive z-scores (attention, memory, executive functioning, and language) and assess whether gender or race/ethnicity modify these associations.MethodsParticipants included 3005 older adults (age range: 50-92) enrolled in the Health and Aging Brain Study-Health Disparities. Social support was measured using the Interpersonal Support and Evaluations List, and chronic stress measured with the Chronic Burden Scale. Linear regression models evaluated associations of chronic stress and/or social support with domain-specific cognitive z-scores, adjusting for age, education, gender, race/ethnicity, and symptoms of anxiety. Interactions between chronic stress or social support and gender or race/ethnicity in relation to cognition were assessed. Additional analyses examined the interrelationship between chronic stress and social support in relation to cognition.ResultsHigher chronic stress was associated with lower cognitive z-scores; results differed by race/ethnicity. Higher social support was associated with higher cognitive z-scores; results differed by gender and race/ethnicity. In models incorporating both chronic stress and social support, associations between social support and cognition remained, however associations between chronic stress and cognition were attenuated. A combination of high chronic stress/low social support, compared to low chronic stress/high social support, was associated with lower cognitive z-scores.ConclusionsHigh chronic stress and low social support is associated with worse cognition. Future studies are needed to understand the underlying mechanisms, with consideration of gender and race/ethnicity.},
}

@article {pmid40567062,
year = {2025},
author = {Siriwardhana, C and Carrazana, E and Liow, K},
title = {Racial and socioeconomic influences on the interplay between Alzheimer's disease-related dementia and cardio-cerebrovascular disease in an aging population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251351216},
doi = {10.1177/13872877251351216},
pmid = {40567062},
issn = {1875-8908},
abstract = {BackgroundCardio and cerebrovascular disease (CVD) and Alzheimer's Disease-Related Dementia (ADRD) significantly impact older adult populations, with interlinked pathways influencing risk and progression. In Hawaii, where over 20% of the population is 65 or older and ethnic diversity is among the highest in the U.S., the relationship between ADRD and CVD requires closer examination, especially concerning racial and socioeconomic factors.ObjectiveThis study aims to assess the effects of race, ethnicity, and socioeconomic status on the bidirectional risk pathways between ADRD and CVD among older populations in Hawaii.MethodsUtilizing a multistate modeling framework, we analyzed nine years of longitudinal Medicare data to track transitions between ADRD, CVD, and mortality outcomes. We investigated associations among racial and ethnic groups, including Native Hawaiian and other Pacific Islander (NHPI), Asian Americans (AA) and white populations, accounting for socioeconomic status to identify disparities in risk progression and outcomes.ResultsThe analysis revealed notable racial and socioeconomic disparities in the transitions between ADRD, heart disease (HD), Stroke, and mortality among Hawaii's older population. Overall, lower socioeconomic status indicates increased risks for transitioning to more severe clinical states and mortality. However, such effects were found to be varied among races: AA, NHPI, and whites. Our findings suggest that socioeconomic status modifies the ADRD, HD, Stroke progression dynamics across different ethnicities.ConclusionsThis study highlights the significant role of race/ethnicity and socioeconomic status in the complex progression of ADRD and CVD.},
}

@article {pmid40567061,
year = {2025},
author = {D'Antonio, F and Panigutti, M and Teghil, A and Blasi, MT and Salzillo, M and Talarico, G and Monti, MS and Bruno, G and Canevelli, M},
title = {Exploring frailty in dementia with Lewy bodies: A pilot, cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352076},
doi = {10.1177/13872877251352076},
pmid = {40567061},
issn = {1875-8908},
abstract = {We aimed to investigate frailty in dementia with Lewy bodies (DLB) and its association with its core features. We retrospectively reviewed the clinical charts of 48 DLB outpatients. Frailty Index (FI) was generated by computing 39 age-related, multidimensional clinical deficits. FI scores varied from 0.08 to 0.54, with a median value of 0.26. FI showed a correlation with the severity of parkinsonism and visuo-spatial impairment, suggesting that some DLB features might be more influenced by frailty, whereas others, such as visual hallucinations, fluctuations, REM-behavior-disorder, seem not. Frailty may contribute to phenotypic variability in DLB; this study could inform future research aimed at clarifying the role of frailty in DLB.},
}

@article {pmid40567059,
year = {2025},
author = {Park, J and Abner, EL and Wang, P and Liu, C and Jicha, G and Harp, JP and Schmitt, FA and Kryscio, RJ},
title = {Estimation of events in cohort studies based on probability of cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251351337},
doi = {10.1177/13872877251351337},
pmid = {40567059},
issn = {1875-8908},
abstract = {BackgroundDementia and Alzheimer's disease-causing pathologies progress slowly over decades, and participants are recruited cognitively intact, so designing studies to observe enough cases within a feasible timeframe is important.ObjectiveIn this study, we used readily available basic predictors, age, family history, sex, and apolipoprotein E (APOE) 4 allele carriership, to generate cumulative incidence functions for serious cognitive impairments over years of follow-up.MethodsThe data were taken from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort established in 1989. The participants were recruited cognitively unimpaired and aged 60+. The probability of serious cognitive impairment was assessed using a multinomial logistic model, with age, the number of risk factors (family history and APOE4 allele) and sex as predictors.ResultsWe estimated that when two or more risk factors are present, the long-term incidence of clinical mild cognitive impairment and dementia is 2.3 to 2.7 times higher than that of the 0-risk group for both sexes, whereas the 0-risk group experienced approximately 7.9% to 11.6% longer observation times for female and 0.9% to 4.8% for male compared to the two or more risks group.ConclusionsThis study presents the expected cumulative incidence functions over varying follow-up times, and the expected observation time of serious cognitive impairment for given family history, carriership of APOE4, age and sex.},
}

@article {pmid40567043,
year = {2025},
author = {Bressler, SG and Grunhaus, D and Aviram, A and Rüdiger, SGD and Hurevich, M and Friedler, A},
title = {Specific phosphorylation patterns control the interplay between aggregation and condensation of Tau-R4 peptides.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5ob00885a},
pmid = {40567043},
issn = {1477-0539},
abstract = {Specific phosphorylation patterns regulate the activity of proteins and play a central role in protein self-assembly. In Tau, such patterns drive the formation of disease-related condensates and aggregates. Understanding their functional impact is essential for studying Tauopathies such as Alzheimer's Disease. Here we show how specific phosphorylation patterns regulate Tau self-assembly and control the interplay between its aggregation and condensation, using a peptide-based approach that allows systematic analysis of libraries of specific phosphorylation patterns at the domain level and is complementary to the current protein-level methods. We applied our methodology to study the effect of specific phosphorylations on the aggregation and condensation of the R4 domain of Tau that is pivotal for its self-assembly, forming the β-helix motif that is common to various Tau patient fibrils. Using advanced phosphopeptide synthesis methods developed in our labs, we generated a library of multi-phosphorylated peptides derived from Tau R4. We found that phosphorylation at Ser341 promotes aggregation, while Ser352 enhances condensation. Phosphorylation at Ser356 inhibits both processes. The source of these different outcomes is the distinct microenvironments around each phosphorylated site. Our results provide a residue-level resolution of how the decision between Tau condensation and aggregation is being made. This was possible by using our peptide-based approach, which is complementary to protein-level method and enables efficient identification of active phosphorylation patterns. These can later be studied at the protein level.},
}

@article {pmid40567033,
year = {2025},
author = {Garrahy, JP},
title = {Astrocytic lipidopathy and bioenergetic failure in ApoE4-associated late-onset Alzheimer's disease: A unifying hypothesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251350338},
doi = {10.1177/13872877251350338},
pmid = {40567033},
issn = {1875-8908},
abstract = {Late-onset Alzheimer's disease (LOAD) is traditionally attributed to amyloid-β (Aβ) accumulation and tau pathology as primary drivers of neurodegeneration. However, growing evidence suggests these may be secondary events arising from earlier disturbances in brain metabolism and lipid homeostasis. The ε4 allele of apolipoprotein E (ApoE4) remains the strongest genetic risk factor for LOAD, with carriers exhibiting both increased lifetime risk and earlier age of onset compared to ε2 or ε3 carriers. ApoE4 disrupts lipid metabolism and is associated with increased lipid droplet accumulation within astrocytes, implicating astrocytic lipidopathy in disease pathogenesis. Here, we propose a self-reinforcing pathogenic feedback loop-driven by dysregulated lipid homeostasis, chronic neuroinflammation, impaired glucose-handling, and cerebrovascular dysfunction-that culminates in astrocytic bioenergetic failure. This framework helps explain why ApoE4 carriers reach a critical bioenergetic threshold earlier in life, triggering the clinical onset of LOAD. Targeting astrocytic lipid homeostasis, through interventions such as blood-brain barrier-permeable statins, choline supplementation, or metabolic therapies, may offer novel strategies to delay disease progression or onset. Beyond AD, the framework proposed here, if validated, may have broader implications for unifying the cellular origins of age-related degenerative diseases and cancer through a shared vulnerability to progressive bioenergetic collapse.},
}

@article {pmid40566894,
year = {2025},
author = {Kim, Y and Nam, YJ and Yoon, S and Cho, YJ and Song, HM and Kim, S and Shin, D and Noh, JY and Lee, SM and Moon, SY and Kim, EJ and Cho, SH and Kim, BC and Choi, SH and Seo, SW and Choi, JW and An, YS and Park, B and Park, YJ and Kang, HY and Woo, HG and Cho, YH and Hong, S and Son, SJ and Lee, SR and Hong, CH and Roh, HW},
title = {Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer's Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts.},
journal = {Psychiatry investigation},
volume = {22},
number = {6},
pages = {699-713},
pmid = {40566894},
issn = {1738-3684},
support = {2024-ER0505-01//Korea National Institute of Health/ ; GRRCAjou2023-B02//GRRC program/ ; //Ajou University Medical Center/ ; 2019R1A5A2026045//National Research Foundation of Korea/ ; //Ministry of Science and ICT/ ; //Korea Health Industry Development Institute/ ; RS-2021-KH113821//Ministry of Health and Welfare/ ; RS-2022-KH125898//Ministry of Health and Welfare/ ; RS-2022-KH130303//Ministry of Health and Welfare/ ; RS-2023-00267453//Ministry of Health and Welfare/ ; RS-2024-00406876//Ministry of Health and Welfare/ ; RS-2024- 00339665//Ministry of Health and Welfare/ ; //Korea Dementia Research Center/ ; },
abstract = {OBJECTIVE: Numerous studies have identified various risk factors associated with Alzheimer's disease (AD). However, the experimental limitations of disease modeling make it challenging to directly interpret their effects. These limitations include constraints of postmortem samples, animal experiments, and challenges associated with brain tissue studies. Ex vivo experiments effectively address these issues by enabling patient-specific identification and highlighting potential biomarkers. This study aimed to characterize the transcriptional profile of fibroblasts derived from patients with AD in response to endoplasmic reticulum (ER) stress and propose potential biomarkers.

METHODS: We utilized an ex vivo platform to identify genes differentially responsive to ER stress. The transcriptional feature of fibroblasts in both healthy controls (n=22) and patients with AD (n=20) was analyzed using bulk RNA sequencing. The cytotoxicity of the selected target gene was evaluated through knockdown experiments.

RESULTS: A total of 468 differentially expressed genes (DEGs) were identified. Gene ontology and pathway enrichment analysis revealed that 210 DEGs, which were less responsive in AD, are involved in lipid-related terms and pathways. By narrowing down AD-related genes, we identified 49 highly reliable AD-associated genes. The most significant gene, DCTN2, exhibited a fold change that positively correlated with cognitive function and negatively correlated with blood-based biomarkers (pTau217, amyloid beta 42/40 ratio), aligning with the amyloid/Tau/neurodegeneration research criteria for AD. Additionally, the knockdown of DCTN2 in glial cell lines resulted in increased cell toxicity and apoptosis.

CONCLUSION: Identifying differentially responsive genes in ex vivo experiments not only provides insights into the pathology of AD but also offers potential biomarkers for disease diagnosis.},
}

@article {pmid40566876,
year = {2025},
author = {Greenaway, AM and Hwang, F and Nasuto, S and Ho, AK},
title = {Home-Based Attentional Bias Modification with Webcam-Based Eye Tracking with Persons with Cognitive Impairment: A Feasibility Study.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/07317115.2025.2523049},
pmid = {40566876},
issn = {1545-2301},
abstract = {OBJECTIVES: Remotely delivered attentional bias modification (ABM) studies involving persons with cognitive impairment are lacking. Thus, the feasibility of an adapted ABM paradigm with webcam-based eye tracking was explored.

METHODS: Four of the eight participants recruited (males, Mage = 69 years, Alzheimer's disease = 3, mild cognitive impairment = 1) completed up to four daily ABM sessions. Tasks comprised pre- and post-intervention depression (PHQ-9), anxiety (GAD-7), and rumination (RRS) measures, a cognitive screen (TICS) (A), affect (PANAS) (B) and dot-probe AB measures (C), and dot-probe ABM (D) (Session 1-A, B, C, D, C, and B; Sessions 2 to 4-B, D, C, and B).

RESULTS: The intervention was feasible (as defined by completion rates) and appeared beneficial in this small sample (as defined by post-intervention improvements in mood). Sessions were long, and task completion/adherence was impacted by task access/participants' ability to complete tasks independently. Mind wandering, stimuli familiarity, and eye/fatigue were reported.

CONCLUSIONS: The intervention requires further adaptation (e.g. fewer eye-tracking tasks per session). Limitations include participant self-selection/loss, a lack of control group, and that the determinants of mood change are unclear.

CLINICAL IMPLICATIONS: ABM, a novel intervention, may be an effective mood-disorder treatment for individuals with cognitive impairment.},
}

@article {pmid40566859,
year = {2025},
author = {Zhu, CW and Schneider, LS and Soleimani, L and Neugroschl, J and Grossman, HT and Schimming, C and Sano, M},
title = {Understanding the Role of Neuropsychiatric Symptoms in Functional Decline in Alzheimer's Disease.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250015},
doi = {10.1176/appi.neuropsych.20250015},
pmid = {40566859},
issn = {1545-7222},
abstract = {OBJECTIVE: The authors explored classes of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), examined the relationship between NPS classes on rate of functional decline over time, and determined whether effects of individual symptoms on functional decline remained after controlling for NPS classes.

METHODS: The authors longitudinally analyzed 9,797 study participants with mild cognitive impairment or AD at baseline in the National Alzheimer's Coordinating Center Uniform Data Set. Function was measured with the Functional Assessment Questionnaire, and NPSs were assessed by using clinician judgment. Latent class analysis (LCA) was used to identify clusters of individuals who shared similar NPS profiles. Linear mixed models were used to estimate the relationship between NPS classes and individual symptom profiles in functional decline over time.

RESULTS: LCA revealed four distinct NPS classes: an asymptomatic-mild group (48.2% of the sample, N=4,721), a second group predominantly having apathy and depression (36.4%, N=3,562), a third group with high rates of multiple symptoms except for hallucinations (12.8%, N=1,250), and a small group with high rates of all symptoms (complex class, 2.7%, N=264). NPS classes differed in baseline function but were not significantly associated with rate of functional decline. When NPS classes were controlled for, persistent apathy remained strongly associated with a faster rate of functional decline. Effects of apathy were observed across NPS classes and disease severity levels.

CONCLUSIONS: Specific symptoms rather than classes of symptoms were associated with the trajectory of functional decline in AD. Apathy may be particularly useful for tracking longitudinal changes in function.},
}

@article {pmid40566858,
year = {2025},
author = {Carlisle, TC and Bateman, JR and Yang, Y and Lachner, C and Stockbridge, MD and Flashman, LA and Chemali, Z and Alzbeidi, N and Pressman, PS and Osibajo, AM and Bobrin, BD and Martinez-Menendez, CJ and Teixeira, AL and Daffner, KR and , },
title = {Antiamyloid Monoclonal Antibodies in Alzheimer's Disease Part 2: Challenges in Dementia Care Delivery System Logistics.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20240203},
doi = {10.1176/appi.neuropsych.20240203},
pmid = {40566858},
issn = {1545-7222},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative illness affecting nearly 7 million people in the United States. Until 2023, no disease-targeting pharmacotherapeutics were widely available outside of research studies. With relatively recent regulatory approval and increasing availability of antiamyloid therapies (AATs) in the United States, management of AD is rapidly shifting from symptomatic and supportive care alone to treatments aimed at disease modification. Appropriate selection of patients for AATs can be challenging and varies among health care settings and systems despite published appropriate-use recommendations. The first of this two-part Treatment in Behavioral Neurology & Neuropsychiatry series from the American Neuropsychiatric Association Dementia Special Interest Group addresses the challenges with patient selection. In this second part, the authors offer dementia-focused health care vignettes to illustrate challenges with AAT delivery encountered in different settings and discuss emerging logistical issues associated with delivery of dementia-focused care based on AAT protocols.},
}

@article {pmid40566818,
year = {2025},
author = {Smail, SW and Kheder, AH and Mustafa, HK and Abdulqadir, SZ and Jalal, KF and Yashooa, RK and Ghayour, MB and Abdolmaleki, A and Shekha, MS},
title = {Kenpaullone attenuates amyloid-beta deposition and neuroinflammation, improving memory in a 5XFAD mouse model of Alzheimer's disease.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2025.2520983},
pmid = {40566818},
issn = {1743-1328},
abstract = {Kenpaullone is known for its neuroprotective and anti-inflammatory properties. We explored the potential of a specific intervention to influence cognitive abilities and disease-related brain changes in a mice model replicating key aspects of Alzheimer's disease (AD). We employed 5XFAD transgenic mice, which develop Aβ plaques and cognitive impairments that mirror those observed in individuals with Alzheimer's disease (AD). The animals were treated with Kenpaullone (1 mg/kg, 3 mg/kg, and 5 mg/kg) or a vehicle (DMSO). The study evaluated memory using the Morris water maze (MWM) and the novel object recognition (NOR) task. This study employed immunohistochemistry, ELISA, and Western blot to analyze Aβ plaques and proinflammatory factors, investigating neurodegeneration. In contrast, the expression of genes related to neurodegeneration and apoptosis was evaluated using polymerase chain reaction (PCR). Administration of Kenpaullone yielded significant improvements in cognitive performance in the 5XFAD mice. Mice that received the 5 mg/kg treatment demonstrated the highest improvement in spatial learning and recognition memory. Furthermore, Kenpaullone decreased the burden of amyloid-beta plaques in key brain regions associated with memory (hippocampus and cortex), along with decreased levels of proinflammatory cytokines. Furthermore, Kenpaullone treatment resulted in a downregulation of genes related to neurodegeneration and apoptosis, suggesting a potential therapeutic benefit in mitigating neural apoptosis in AD. Our results suggest that Kenpaullone holds promise for improving cognitive function and mitigating neuropathological changes in AD, warranting further exploration as a potential medicinal substance.},
}

@article {pmid40566800,
year = {2025},
author = {Germann, J and Amaral, RSC and Tomaszczyk, J and Yamamoto, K and Elias, GJB and Gouveia, FV and Vasilevskaya, A and Taghdiri, F and Devenyi, GA and Sankar, T and Leoutsakos, JM and Munro, CA and Rosenberg, PB and Lyketsos, CG and Oh, ES and Anderson, WS and Mari, Z and Fosdick, L and Drake, KE and Targum, SD and Pendergrass, JC and Burke, A and Salloway, S and Asaad, WF and Ponce, FA and Sabbagh, M and Wolk, DA and Baltuch, G and Okun, MS and Foote, KD and Giacobbe, P and McAndrews, MP and Tang-Wai, DF and Smith, GS and Tartaglia, MC and Chakravarty, MM and Lozano, AM and , },
title = {Biomarker changes associated with fornix deep brain stimulation in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70394},
doi = {10.1002/alz.70394},
pmid = {40566800},
issn = {1552-5279},
support = {R01AG042165//NIH)/ ; P30 AG066507/AG/NIA NIH HHS/United States ; 202109BPF-471913-BPF-ADHD-184776//Canadian Institutes of Health Research Banting fellowship/ ; R01 NS131342/NS/NINDS NIH HHS/United States ; R01 NR014852/NR/NINR NIH HHS/United States ; R01NS096008//Dr. Okun's research/ ; UH3NS119844//Dr. Okun's research/ ; U01NS119562//Dr. Okun's research/ ; R25NS108939//Dr. Okun is a multi-PI of the NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/pathology/cerebrospinal fluid ; *Deep Brain Stimulation/methods ; *Fornix, Brain/diagnostic imaging ; Male ; Female ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Aged ; *Hippocampus/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; tau Proteins/cerebrospinal fluid ; Atrophy ; Middle Aged ; },
abstract = {INTRODUCTION: Deep brain stimulation of the fornix (fx-DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease-modifying potential. Here we examined changes resulting from fx-DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx-DBS.

METHODS: Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers.

RESULTS: We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total-tau ratio in DBS patients.

DISCUSSION: These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients.

HIGHLIGHTS: Fornix deep brain stimulation (fx-DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx-DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total-tau CSF ratio. These findings highlight the potential of fx-DBS to modify AD.},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/pathology/cerebrospinal fluid
*Deep Brain Stimulation/methods
*Fornix, Brain/diagnostic imaging
Male
Female
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Aged
*Hippocampus/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
tau Proteins/cerebrospinal fluid
Atrophy
Middle Aged

@article {pmid40566796,
year = {2025},
author = {Burns, JM and Morris, JK and Vidoni, ED and Wilkins, HM and Choi, IY and Lee, P and Hunt, SL and Mahnken, JD and Brooks, WM and Lepping, RJ and Gupta, A and Esterline, R and Oscarsson, J and Swerdlow, RH},
title = {Effects of the SGLT2 inhibitor dapagliflozin in early Alzheimer's disease: A randomized controlled trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70416},
doi = {10.1002/alz.70416},
pmid = {40566796},
issn = {1552-5279},
mesh = {Humans ; *Benzhydryl Compounds/therapeutic use/pharmacology ; *Glucosides/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Double-Blind Method ; Male ; Female ; Aged ; Aspartic Acid/analogs & derivatives/metabolism ; Brain/drug effects/metabolism ; Treatment Outcome ; Middle Aged ; Cognition/drug effects ; },
abstract = {INTRODUCTION: Due to its metabolic effects, dapagliflozin, a sodium-glucose transporter 2 (SGLT2) inhibitor, holds potential as an Alzheimer's disease (AD) therapeutic.

METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group, 12-week single-site study to investigate the effect of dapagliflozin in participants with probable AD (Mini-Mental State Examination [MMSE] score 15-26). We planned to enroll 48 participants with 2:1 randomization to 10 mg dapagliflozin once daily (n = 32) versus matching placebo (n = 16). The primary objective was the effect of dapagliflozin on cerebral N-acetylaspartate (NAA). We also assessed safety, glycemic control, body composition, brain metabolism, and cognition.

RESULTS: There was no change in the primary outcome. There were no significant adverse event differences. Hemoglobin A1c, fat mass, and fat-free lean mass decreased; brain glutathione increased; and Stroop Interference test (but not other cognitive test) performance improved.

DISCUSSION: Treated participants manifested metabolic effects observed in clinical studies of other cohorts. In AD, dapagliflozin use may affect the brain.

HIGHLIGHTS: Dapagliflozin did not alter magnetic resonance spectroscopy N-acetylaspartate (primary outcome) in this exploratory Alzheimer's disease (AD) trial. Dapagliflozin-induced glucose disposal is sufficient to alter systemic metabolism. AD patients taking dapagliflozin exhibited metabolic effects seen in diabetics.},
}

Humans
*Benzhydryl Compounds/therapeutic use/pharmacology
*Glucosides/therapeutic use
*Alzheimer Disease/drug therapy/metabolism
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Double-Blind Method
Male
Female
Aged
Aspartic Acid/analogs & derivatives/metabolism
Brain/drug effects/metabolism
Treatment Outcome
Middle Aged
Cognition/drug effects

@article {pmid40566790,
year = {2025},
author = {Stankeviciute, L and Tort-Colet, N and Fernández-Arcos, A and Sánchez-Benavides, G and Minguillón, C and Fauria, K and Holst, SC and Garcés, P and Mueggler, T and Zetterberg, H and Blennow, K and Iranzo, Á and Suárez-Calvet, M and Gispert, JD and Molinuevo, JL and Grau-Rivera, O and , },
title = {Associations between objective sleep metrics and brain structure in cognitively unimpaired adults: interactions with sex and Alzheimer's biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70353},
doi = {10.1002/alz.70353},
pmid = {40566790},
issn = {1552-5279},
support = {100010434//'la Caixa' Foundation/ ; LCF/PR/GN17/50300004//'la Caixa' Foundation/ ; TriBEKa‑17‑519007//TriBEKa Imaging Platform project/ ; //Universities and Research Secretariat/ ; //Ministry of Business and Knowledge/ ; 2017-SGR-892//Catalan Government/ ; 101053962//European Union's Horizon Europe/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; //AD Strategic Fund/ ; ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; //Bluefield Project/ ; //Olav Thon Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; FO2017‑0243//Hjärnfonden/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute/ ; 2017‑00915//Swedish Research Council/ ; 201809-2016862//Alzheimer Drug Discovery Foundation/ ; RDAPB‑201809‑2016615//Alzheimer Drug Discovery Foundation/ ; AF‑742881//Swedish Alzheimer Foundation/ ; //Swedish government and the County Councils/ ; ALFGBG‑715986//ALF‑agreement/ ; JPND2019‑466‑236//European Union Joint Program for Neurodegenerative Disorders/ ; 1R01AG068398‑01/NH/NIH HHS/United States ; ZEN‑21‑848495//Alzheimer's Association 2021 Zenith/ ; /ERC_/European Research Council/International ; 948677//European Union's Horizon/ ; PI19/00117//Instituto de Salud Carlos III/ ; PI22/00456//Instituto de Salud Carlos III/ ; //EU's Horizon 2020/ ; 860197//Marie Skłodowska-Curie/ ; 847648//Marie Skłodowska-Curie/ ; LCF/BQ/PR21/11840004//Marie Skłodowska-Curie/ ; RYC‑2013‑13054//Spanish Ministry of Science and Innovation/ ; 115952//EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD/ ; 2021//EIT Digital/ ; RTI2018‑102261//Ministerio de Ciencia y Universidades/ ; PID2020-119556RA-I00//Ministerio de Ciencia e Innovacion, Spanish Research Agency/ ; 2019-AARF-644568//Alzheimer's Association Research Fellowship Program/ ; IJC2020-043417-I//Spanish Ministry of Science, Innovation and Universities/ ; },
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; tau Proteins/cerebrospinal fluid ; Aged ; *Sleep/physiology ; Middle Aged ; *Sleep Wake Disorders ; Actigraphy ; Sex Factors ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Sleep disturbances are prevalent in Alzheimer's disease (AD), probably emerging during its preclinical stage. Poor subjective sleep quality is linked to reduced brain volume and cortical thickness (CTh), but associations with objective sleep measures, particularly regarding sex and AD pathology, remain unclear.

METHODS: We characterized 171 cognitively unimpaired adults from the ALzheimer and FAmilies (ALFA) Sleep study using actigraphy, MRI, amyloid beta 42/40, and phosphorylated tau at threonine 181 in cerebrospinal fluid.

RESULTS: Lower sleep efficiency, higher wake after sleep onset (WASO), and sleep fragmentation were associated with lower CTh in the medial temporal lobe and other regions linked with AD and sleep disruption, even after adjusting for AD biomarkers. Sex and AD biomarkers modified these associations, with longer WASO showing a stronger correlation with lower CTh in females.

DISCUSSION: Disrupted sleep may reduce cortical integrity independently of AD biomarkers, suggesting alternative pathways. Females appear more vulnerable to impaired sleep, and AD pathology may exacerbate AD-related changes in CTh.

HIGHLIGHTS: Poor sleep efficiency, increased WASO, and sleep fragmentation are associated with reduced CTh in regions vulnerable to early AD, independently of amyloid and tau pathology. In the presence of AD pathology, this relationship is altered, with A+T+ individuals exhibiting increased CTh associated with sleep disruption. Sex-specific effects suggest females are more vulnerable to sleep-related cortical thinning. These findings highlight the potential of targeting sleep as a secondary prevention strategy to preserve brain integrity and mitigate neurodegenerative processes in AD-vulnerable regions.},
}

Humans
Female
Male
*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
tau Proteins/cerebrospinal fluid
Aged
*Sleep/physiology
Middle Aged
*Sleep Wake Disorders
Actigraphy
Sex Factors
Peptide Fragments/cerebrospinal fluid

@article {pmid40566759,
year = {2025},
author = {Wang, J and Ma, X and Lu, J and Wu, J and Xiao, Z and Zhang, H and Bao, W and Ding, S and Zheng, L and Liang, X and Guan, Y and Zuo, C and Ding, D and Zhao, Q and , },
title = {Clinical features, biomarker profiles, and neuroimaging characteristics in patients from memory clinic in china: The Shanghai Memory Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70378},
doi = {10.1002/alz.70378},
pmid = {40566759},
issn = {1552-5279},
support = {82371429//National Natural Science Foundation of China/ ; 82071200//National Natural Science Foundation of China/ ; 82173599//National Natural Science Foundation of China/ ; SQ2021AAA010157//National Ministry of Science and Technology/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; ZJ LAB//Shanghai Municipal Science and Technology Major Project/ ; },
mesh = {Humans ; China ; Male ; Female ; Biomarkers/blood ; *Cognitive Dysfunction/diagnostic imaging ; tau Proteins/blood ; Aged ; Positron-Emission Tomography ; Amyloid beta-Peptides/blood ; *Alzheimer Disease/diagnostic imaging ; *Neuroimaging ; Neuropsychological Tests ; Middle Aged ; Cohort Studies ; Brain/diagnostic imaging ; },
abstract = {INTRODUCTION: Despite advances in biomarker assessment, molecular neuroimaging, and disease-modifying therapies for cognitive disorders, China lacks well-characterized clinical cohorts integrating comprehensive clinical assessments and multimodal biomarkers.

METHODS: The Shanghai Memory Study (SMS), an ongoing hospital-based cohort, enrolled participants undergoing clinical/neuropsychological assessments, genotyping, multimodal imaging, and biospecimen collection.

RESULTS: From 2012 to 2024, 2001 participants were enrolled: 115 cognitively unimpaired (CU), 938 with mild cognitive impairment (MCI), and 948 with dementia. Positron emission tomography (PET) scan revealed A+/T+ positivity rates of 15.8% in CU, 51.2% in MCI, and 100% in Alzheimer's disease dementia (ADD). Plasma tau phosphorylated at threonine 181 (p-tau181) level increased gradually across the AD continuum. Blood p-tau181 and 18F-Florzolotau PET showed comparable utility for amyloid status identification. In a subcohort of 251 amnestic MCI (aMCI) patients, low Aβ42/Aβ40 and elevated p-tau181 predicted 4.7-year ADD risk.

DISCUSSION: By offering an integrated framework, SMS will facilitate the exploration of AD pathogenesis and the understanding of cognitive disorders.

HIGHLIGHTS: The SMS is an ongoing prospective cohort study based on a memory clinic in China. The SMS has established a relatively large-scale dataset that includes clinical data, biofluid markers, MRI and PET imaging, and novel biomarkers. By offering an integrated framework, SMS aims to facilitate the exploration of AD pathogenesis and deepen our understanding of cognitive disorders.},
}

Humans
China
Male
Female
Biomarkers/blood
*Cognitive Dysfunction/diagnostic imaging
tau Proteins/blood
Aged
Positron-Emission Tomography
Amyloid beta-Peptides/blood
*Alzheimer Disease/diagnostic imaging
*Neuroimaging
Neuropsychological Tests
Middle Aged
Cohort Studies
Brain/diagnostic imaging

@article {pmid40566684,
year = {2025},
author = {Ban, Y and Jiang, J and Yang, H and Jia, H and Pang, Y and Cheng, X and Yan, J and Liao, Q and Li, C and Lv, B and Feng, Y},
title = {The complete synthetic pathway of echinacoside from Cistanche deserticola and its de novo biosynthesis in yeast.},
journal = {Plant communications},
volume = {},
number = {},
pages = {101430},
doi = {10.1016/j.xplc.2025.101430},
pmid = {40566684},
issn = {2590-3462},
abstract = {Echinacoside (ECH), a representative phenylethanol glycoside, possesses diverse pharmacological properties and has been employed in the treatment of neurodegenerative disorders (e.g., Parkinson's and Alzheimer's diseases), ischemic brain injury, and cancer. The growing therapeutic demand for ECH has highlighted the need for scalable production. However, conventional methods face significant challenges: chemical synthesis is hindered by the compound's structural complexity, while plant extraction is limited by the low natural yield of ECH from Cistanche deserticola, a parasitic desert plant with host-dependent growth. To establish a sustainable microbial biosynthesis platform, we first deciphered the biosynthetic pathway of ECH in C. deserticola by integrating metabolomic analyses of plant tissues and callus cultures. This enabled the identification of key precursors, enzymatic steps, and regulatory mechanisms. Leveraging this knowledge, we engineered Saccharomyces cerevisiae for de novo ECH production by reconstructing the heterologous pathway, achieving a titer of 7.52 ± 1.42 mg/L. Our study not only provides a foundation for the industrial-scale production of ECH but also deepens the understanding of bioactive compound biosynthesis in parasitic plants, offering insights for future pathway engineering efforts.},
}

@article {pmid40566132,
year = {2025},
author = {Hamzeh, J and Harati, H and Ayoubi, F and Saab, MB and Saab, L and Al Ahmar, E and Estephan, E},
title = {Visualization of the Glymphatic System Through Brain Magnetic Resonance in Human Subjects with Neurodegenerative Disorders: A Systematic Review and Meta-Analysis.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124387},
pmid = {40566132},
issn = {2077-0383},
support = {NA//La Sagesse University/ ; },
abstract = {Background: One of the major contributors to homeostasis at the level of the central nervous system, specifically the brain, is the glymphatic system, which is described as an exchange occurring at the level of and between the interstitial fluid and cerebrospinal fluid that has been linked to neurodegenerative processes. Methods: Fourteen studies were included after PROSPERO registration and a literature search. Screening, reviewing, and data extraction were performed by two reviewers. Quality assessment scales were used. General continuous and subgroup analysis, heterogeneity tests, and random effect models were run using SPSS. Forest plots were constructed based on subgroup analysis. Results: Significant correlations (p < 0.05) were detected between MRI indices and outcomes quantifying neurodegenerative diseases. Studies on Alzheimer's disease showed a positive correlation between diffusivity indices and cognitive scores. Studies on Parkinson's disease showed negative correlations between diffusivity indices and disease severity, progression, and motor function (p < 0.05). As for other conditions, the conclusions remain uncertain, yet positive results were detected (p < 0.05). Conclusions: Positive significant correlations were deduced between the ALPS index and cognitive scores, indicating that low cognition is correlated with a low ALPS index and enlarged PVSs. Negative significant correlations were deduced between ALPS indices and UPDRS scores, indicating motor dysfunction is correlated with lower ALPS indices and enlarged PVSs. Finally, MRI parameters may help to deduce disease progression across subgroups. Despite the presence of heterogeneity between studies, significant correlations with moderate to large effect sizes were detected. Glymphatic dysfunction measured through MRI indices is correlated with neurodegenerative changes across various neurological conditions.},
}

@article {pmid40566048,
year = {2025},
author = {Țieranu, EN and Cureraru, SI and Târtea, GC and Vladuțu, VC and Cojocaru, PA and Piorescu, MTL and Țieranu, LM},
title = {Acute Myocardial Infarction and Diffuse Coronary Artery Disease in a Patient with Multiple Sclerosis: A Case Report and Literature Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124304},
pmid = {40566048},
issn = {2077-0383},
abstract = {Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that leads to disabilities such as difficulty moving and slowed cognitive processing. It is the leading non-traumatic cause of disability worldwide. MS also has a high potential to become a model for neurodegenerative diseases with a progression like Alzheimer's or Parkinson's. Cardiovascular diseases (CVDs) remain the leading cause of global deaths and have a considerable economic impact. The higher incidence of cardiovascular comorbidities in patients with MS compared to healthy individuals of the same age worsens the prognosis of neurological pathology, leading to a higher level of disability, poorer physical outcomes, higher depression scores, cognitive aging, and diminished quality of life. Classical observational studies often have questionable elements that can represent a source of error, making it difficult to establish a causal relationship between MS and CVD. Genetic studies, including genome-wide evaluation, may resolve this issue and may represent a topic for future research. We report the case of a 31-year-old male patient with a history of multiple sclerosis (MS) diagnosed seven years prior, who presented with acute chest pain upon returning from vacation. Despite the previous recommendation for disease-modifying therapy, the patient had discontinued treatment by personal choice. Electrocardiography (ECG) revealed ST-segment elevation in inferior leads, and emergent coronary angiography identified severe multi-vessel coronary artery disease (CAD), requiring immediate revascularization. This case highlights the potential cardiovascular risks in young patients with MS and the importance of continuous medical supervision.},
}

@article {pmid40566003,
year = {2025},
author = {Theodorou, A and Fanouraki, S and Bakola, E and Papagiannopoulou, G and Palaiodimou, L and Chondrogianni, M and Stefanou, MI and Stavrinou, L and Athanasaki, A and Psychogios, K and Kargiotis, O and Safouris, A and Velonakis, G and Paraskevas, GP and Tsivgoulis, G},
title = {Clinical Management of Cerebral Amyloid Angiopathy.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124259},
pmid = {40566003},
issn = {2077-0383},
abstract = {Background: Cerebral amyloid angiopathy (CAA) represents a progressive cerebrovascular disorder, characterized by aberrant accumulation of beta-amyloid isoforms in cortical and leptomeningeal vessel walls of cerebrum and cerebellum. Methods: We sought to investigate the clinical manifestations, current different diagnostic tools, various therapeutic strategies and most uncommon subtypes of the disease. Results: The vast majority of CAA remains sporadic, with increasing prevalence with age and very frequent coexistence with Alzheimer's disease. Clinically, CAA can present with spontaneous lobar intracerebral hemorrhage, transient focal neurologic episodes attributed to convexity subarachnoid hemorrhage or cortical superficial siderosis, and progressive cognitive decline leading to dementia. Inflammatory CAA subtype should be recognized early and treated promptly so that better functional outcomes may be achieved. Moreover, genetic and iatrogenic CAA forms are rare, yet increasingly recognized during the last years. Therapeutic management remains challenging for clinicians, especially when markers indicative of higher bleeding risk are present. A targeted therapy does not currently exist. However, various clinical trials are in progress, focusing on offering new promising insights into the disease treatment. Conclusions: This review aims to deepen our understanding of CAA diagnosis and therapeutic approach but also summarizes current evidence on the most uncommon subtypes of this cerebral small-vessel disease.},
}

@article {pmid40566001,
year = {2025},
author = {Simfukwe, C and An, SSA and Youn, YC},
title = {Investigating Gamma Frequency Band PSD in Alzheimer's Disease Using qEEG from Eyes-Open and Eyes-Closed Resting States.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124256},
pmid = {40566001},
issn = {2077-0383},
support = {PJ01712403//Cooperative Research Program for Agriculture Science and Technology Development Rural Development Administration/ ; RS-2023-00251396 and 2021R1A6A1A03038996//Republic of Korea, and a basic science research program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; },
abstract = {Background/Objectives: Gamma oscillations (30-100 Hz), which are essential for memory, attention, and cortical synchronization, remain underexplored in Alzheimer's disease (AD) research. While resting-state EEG studies have predominantly examined lower frequency bands (delta to beta), gamma activity may more accurately reflect early synaptic dysfunction and other mechanisms relevant to AD pathophysiology. AD is a common age-related neurodegenerative disorder frequently associated with altered resting-state EEG (rEEG) patterns. This study analyzed gamma power spectral density (PSD) during eyes-open (EOR) and eyes-closed (ECR) resting-state EEG in AD patients compared to cognitively normal (CN) individuals. Methods: rEEG data from 534 participants (269 CN, 265 AD) aged 40-90 were analyzed. Quantitative EEG (qEEG) analysis focused on the gamma band (30-100 Hz) using PSD estimation with the Welch method, coherence matrices, and coherence-based functional connectivity. Data preprocessing and analysis were performed using EEGLAB and Brainstorm in MATLAB R2024b. Group comparisons were conducted using ANOVA for unadjusted models and linear regression with age adjustment using log10-transformed PSD values in Python (version 3.13.2, 2025). Results: AD patients exhibited significantly elevated gamma PSD in frontal and temporal regions during EOR and ECR states compared to CN. During ECR, gamma PSD was markedly higher in the AD group (Mean = 0.0860 ± 0.0590) than CN (Mean = 0.0042 ± 0.0010), with a large effect size (Cohen's d = 1.960, p < 0.001). Conversely, after adjusting for age, the group difference was no longer statistically significant (β = -0.0047, SE = 0.0054, p = 0.391), while age remained a significant predictor of gamma power (β = -0.0008, p = 0.019). Pairwise coherence matrix and coherence-based functional connectivity were increased in AD during ECR but decreased in EOR relative to CN. Conclusions: Gamma oscillatory activity in the 30-100 Hz range differed significantly between AD and CN individuals during resting-state EEG, particularly under ECR conditions. However, age-adjusted analyses revealed that these differences are not AD-specific, suggesting that gamma band changes may reflect aging-related processes more than disease effects. These findings contribute to the evolving understanding of gamma dynamics in dementia and support further investigation of gamma PSD as a potential, age-sensitive biomarker.},
}

@article {pmid40565990,
year = {2025},
author = {Pagan, F and Torres-Yaghi, Y and Hebron, M and Wilmarth, B and Turner, RS and Matar, S and Liu, X and Ferrante, D and Esposito, G and Ahn, J and Moussa, C},
title = {Safety, Cognitive, and Behavioral Outcomes in Patients with Dementia with Lewy Bodies Treated with Nilotinib.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124245},
pmid = {40565990},
issn = {2077-0383},
support = {1R01AG062463-19/NH/NIH HHS/United States ; 1R01AG062463-19/NH/NIH HHS/United States ; },
abstract = {Background/Objectives: We previously demonstrated that nilotinib can sufficiently enter the brain to pharmacologically inhibit discoidin domain receptors (DDR)-1 in patients with Parkinson's and Alzheimer's disease. We primarily hypothesized that nilotinib is safe, and may alter disease-related biomarkers to improve, motor, cognitive and/or behavioral features in dementia with Lewy bodies (DLB). Methods: Forty-three participants were randomized 1:1 into nilotinib, 200 mg, or matching placebo in a single-center, phase 2, randomized, double-blind study. Study drug was taken orally once daily for 6 months followed by one-month wash-out. Results: Of 43 individuals enrolled, 14 were women (33%); age (mean ± SD) was 73 ± 8.5 years. Nilotinib was safe and well-tolerated, and more adverse events were noted in the placebo (74) vs. nilotinib (37) groups (p = 0.054). The number of falls were reduced in the nilotinib (six) compared to placebo (21) group (p = 0.006). Cerebrospinal fluid homovanillic acid, a biomarker of dopamine levels, was increased (p = 0.004), while the ratio of pTau181/Aβ42 was reduced (p = 0.034). The Alzheimer's Disease Assessment Scale-cognition 14 improved by 2.8 pts (p = 0.037), and no differences were observed in Movement Disorders Society-Unified Parkinson's Disease Rating Scale parts II and III. However, part I (cognition) improved (p = 0.044) in nilotinib compared to placebo. Conclusions: Nilotinib demonstrates favorable safety, biomarkers, and efficacy outcomes in patients with DLB supporting further trials in DLB or advanced Parkinson's disease with dementia.},
}

@article {pmid40565582,
year = {2025},
author = {Rother, F and Parmar, AR and Bodenhagen, JS and Marvaldi, L and Hartmann, E and Bader, M},
title = {Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice.},
journal = {Genes},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/genes16060690},
pmid = {40565582},
issn = {2073-4425},
support = {2021 Grant//Rita Levi Montalcini 2021 Grant (MIUR, Italy)/ ; MIUR project "Dipartimenti di Eccellenza 2023-2027"//Ministero dell'Istruzione dell'Università e della Ricerca/ ; },
mesh = {Animals ; *alpha Karyopherins/genetics/deficiency ; *Attention Deficit Disorder with Hyperactivity/genetics/pathology/metabolism ; Mice ; Mice, Knockout ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Male ; },
abstract = {Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (Kpna3-KO) or KPNA4 (Kpna4-KO). The motoric abilities and locomotion at different time points in ageing were tested to study the role of these two genes on motor neuron function. While we did not find deficits related to motor neurons in both mouse models, we discovered a hypermotoric phenotype in KPNA4-deficient mice. Attention deficit/hyperactivity disorder (ADHD) is caused by a combination of genetic, environmental and neurobiological factors and a number of genes have been suggested in genome-wide association studies to contribute to ADHD, including KPNA4. Here we provide supportive evidence for KPNA4 as a candidate pathogenic factor in ADHD, by analysing Kpna4-KO mice which show ADHD-like symptoms.},
}

Animals
*alpha Karyopherins/genetics/deficiency
*Attention Deficit Disorder with Hyperactivity/genetics/pathology/metabolism
Mice
Mice, Knockout
Disease Models, Animal
Motor Neurons/metabolism/pathology
Male

@article {pmid40565571,
year = {2025},
author = {Cerantonio, A and Greco, BM and Citrigno, L and De Benedittis, S and Qualtieri, A and Maletta, R and Montesanto, A and Passarino, G and Spadafora, P and Cavalcanti, F},
title = {Epigenetic Clocks and Their Prospective Application in the Complex Landscape of Aging and Alzheimer's Disease.},
journal = {Genes},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/genes16060679},
pmid = {40565571},
issn = {2073-4425},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Aging/genetics ; *Epigenesis, Genetic ; DNA Methylation/genetics ; Biological Clocks/genetics ; Cognitive Dysfunction/genetics ; },
abstract = {Nowadays, scientists are making efforts to elucidate the mechanisms involved in the phenotypic changes underlying the aging process in order to develop favorable therapeutical interventions. Epigenetic modifications, in particular DNA methylation, play a crucial role in the aging process, and this parameter has been used to set epigenetic clocks, algorithms that predict an individual's biological age based on a defined set of CpGs. In this review, we focus on the most recent literature to discuss the use of epigenetic clocks in the context of cognitive decline and dysregulation of Alzheimer's disease (AD)-related gene expression. We have summarized all published scientific papers in which epigenetic clocks have been applied to measure age acceleration in blood and brain specimens from patients affected with AD. Progressive age acceleration, consistent with a specific DNA methylation signature, was observed in patients affected by AD, and it was correlated with the onset of complex diseases, mitochondrial alterations, dementia and cognitive decline, even in the early stages of these conditions. The use of epigenetic clocks might be a valuable biomarker to enable an earlier identification of ideal measures to reverse modifications caused by aging and to mitigate multiple aspects of disease/aging mechanisms.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Aging/genetics
*Epigenesis, Genetic
DNA Methylation/genetics
Biological Clocks/genetics
Cognitive Dysfunction/genetics

@article {pmid40565359,
year = {2025},
author = {Padilla-Martínez, II and Cruz, A and García-Báez, EV and Mendieta-Wejebe, JE and Rosales-Hernández, MC},
title = {Condensation Reactions of 2-Aminothiophenoles to Afford 2-Substituted Benzothiazoles of Biological Interest: A Review (2020-2024).},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125901},
pmid = {40565359},
issn = {1422-0067},
mesh = {*Benzothiazoles/chemistry/chemical synthesis/pharmacology ; Humans ; Structure-Activity Relationship ; Antineoplastic Agents/pharmacology/chemical synthesis/chemistry ; },
abstract = {Several benzothiazole (BT) derivatives have recently been explored in medicinal chemistry, and they are frequently reported in the literature. The interest in this kind of heterocyclic compounds and their structural hybrids has been increasing, as shown by several reviews reported over the last decade. In this context, we found that about 70 articles related to the synthesis of BT derivatives that studied their biological activities were published in the last five years. From this, we prepared a review on the synthesis and biological activity studies about this topic. In this bibliographic review it was found that medicinal chemists also explore BT derivatives in search of anticancer and anti-Alzheimer's candidates. This review comprehends 70 articles, published between 2020 and 2024, related to the synthesis of BT derivatives with the purpose of assessing their biological activities. On the other hand, BT derivatives have been explored as molecular species that perform two or more biological actions, called multifunctional drugs. Some accounts related to the structure-activity relationship which provide a framework for drug discovery and design are also discussed. The synthetic methods of BT synthesis include the use of biocatalysts, solvent-free conditions, photocatalysts, and catalysts supported on nanoparticles. Studies also explore renewable energy sources such as microwave, UV, and visible-light and mechanochemical sources.},
}

*Benzothiazoles/chemistry/chemical synthesis/pharmacology
Humans
Structure-Activity Relationship
Antineoplastic Agents/pharmacology/chemical synthesis/chemistry

@article {pmid40565303,
year = {2025},
author = {Xiang, Y and Gu, Q and Liu, D},
title = {Brain Endothelial Cells in Blood-Brain Barrier Regulation and Neurological Therapy.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125843},
pmid = {40565303},
issn = {1422-0067},
support = {KYCX23_3386//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; },
mesh = {*Blood-Brain Barrier/metabolism/pathology ; Humans ; *Endothelial Cells/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; *Nervous System Diseases/therapy/metabolism/pathology ; Wnt Signaling Pathway ; Tight Junctions/metabolism ; },
abstract = {Brain endothelial cells (BECs) constitute the core component of the blood-brain barrier (BBB), regulating substance exchange between blood and the brain parenchyma to maintain central nervous system homeostasis. In pathological states, the BBB exhibits the disruption of tight junctions, endothelial cell (EC) damage, and increased permeability, accompanied by neuroinflammation, oxidative stress, and abnormal molecular signaling pathways, leading to neurotoxic effects in the brain parenchyma and exacerbating neurodegeneration and disease progression. This review systematically summarizes the developmental origin, structural characteristics, and pathological mechanisms of BECs in diseases such as Alzheimer's disease, multiple sclerosis, stroke, and glioblastoma with a particular focus on the regulatory mechanisms of the Wnt/β-catenin and VEGF signaling pathways. By integrating the latest research advances, this review aims to provide a comprehensive perspective for understanding the role of BECs in physiological and pathological states and to provide a theoretical basis for the development of BBB-based therapeutic approaches for neurological diseases.},
}

*Blood-Brain Barrier/metabolism/pathology
Humans
*Endothelial Cells/metabolism/pathology
Animals
*Brain/metabolism/pathology
*Nervous System Diseases/therapy/metabolism/pathology
Wnt Signaling Pathway
Tight Junctions/metabolism

@article {pmid40565294,
year = {2025},
author = {Kim, JH and Choe, YM and Choi, HJ and Lee, BC and Suh, GH and Kim, SG and Kim, HS and Hwang, J and Yi, D and Kim, JW},
title = {Body Circumference and Cognitive Function: Role of Apolipoprotein E ε4 in the Elderly.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125831},
pmid = {40565294},
issn = {1422-0067},
support = {HURF-2023-36//Hallym University/ ; },
mesh = {Humans ; Aged ; *Apolipoprotein E4/genetics/metabolism ; Male ; *Cognition/physiology ; Female ; Aged, 80 and over ; Waist Circumference ; Neuropsychological Tests ; Aging/genetics ; Alleles ; },
abstract = {This study examined the relationships between mid-arm circumference (MAC) and calf circumference (CC) with cognitive performance, considering the moderating effect of apolipoprotein E ε4 allele (APOE4) status. Data from 196 older adults (65-90 years) in the General Lifestyle and AD (GLAD) study were analyzed. Cognitive performance was assessed using the CERAD neuropsychological battery, with episodic memory score (EMS) and non-memory score (NMS) as primary outcomes. Multiple linear regression analyses examined associations between MAC, CC, and waist circumference (WC) with cognition, adjusting for key covariates. Interaction effects with APOE4 status were also explored. Higher MAC (or MAC/WC) significantly correlated with better EMS, while higher CC (or CC/WC) correlated with better NMS, even after Bonferroni correction (PB < 0.0125). These associations were stronger in APOE4-negative individuals but not significant in APOE4-positive participants. WC was not associated with cognitive measures. The results suggest that Upper- and lower-limb musculature may play distinct roles in cognitive function, with MAC linked to episodic memory and CC to non-memory cognition, particularly in APOE4-negative individuals. These findings highlight the potential of muscle health maintenance as a strategy for preserving cognitive function in aging populations.},
}

Humans
Aged
*Apolipoprotein E4/genetics/metabolism
Male
*Cognition/physiology
Female
Aged, 80 and over
Waist Circumference
Neuropsychological Tests
Aging/genetics
Alleles

@article {pmid40565291,
year = {2025},
author = {Uceda, S and Reiriz, M and Echeverry-Alzate, V and Beltrán-Velasco, AI},
title = {The Interplay Between Exosomes and Gut Microbiota in Neuroinflammation: A New Frontier in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125828},
pmid = {40565291},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/pathology/etiology ; *Exosomes/metabolism ; *Gastrointestinal Microbiome ; Animals ; *Neuroinflammatory Diseases/metabolism/microbiology ; Dysbiosis ; Biomarkers/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition that is characterized by the accumulation of amyloid-β, the hyperphosphorylation of tau, and persistent neuroinflammation. However, these hallmarks alone do not fully capture the intricacies of AD pathology, thus necessitating the investigation of emerging mechanisms and innovative tools. Exosomes (nanoscale vesicles involved in cell communication and immune modulation) have emerged as pivotal cellular vehicles due to their dual role-both in the propagation of pathological proteins and the regulation of inflammatory responses. Furthermore, these vesicles have been demonstrated to play a crucial role in the mediation of the effects of microbiota-derived metabolites and the reflection of systemic influences such as dysbiosis, thereby establishing a link between the gut-brain axis and the progression of AD. A comprehensive narrative literature review was conducted using the following databases: ScienceDirect, Scopus, Wiley, Web of Science, Medline, and PubMed, covering studies published between 2015 and 2025. Inclusion and exclusion criteria were established to select research addressing exosomal biogenesis, their functional and diagnosis role, their therapeutic potential, and the emerging evidence on microbiota-exosome interplay in Alzheimer's disease. Exosomes have been identified as integral mediators of intercellular communication, reflecting the molecular state of the central nervous system. These particles have been shown to promote the propagation of pathological proteins, modulate neuroinflammatory responses, and serve as non-invasive biomarkers due to their detectability in peripheral fluids. Advances in exosomal engineering and microbiome-based interventions underscore the potential for targeting systemic and CNS-specific mechanisms to develop integrative therapies for AD. Exosomes present a promising approach for the early diagnosis and personalized treatment of Alzheimer's disease. However, methodological challenges and ongoing controversies, including those related to the influence of systemic factors such as dysbiosis, necessitate multidisciplinary research to optimize and standardize these strategies.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/pathology/etiology
*Exosomes/metabolism
*Gastrointestinal Microbiome
Animals
*Neuroinflammatory Diseases/metabolism/microbiology
Dysbiosis
Biomarkers/metabolism

@article {pmid40565289,
year = {2025},
author = {Ando, K and Thazin Htut, M and Antonelli, EM and Kosa, AC and Lopez-Gutierrez, L and Quintanilla-Sánchez, C and Aydin, E and Doeraene, E and Nagaraj, S and Ramos, AR and Coulonval, K and Roger, PP and Brion, JP and Leroy, K},
title = {Dysregulation of Inositol Polyphosphate 5-Phosphatase OCRL in Alzheimer's Disease: Implications for Autophagy Dysfunction.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125827},
pmid = {40565289},
issn = {1422-0067},
support = {NA//the Belgian Fondation Recherche Alzheimer/ Stichting Alzheimer Onderzoek/ ; NA//Belgian FRS-FNRS/ ; T.0023.15//the Belgian Fonds de la Recherche Scientifique Médicale/ ; NA//the Fund Aline (King Baudouin Foundation)/ ; NA//the ULB Génicot Fund/ ; NA//Fondation Médicale Reine Elisabeth/ ; NA//the Academic Medical Interdisciplinary Research (AMIR) Foundation/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; *Autophagy ; Animals ; Humans ; Mice ; Mice, Transgenic ; *Phosphoric Monoester Hydrolases/metabolism/genetics ; Disease Models, Animal ; Brain/metabolism/pathology ; tau Proteins/metabolism ; Male ; Female ; Beclin-1/metabolism ; Aged ; Aged, 80 and over ; },
abstract = {Autophagy is impaired in Alzheimer's disease (AD), particularly at the stage of autophagosome-lysosome fusion. Recent studies suggest that the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) is involved in this fusion process; however, its role in AD pathophysiology remains largely unclear. In this study, we investigated the localization and expression of OCRL in post-mortem AD brains and in a 5XFAD transgenic mouse model. While OCRL RNA levels were not significantly altered, OCRL protein was markedly reduced in the RIPA-soluble fraction and positively correlated with the autophagy marker Beclin1. Immunohistochemical analysis revealed OCRL immunoreactivity in neuronal cytoplasm, granulovacuolar degeneration bodies, and plaque-associated dystrophic neurites in AD brains. Furthermore, OCRL overexpression in a FRET-based tau biosensor cell model significantly reduced the tau-seeding-induced FRET signal. These findings suggest that OCRL dysregulation may contribute to autophagic deficits and the progression of tau pathology in AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
*Autophagy
Animals
Humans
Mice
Mice, Transgenic
*Phosphoric Monoester Hydrolases/metabolism/genetics
Disease Models, Animal
Brain/metabolism/pathology
tau Proteins/metabolism
Male
Female
Beclin-1/metabolism
Aged
Aged, 80 and over

@article {pmid40565249,
year = {2025},
author = {Vadisiute, A and Garcia-Rates, S and Coen, CW and Greenfield, SA and Molnár, Z},
title = {Widespread Changes in the Immunoreactivity of Bioactive Peptide T14 After Manipulating the Activity of Cortical Projection Neurons.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125786},
pmid = {40565249},
issn = {1422-0067},
support = {G00900901/MRC_/Medical Research Council/United Kingdom ; No 21138077//Research Grants from St John's College Research Centre/ ; },
mesh = {Animals ; Mice ; *Neurons/metabolism ; *Acetylcholinesterase/metabolism ; Male ; Substantia Nigra/metabolism ; Motor Cortex/metabolism ; *Peptides/metabolism ; Mice, Inbred C57BL ; Corpus Striatum/metabolism ; },
abstract = {Previous studies have suggested that T14, a 14-amino-acid peptide derived from acetylcholinesterase (AChE), functions as an activity-dependent signalling molecule with key roles in brain development, and its dysregulation has been linked to neurodegeneration in Alzheimer's disease. In this study, we examined the distribution of T14 under normal developmental conditions in the mouse forebrain, motor cortex (M1), striatum (STR), and substantia nigra (SN). T14 immunoreactivity declined from E16 to E17 and further decreased by P0, then peaked at P7 during early postnatal development before declining again by adulthood at P70. Lower T14 immunoreactivity in samples processed without Triton indicated that T14 is primarily localised intracellularly. To explore the relationship between T14 expression and neuronal activity, we used mouse models with chronic silencing (Rbp4Cre-Snap25), acute silencing (Rbp4Cre-hM4Di), and acute activation (Rbp4Cre-hM3D1). Chronic silencing altered the location and size of intracellular T14-immunoreactive particles in adult brains, while acute silencing had no observable effect. In contrast, acute activation increased T14+ density in the STR, modified T14 puncta size near Rbp4Cre cell bodies in M1 layer 5 and their projections to the STR, and enhanced co-localisation of T14 with presynaptic terminals in the SN.},
}

Animals
Mice
*Neurons/metabolism
*Acetylcholinesterase/metabolism
Male
Substantia Nigra/metabolism
Motor Cortex/metabolism
*Peptides/metabolism
Mice, Inbred C57BL
Corpus Striatum/metabolism

@article {pmid40565209,
year = {2025},
author = {Kukolj, M and Oršolić, N and Langer Horvat, L and Nikolić, B and Ocrt, T and Branović Čakanić, K and Gračan, R and Zrinščak, I and Jazvinšćak Jembrek, M and Šimić, G},
title = {Quercetin as a Therapeutic Option in a Rat Model of Aluminum Chloride- and D-Galactose-Induced Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125743},
pmid = {40565209},
issn = {1422-0067},
support = {IP-2014-09-9730//Croatian Science Foundation/ ; },
mesh = {Animals ; *Aluminum Chloride/toxicity ; Rats ; *Quercetin/pharmacology/therapeutic use ; Disease Models, Animal ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Galactose/toxicity ; Male ; Antioxidants/pharmacology ; Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects/pathology ; *Neurodegenerative Diseases/drug therapy/chemically induced/metabolism/pathology ; Neurons/drug effects/metabolism ; Rats, Wistar ; Brain-Derived Neurotrophic Factor/metabolism ; Acetylcholinesterase/metabolism ; },
abstract = {Aluminum (Al) is one of the most abundant metals on Earth and is well known as an environmental neurotoxic agent in the pathogenesis of Alzheimer's disease. Aluminum toxicity is associated with oxidative stress, reduction of antioxidant enzymes, and disruption of the balance of cellular metals, such as iron (Fe), calcium (Ca), and copper (Cu), which causes structural and functional changes in the nervous tissue of the brain or peripheral nervous system. The intake of functional foods, rich in antioxidants, such as quercetin, may be beneficial in combating oxidative stress and neurodegenerative changes in the brain. The aim of this study was to provide deeper insight into the cellular and molecular neuroprotective effects of quercetin in regulating amyloid-beta (Aβ) accumulation, tau pathology, and neuroinflammation in the Al/D-galactose-induced rat model (Al/D-gal) of AD. The results showed that quercetin successfully modulated the impaired homeostatic and neuropathological consequences of aluminum chloride and D-galactose administration over 28 days: it directly protected neurons by regulating the level of oxidative stress and antioxidants, reduced Aβ aggregation by inhibiting the activity of acetylcholinesterase (AChE), increased the survival, growth, and differentiation of nerve cells by maintaining the level of brain-derived neurotrophic factor (BDNF), and regulated microglial immunoreactivity and neuroinflammation by reducing the level of proinflammatory cytokines. The multiple effects confirm that quercetin can be applied as an alternative non-pharmaceutical approach in reducing Al-induced neurotoxicity and maintaining adaptive homeostasis, which consequently affects the functioning of the central nervous system and the whole organism.},
}

Animals
*Aluminum Chloride/toxicity
Rats
*Quercetin/pharmacology/therapeutic use
Disease Models, Animal
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
*Galactose/toxicity
Male
Antioxidants/pharmacology
Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced
Amyloid beta-Peptides/metabolism
Brain/metabolism/drug effects/pathology
*Neurodegenerative Diseases/drug therapy/chemically induced/metabolism/pathology
Neurons/drug effects/metabolism
Rats, Wistar
Brain-Derived Neurotrophic Factor/metabolism
Acetylcholinesterase/metabolism

@article {pmid40565183,
year = {2025},
author = {Kim, JH and Park, S and Jung, H and Lee, EH and Lee, ES and Lee, JJ and Sohn, JH},
title = {Comparison of Cognitive Deterioration Between Propofol and Remimazolam Anesthesia in ApoE4 Knock-In Mouse Model.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125718},
pmid = {40565183},
issn = {1422-0067},
support = {Hallym 2021-74//Hana Pharm (South Korea)/ ; 0//Hallym University Research Fund/ ; },
mesh = {Animals ; *Propofol/adverse effects/pharmacology ; Mice ; Male ; Disease Models, Animal ; *Apolipoprotein E4/genetics/metabolism ; *Benzodiazepines/adverse effects/pharmacology ; Hippocampus/drug effects/metabolism/pathology ; Alzheimer Disease/pathology ; *Cognitive Dysfunction/chemically induced ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Anesthesia/adverse effects ; Maze Learning/drug effects ; Neurons/drug effects ; Gene Knock-In Techniques ; },
abstract = {Perioperative neurocognitive disorder (PND) is a concern following anesthesia, particularly in individuals at risk for Alzheimer's disease (AD). This study compared the cognitive and pathological effects of propofol and remimazolam in a mouse model with AD following surgery. Five-month-old male ApoE4-KI mice underwent abdominal surgery under either propofol (170 mg/kg) or remimazolam (85 mg/kg) anesthesia. Cognitive function was assessed using the Morris water maze and Y-maze, and neuronal apoptosis and amyloid-beta (Aβ) deposition in the CA3 and dentate gyrus (DG) of the hippocampus were evaluated preoperatively and at 2, 4, and 7 days postoperatively. Both groups showed similar postoperative cognitive functions, with increased relative escape latency at day 2 and decreased relative spontaneous alternation at days 4 and 7. However, the neuropathological analysis revealed that propofol-induced significantly more neuronal death in the CA3 (days 4 and 7) and DG (days 2, 4, and 7), and greater Aβ accumulation in the CA3 (days 2 and 4) and DG (days 2 and 7) compared to remimazolam (p < 0.05). Propofol was associated with more pronounced neuropathologic changes in the hippocampus compared to remimazolam. These findings suggest remimazolam may be a safer anesthetic for patients at risk for neurodegenerative disorders, as it is associated with less severe hippocampal pathology, which is characteristic of AD.},
}

Animals
*Propofol/adverse effects/pharmacology
Mice
Male
Disease Models, Animal
*Apolipoprotein E4/genetics/metabolism
*Benzodiazepines/adverse effects/pharmacology
Hippocampus/drug effects/metabolism/pathology
Alzheimer Disease/pathology
*Cognitive Dysfunction/chemically induced
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Anesthesia/adverse effects
Maze Learning/drug effects
Neurons/drug effects
Gene Knock-In Techniques

@article {pmid40565142,
year = {2025},
author = {Zaki, MG and Jakova, E and Pordeli, M and Setork, E and Taghibiglou, C and Cayabyab, FS},
title = {The Anti-Parkinsonian A2A Receptor Antagonist Istradefylline (KW-6002) Attenuates Behavioral Abnormalities, Neuroinflammation, and Neurodegeneration in Cerebral Ischemia: An Adenosinergic Signaling Link Between Stroke and Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125680},
pmid = {40565142},
issn = {1422-0067},
support = {G-16-00014633//Heart and Stroke Foundation of Canada/ ; SHRF CID #5146//Saskatchewan Health Research Foundation Collaborative Innovation and Development Grant/ ; RGPIN-2015-03850//Natural Sciences and Engineering Research Council of Canada Discovery Grant/ ; },
mesh = {Animals ; Male ; *Purines/pharmacology/therapeutic use ; Rats ; *Adenosine A2 Receptor Antagonists/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy/metabolism ; *Brain Ischemia/drug therapy/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Rats, Sprague-Dawley ; *Stroke/drug therapy/metabolism ; Neuroprotective Agents/pharmacology ; Receptor, Adenosine A2A/metabolism ; Signal Transduction/drug effects ; Behavior, Animal/drug effects ; Adenosine/metabolism ; Disease Models, Animal ; },
abstract = {Stroke, the third leading cause of death worldwide, is a major cause of functional disability. Cerebral ischemia causes a rapid elevation of adenosine, the main neuromodulator in the brain. The inhibition of adenosine A2A receptors (A2ARs) has been introduced as a potential target in neurodegenerative disorders involving extracellular adenosine elevation. Istradefylline, a selective A2AR antagonist, has been approved for Parkinson's disease (PD) adjunctive therapy and showed neuroprotective effects in PD and Alzheimer's disease. However, the role of A2ARs in post-stroke neuronal damage and behavioral deficits remains unclear. We recently showed that A2AR antagonism prevented the adenosine-induced post-hypoxia synaptic potentiation of glutamatergic neurotransmission following the hypoxia/reperfusion of hippocampal slices. Here, we investigated the potential neuroprotective effects of istradefylline in male Sprague-Dawley rats subjected to pial vessel disruption (PVD) used to model a small-vessel stroke. Rats were treated with either a vehicle control or istradefylline (3 mg/kg i.p.) following PVD surgery for three days. Istradefylline administration prevented anxiety and depressive-like behaviors caused by PVD stroke. In addition, istradefylline significantly attenuated ischemia-induced cognitive impairment and motor deficits. Moreover, istradefylline markedly reduced hippocampal neurodegeneration, as well as GFAP/Iba-1, TNF-α, nNOS, and iNOS levels after PVD, but prevented the downregulation of anti-inflammatory markers TGF-β1 and IL-4. Together, these results suggest a molecular link between stroke and PD and that the anti-PD drug istradefylline displays translational potential for drug repurposing as a neuroprotective agent for cerebral ischemic damage.},
}

Animals
Male
*Purines/pharmacology/therapeutic use
Rats
*Adenosine A2 Receptor Antagonists/pharmacology/therapeutic use
*Parkinson Disease/drug therapy/metabolism
*Brain Ischemia/drug therapy/metabolism
*Neuroinflammatory Diseases/drug therapy/metabolism
Rats, Sprague-Dawley
*Stroke/drug therapy/metabolism
Neuroprotective Agents/pharmacology
Receptor, Adenosine A2A/metabolism
Signal Transduction/drug effects
Behavior, Animal/drug effects
Adenosine/metabolism
Disease Models, Animal

@article {pmid40565140,
year = {2025},
author = {Zohar, K and Lezmi, E and Reichert, F and Eliyahu, T and Rotshenker, S and Weinstock, M and Linial, M},
title = {Temporal Shifts in MicroRNAs Signify the Inflammatory State of Primary Murine Microglial Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125677},
pmid = {40565140},
issn = {1422-0067},
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Microglia/metabolism/drug effects/pathology ; Mice ; *Inflammation/genetics/metabolism/pathology ; Lipopolysaccharides/pharmacology ; Cells, Cultured ; Gene Expression Regulation/drug effects ; Signal Transduction/drug effects ; },
abstract = {The primary function of microglia is to maintain brain homeostasis. In neurodegenerative diseases like Alzheimer's, microglia contribute to neurotoxicity and inflammation. In this study, we exposed neonatal murine primary microglial cultures to stimuli mimicking pathogens, injury, or toxins. Treatment with benzoyl ATP (bzATP) and lipopolysaccharide (LPS) triggered a coordinated increase in interleukin and chemokine expression. We analyzed statistically significant differentially expressed microRNAs (DEMs) at 3 and 8 h post-activation, identifying 33 and 57 DEMs, respectively. Notably, miR-155, miR-132, miR-3473e, miR-222, and miR-146b showed strong temporal regulation, while miR-3963 was sharply downregulated by bzATP. These DEMs regulate inflammatory pathways, including TNFα and NFκB signaling. We also examined the effect of ladostigil, a neuroprotective agent known to reduce oxidative stress and inflammation. At 8 h post-activation, ladostigil induced upregulation of anti-inflammatory miRNAs, such as miR-27a, miR-27b, and miR-23b. Our findings suggest that miRNA profiles reflect microglial responses to inflammatory cues and that ladostigil modulates these responses. This model of controlled microglial activation offers a powerful tool with which to study inflammation in the aging brain and the progression of neurodegenerative diseases.},
}

Animals
*MicroRNAs/genetics/metabolism
*Microglia/metabolism/drug effects/pathology
Mice
*Inflammation/genetics/metabolism/pathology
Lipopolysaccharides/pharmacology
Cells, Cultured
Gene Expression Regulation/drug effects
Signal Transduction/drug effects

@article {pmid40565068,
year = {2025},
author = {Zakrzeska, A and Kołodziejczyk, A and Komorowski, P and Sokołowska, P and Rokita, B and Wach, RA and Siatkowska, M},
title = {Neuroprotective Potential of Betulin and Its Drug Formulation with Cyclodextrin-In Vitro Assessment.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125605},
pmid = {40565068},
issn = {1422-0067},
mesh = {*Neuroprotective Agents/pharmacology/chemistry ; Humans ; *Triterpenes/pharmacology/chemistry ; Oxidative Stress/drug effects ; Hydrogen Peroxide/pharmacology/toxicity ; Apoptosis/drug effects ; *Cyclodextrins/chemistry/pharmacology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; Antioxidants/pharmacology ; Drug Compounding ; Betulinic Acid ; },
abstract = {Central nervous system disorders, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, are associated with complex pathophysiological mechanisms involving oxidative stress, inflammation, and protein misfolding. According to the literature, betulin, a natural compound derived from the bark of birch trees, demonstrates promising neuroprotective effects. This study investigates the neuroprotective potential of betulin and its complex with cyclodextrin, referred to as Betula Forte, using an in vitro model of differentiated SH-SY5Y neuroblastoma cells. Specifically, the study explores the antioxidant and antiapoptotic properties of these compounds under oxidative stress induced by hydrogen peroxide (H2O2). Our results indicated that Betula Forte exhibited lower cytotoxicity compared to betulin alone. Both substances enhanced cell viability in pre-incubation and co-incubation models, with Betula Forte showing superior efficacy under severe oxidative stress. Additionally, both substances exhibited protective effects against H2O2-induced oxidative stress and apoptosis, as evidenced by reduced levels of reactive oxygen species (ROS) and a lower number of apoptotic cells compared with the H2O2-treated cells. These findings suggest that Betula Forte, due to lower cytotoxicity, may offer a more effective neuroprotective strategy than betulin alone, highlighting its potential as a therapeutic agent for neurodegenerative diseases.},
}

*Neuroprotective Agents/pharmacology/chemistry
Humans
*Triterpenes/pharmacology/chemistry
Oxidative Stress/drug effects
Hydrogen Peroxide/pharmacology/toxicity
Apoptosis/drug effects
*Cyclodextrins/chemistry/pharmacology
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Cell Survival/drug effects
Antioxidants/pharmacology
Drug Compounding
Betulinic Acid

@article {pmid40565005,
year = {2025},
author = {Alexandra Lopes, P and Guil-Guerrero, JL},
title = {Beyond Transgenic Mice: Emerging Models and Translational Strategies in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125541},
pmid = {40565005},
issn = {1422-0067},
support = {UIDB/00276/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0059/2020//Fundação para a Ciência e a Tecnologia/ ; FCT.2022.08133.PTDC//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/DL57/2016/CP1438/CT0007//FCT Stimulus of Scientific Employment Program to P.A.L./ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; Humans ; *Disease Models, Animal ; Mice, Transgenic ; Mice ; *Translational Research, Biomedical/methods ; Amyloid beta-Peptides/metabolism ; Drosophila melanogaster ; Zebrafish ; Caenorhabditis elegans ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a leading cause of dementia and a growing public health concern worldwide. Despite decades of research, effective disease-modifying treatments remain elusive, partly due to limitations in current experimental models. The purpose of this review is to critically assess and compare existing murine and alternative models of AD to identify key strengths, limitations, and future directions for model development that can enhance translational relevance and therapeutic discovery. Traditional transgenic mouse models have advanced the understanding of amyloid-beta and tau pathologies, but often fail to capture the complexity of sporadic, late-onset AD. In response, alternative models-including zebrafish, Drosophila melanogaster, Caenorhabditis elegans, non-human primates, and human brain organoids-are gaining traction due to their complementary insights and diverse experimental advantages. This review also discusses innovations in genetic engineering, neuroimaging, computational modelling, and drug repurposing that are reshaping the landscape of AD research. By integrating these diverse approaches, the review advocates for a multi-model, multidisciplinary strategy to improve the predictive power, accelerate clinical translation, and inform personalised therapeutic interventions. Ethical considerations and equitable access to diagnostics and emerging treatments are also emphasised. Ultimately, this work aims to support the development of more accurate, effective, and human-relevant models to combat AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Animals
Humans
*Disease Models, Animal
Mice, Transgenic
Mice
*Translational Research, Biomedical/methods
Amyloid beta-Peptides/metabolism
Drosophila melanogaster
Zebrafish
Caenorhabditis elegans
Brain/metabolism/pathology

@article {pmid40564996,
year = {2025},
author = {Blanco-Hernán, P and Aguado, L and Asensio, MJ and Gómez-Soria, A and de la Villa, P and Casarejos, MJ and Mansilla, A},
title = {The Retinal Dopaminergic Circuit as a Biomarker for Huntington's and Alzheimer's Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125532},
pmid = {40564996},
issn = {1422-0067},
support = {PID2022-137331OB-C32//Ministerio de Ciencia, Innovación y Universidades/ ; },
mesh = {Animals ; *Huntington Disease/metabolism/pathology/diagnosis ; *Alzheimer Disease/metabolism/pathology/diagnosis ; Biomarkers/metabolism ; *Retina/metabolism/pathology ; *Dopamine/metabolism ; Mice ; Disease Models, Animal ; Receptors, Dopamine D2/metabolism/genetics ; Humans ; Tyrosine 3-Monooxygenase/metabolism ; Receptors, Dopamine D1/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Female ; *Dopaminergic Neurons/metabolism ; },
abstract = {Retinal dysfunction is emerging as a potential early marker of neurodegenerative diseases. Within the retina, the dopaminergic circuit, comprising dopaminergic amacrine cells, dopamine synthesis and turnover, and dopamine receptor signalling, is essential for visual processing, particularly colour contrast perception. Disruption of this circuit may underline early retinal alterations observed in Huntington's disease (HD) and Alzheimer's disease (AD). In this study, we systematically analysed retinal dopaminergic dysfunction in murine models of HD (genetic origin) and AD (sporadic), across different disease stages. We assessed dopamine levels, turnover, tyrosine hydroxylase expression, D1 and D2 receptor gene expression, and neurotransmitter balance. HD mice showed early and marked alterations: reduced dopamine content, decreased tyrosine hydroxylase, increased turnover, and downregulation of D1 receptor expression-all preceding motor symptoms and detectable brain pathology. In contrast, AD mice showed only mild changes at later stages; however, clinical evidence suggests that similar dysfunction may occur earlier in human AD. These findings position retinal dopaminergic disruption as a potential early biomarker in HD and possibly in AD. While the current study relies on invasive techniques in animal models, it lays the groundwork for non-invasive retinal assessments, such as electroretinography or optical coherence tomography, as promising tools for early diagnosis and disease monitoring in neurodegeneration.},
}

Animals
*Huntington Disease/metabolism/pathology/diagnosis
*Alzheimer Disease/metabolism/pathology/diagnosis
Biomarkers/metabolism
*Retina/metabolism/pathology
*Dopamine/metabolism
Mice
Disease Models, Animal
Receptors, Dopamine D2/metabolism/genetics
Humans
Tyrosine 3-Monooxygenase/metabolism
Receptors, Dopamine D1/metabolism/genetics
Male
Mice, Inbred C57BL
Female
*Dopaminergic Neurons/metabolism

@article {pmid40564976,
year = {2025},
author = {Tandon, R and Mei, Y and Lah, JJ and Mitchell, CS},
title = {Comprehensive Anatomical Staging Predicts Clinical Progression in Mild Cognitive Impairment: A Data-Driven Approach.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125514},
pmid = {40564976},
issn = {1422-0067},
support = {R35GM152245/NH/NIH HHS/United States ; U19 AG056169/NH/NIH HHS/United States ; R01 AG070937/NH/NIH HHS/United States ; RD004723/NH/NIH HHS/United States ; 253558//Chan Zuckerberg Initiative/ ; 194427//National Science Foundation/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/diagnostic imaging/diagnosis ; Disease Progression ; Male ; Female ; Aged ; Positron-Emission Tomography ; *Alzheimer Disease/pathology/diagnostic imaging/diagnosis ; Biomarkers/cerebrospinal fluid ; Prognosis ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Neuropsychological Tests ; },
abstract = {Alzheimer's disease (AD) presents significant challenges in clinical practice due to its heterogeneous manifestation and variable progression rates. This work develops a comprehensive anatomical staging framework to predict progression from mild cognitive impairment (MCI) to AD. Using the ADNI database, the scalable Subtype and Stage Inference (s-SuStaIn) model was applied to 118 neuroanatomical features from cognitively normal (n = 504) and AD (n = 346) participants. The framework was validated on 808 MCI participants through associations with clinical progression, CSF and FDG-PET biomarkers, and neuropsychiatric measures, while adjusting for common confounders (age, gender, education, and APOE ε4 alleles). The framework demonstrated superior prognostic accuracy compared to traditional risk assessment (C-index = 0.73 vs. 0.62). Four distinct disease subtypes showed differential progression rates, biomarker profiles (FDG-PET and CSF Aβ42), and cognitive trajectories: Subtype 1, subcortical-first pattern; Subtype 2, executive-cortical pattern; Subtype 3, disconnection pattern; and Subtype 4, frontal-executive pattern. Stage-dependent changes revealed systematic deterioration across diverse cognitive domains, particularly in learning acquisition, visuospatial processing, and functional abilities. This data-driven approach captures clinically meaningful disease heterogeneity and improves prognostication in MCI, potentially enabling more personalized therapeutic strategies and clinical trial design.},
}

Humans
*Cognitive Dysfunction/pathology/diagnostic imaging/diagnosis
Disease Progression
Male
Female
Aged
Positron-Emission Tomography
*Alzheimer Disease/pathology/diagnostic imaging/diagnosis
Biomarkers/cerebrospinal fluid
Prognosis
Aged, 80 and over
Brain/pathology/diagnostic imaging
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Neuropsychological Tests

@article {pmid40564963,
year = {2025},
author = {Ye, F and Li, M and Liu, M and Wu, X and Tian, F and Gong, Y and Cao, Y and Zhang, J and Zhang, X and Qin, C and Zhang, L},
title = {Co-Aggregation of Syndecan-3 with β-Amyloid Aggravates Neuroinflammation and Cognitive Impairment in 5×FAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125502},
pmid = {40564963},
issn = {1422-0067},
support = {2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 2023-PT180-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; Grant No. 82161138027//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Syndecan-3/metabolism/genetics ; Disease Models, Animal ; *Cognitive Dysfunction/metabolism/pathology ; Male ; Mice, Transgenic ; Brain/metabolism/pathology ; STAT3 Transcription Factor/metabolism ; },
abstract = {Abnormal deposition of β-amyloid (Aβ) is a core pathological feature of Alzheimer's disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of amyloid plaques. However, its regulatory mechanism in the process of Aβ deposition remains unclear. This study aims to clearly define the role of SDC3 in Aβ aggregation and neuroinflammation, two critical processes in AD pathogenesis. Specifically, we investigate how SDC3 modulates Aβ aggregation and its interaction with neuroinflammatory pathways, which may contribute to the progression of AD. By elucidating the mechanisms underlying SDC3's involvement in these processes, we seek to provide new insights into potential therapeutic targets for AD. In this study, a 5×FAD mouse model with downregulated SDC3 expression was constructed. Behavioral assessments and synaptic function tests were performed to explore the effects of SDC3 on cognition in 5×FAD mice. Immunofluorescence co-localization technology was utilized to analyze the pathological co-deposition of SDC3 and Aβ in the hippocampus, cortex, and meningeal blood vessels. Quantitative assessments of pro-inflammatory cytokines such as Tnf-α and Cxcl10 in the brain were performed through histopathological analysis combined with qPCR. Western blotting was used to examine the phosphorylation status of STAT1/STAT3 and the expression changes of IBA1/GFAP to systematically analyze the molecular mechanisms through which SDC3 regulates AD pathology. This study revealed that SDC3 expression was significantly upregulated in the brain regions of the 5×FAD model mice and co-localized pathologically with Aβ. Cell lineage tracing analysis showed that the elevated SDC3 expression primarily originated from glial cells. Behavioral and pathological results demonstrated that downregulation of SDC3 significantly improved cognitive dysfunction in the model mice and effectively reduced the Aβ burden in the brain. Molecular mechanism studies showed that downregulation of SDC3 reduced the phosphorylation of STAT1 and STAT3, thereby inhibiting the activation of the JAK-STAT and cGAS-STING signaling pathways, reducing the activation of microglia/astrocytes and suppressing the expression of pro-inflammatory cytokines such as Tnf-α and Cxcl10. This study reveals that SDC3 co-localizes with Aβ pathology and synergistically exacerbates neuroinflammation. Knockdown of SDC3 can simultaneously reduce both Aβ deposition and the release of inflammatory factors from glial cells. Mechanistic research indicates that SDC3 drives a "glial activation-cytokine release" vicious cycle through the JAK-STAT and cGAS-STING signaling pathways. These findings suggest that SDC3 may serve as a key hub coordinating amyloid pathology and neuroinflammation in AD, providing new insights for the development of combination therapies targeting the HSPG network.},
}

Animals
*Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
*Syndecan-3/metabolism/genetics
Disease Models, Animal
*Cognitive Dysfunction/metabolism/pathology
Male
Mice, Transgenic
Brain/metabolism/pathology
STAT3 Transcription Factor/metabolism

@article {pmid40564837,
year = {2025},
author = {Alhassan, AM and Altmami, NI},
title = {Fuzzy Optimized Attention Network with Multi-Instance Deep Learning (FOAN-MIDL) for Alzheimer's Disease Diagnosis with Structural Magnetic Resonance Imaging (sMRI).},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/diagnostics15121516},
pmid = {40564837},
issn = {2075-4418},
abstract = {Background/Objectives: Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive neurodegeneration, resulting in cognitive impairment and structural brain changes. Although no curative treatment exists, pharmacological therapies like cholinesterase inhibitors and NMDA receptor antagonists may deliver symptomatic relief and modestly delay disease progression. Structural magnetic resonance imaging (sMRI) is a commonly utilized modality for the diagnosis of brain neurological diseases and may indicate abnormalities. However, improving the recognition of discriminative characteristics is the primary difficulty in diagnosis utilizing sMRI. Methods: To tackle this problem, the Fuzzy Optimized Attention Network with Multi-Instance Deep Learning (FOA-MIDL) system is presented for the prodromal phase of mild cognitive impairment (MCI) and the initial detection of AD. Results: An attention technique to estimate the weight of every case is presented: the fuzzy salp swarm algorithm (FSSA). The swarming actions of salps in oceans serve as the inspiration for the FSSA. When moving, the nutrient gradients influence the movement of leading salps during global search exploration, while the followers fully explore their local environment to adjust the classifiers' parameters. To balance the relative contributions of every patch and produce a global distinct weighted image for the entire brain framework, the attention multi-instance learning (MIL) pooling procedure is developed. Attention-aware global classifiers are presented to improve the understanding of the integral characteristics and form judgments for AD-related categorization. The Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker, and Lifestyle Flagship Study on Ageing (AIBL) provided the two datasets (ADNI and AIBL) utilized in this work. Conclusions: Compared to many cutting-edge techniques, the findings demonstrate that the FOA-MIDL system may determine discriminative pathological areas and offer improved classification efficacy in terms of sensitivity (SEN), specificity (SPE), and accuracy.},
}

@article {pmid40564830,
year = {2025},
author = {Simfukwe, C and An, SSA and Youn, YC},
title = {Time-Frequency Domain Analysis of Quantitative Electroencephalography as a Biomarker for Dementia.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/diagnostics15121509},
pmid = {40564830},
issn = {2075-4418},
support = {Project No. PJ01712403//Cooperative Research Program for Agriculture Science and Technology Development Rural Development Administration/ ; RS-2023-00251396 and 2021R1A6A1A03038996//Republic of Korea, and a basic science research program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; },
abstract = {Biomarkers currently used to diagnose dementia, including Alzheimer's disease (AD), primarily detect molecular and structural brain changes associated with the condition's pathology. Although these markers are pivotal in detecting disease-specific neuropathological hallmarks, their association with the clinical manifestations of dementia frequently remains poorly defined and exhibits considerable variability. These biomarkers may show abnormalities in cognitively healthy individuals and frequently fail to accurately represent the severity of cognitive and functional impairments in individuals with dementia. Research indicates that synaptic degeneration and functional impairment occur early in the progression of AD and exhibit the strongest correlation with clinical symptoms. This identifies brain functional impairment measurements as promising early indicators for AD detection. Electroencephalography (EEG), a non-invasive and cost-effective method with high temporal resolution, is used as a biomarker for the early detection and diagnosis of AD through frequency-domain analysis of quantitative EEG (qEEG). Many researchers demonstrate that qEEG measures effectively identify disruptions in neuronal activity, including alterations in activity patterns, topographical distribution, and synchronization. Specific findings along the stages of AD include impaired neuronal synchronization, generalized EEG slowing, and an increase in lower-frequency bands accompanied by a decrease in higher-frequency bands of resting state EEG. Moreover, qEEG helps clinicians effectively correlate indicators of AD neuropathology and distinguish between various forms of dementia, positioning it as a promising, low-cost, non-invasive biomarker for dementia. However, additional clinical investigation is required to clarify the diagnostic and prognostic significance of qEEG measurements as early functional markers for AD. This narrative review examines time-frequency domain qEEG analysis as a potential biomarker across various types of dementia. Through a structured search of PubMed and Scopus, we identified studies assessing spectral and connectivity-based qEEG features. Consistent findings include EEG slowing, reduced functional connectivity, and network desynchronization. The review outlines key methodological challenges, such as lack of standardization and limited longitudinal validation, and recommends integrative, multimodal approaches to enhance diagnostic precision and clinical applicability.},
}

@article {pmid40564769,
year = {2025},
author = {Abbas, S and Yeniad, M and Rahebi, J},
title = {Alzheimer's Disease Prediction Using Fisher Mantis Optimization and Hybrid Deep Learning Models.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/diagnostics15121449},
pmid = {40564769},
issn = {2075-4418},
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory, cognitive, and behavioral decline. Early and accurate diagnosis is critical for timely treatment and management. This study proposes a novel hybrid deep learning framework, GLCM + VGG16 + FMO + CNN-LSTM, to improve AD diagnosis using MRI data. Methods: MRI images were preprocessed through normalization and noise reduction. Feature extraction combined texture features from the Gray-Level Co-occurrence Matrix (GLCM) and spatial features extracted from a pretrained VGG-16 network. Fisher Mantis Optimization (FMO) was employed for optimal feature selection. The selected features were classified using a CNN-LSTM model, capturing both spatial and temporal patterns. The MLP-LSTM model was included only for benchmarking purposes. The framework was evaluated on The ADNI and MIRIAD datasets. Results: The proposed method achieved 98.63% accuracy, 98.69% sensitivity, 98.66% precision, and 98.67% F1-score, outperforming CNN + SVM and 3D-CNN + BiLSTM by 2.4-3.5%. Comparative analysis confirmed FMO's superiority over other metaheuristics, such as PSO, ACO, GWO, and BFO. Sensitivity analysis demonstrated robustness to hyperparameter changes. Conclusions: The results confirm the efficacy and stability of the GLCM + VGG16 + FMO + CNN-LSTM model for accurate and early AD diagnosis, supporting its potential clinical application.},
}

@article {pmid40564576,
year = {2025},
author = {Wright, G and Woodstoke, NS and Dodd, E and Cheston, R},
title = {"Diagnosis in the Prime of Your Life": Facilitator Perspectives on Adapting the Living Well with Dementia (LivDem) Post-Diagnostic Course for Younger Adults.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/bs15060794},
pmid = {40564576},
issn = {2076-328X},
abstract = {The Living Well with Dementia (LivDem) group intervention aims to support people to adjust following a diagnosis of dementia and is delivered across the UK and abroad. However, LivDem was designed for older people with dementia and may not address the needs of younger adults. This study aimed to identify the perspectives of LivDem facilitators on adapting the LivDem course for younger adults. Data was collected as part of an online facilitator survey and included questions requiring either ordinal or free-text responses. Responses from fifteen facilitators were analysed using descriptive statistics and Reflexive Thematic Analysis. The former indicated that participants believed that LivDem could be beneficial for younger adults and were in favour of it being adapted. Qualitative analysis generated two main themes, the first of which ('The domino effect': Unique Challenges for Younger Adults) had two subthemes: 'Life and opportunities stripped away' and 'Impacting on everyone'. Theme 2, 'Good to be with peers': The Importance of Age-Appropriate Support, also had two subthemes: Groups 'full of old people' and Groups 'specifically for younger people'. These findings reinforce the argument for creating age-appropriate services for people with young-onset dementia and will inform an adapted version of LivDem that provides age-appropriate support.},
}

@article {pmid40564462,
year = {2025},
author = {Wang, H and Zhong, C and Mi, Y and Li, G and Zhang, C and Chen, Y and Li, X and Liu, Y and Liu, G},
title = {Exploration of Cytokines That Impact the Therapeutic Efficacy of Mesenchymal Stem Cells in Alzheimer's Disease.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {6},
pages = {},
doi = {10.3390/bioengineering12060646},
pmid = {40564462},
issn = {2306-5354},
support = {2024YFA1107304//National Key Research and Development Program of China/ ; Z221100007922028//Beijing Municipal Science and Technology Project/ ; },
abstract = {Current therapies for Alzheimer's disease (AD) includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and amyloid beta (Aβ)/Tau-targeting drugs. While these drugs improve cognitive decline and target the pathological mechanisms, their outcomes still are still in debate. Mesenchymal stem cells (MSCs) offer a regenerative approach by modulating neuroinflammation and promoting neuroprotection. Although the paracrine of MSCs is efficient in various AD preclinical studies and the exosomes of MSCs have entered clinical trials, the key cytokines driving the efficacy remain unclear. Here, we evaluated human umbilical cord-derived MSCs (hUC-MSCs) and employed gene-silenced MSCs (siHGF-MSCs, siTNFR1-MSCs, siBDNF-MSCs) in APP/PS1 AD mice to investigate specific mechanisms. hUC-MSCs significantly reduced Aβ/Tau pathology and neuroinflammation, with cytokine-specific contributions: silencing HGF predominantly reduced Aβ/Tau clearance, although silencing TNFR1 or BDNF showed modest effects; silencing TNFR1 or BDNF more prominently weakened anti-neuroinflammation, while silencing HGF exerted a weaker influence. All three cytokines partially contributed to oxidative stress reduction and cognitive improvements. Our study highlights MSC-driven AD alleviation as a multifactorial strategy and reveals specific cytokines alleviating different aspects of AD pathology.},
}

@article {pmid40564227,
year = {2025},
author = {Kim, E and Zhang, K and Abdi, M and Li, WT and Xin, R and Wang-Rodriguez, J and Ongkeko, WM},
title = {Evaluating Genomic and Clinical Risk Factors for Alzheimer's Disease in Individuals with Hypertension.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061508},
pmid = {40564227},
issn = {2227-9059},
support = {RG104647//University of California System/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative condition whose growing prevalence has become an increasingly important public health concern as the population ages. The lack of a definitive cure elevates the importance of identifying risk factors that are crucial for prevention efforts. Hypertension (HTN) and obesity have emerged as two highly widespread, interrelated conditions that have independently been associated with AD risk. Despite extensive research into AD pathology, the impact of obesity in a hypertensive population is not well explored. This study aims to investigate how obesity and blood pressure control within a hypertensive population may interact with genomic risk and environmental factors to influence AD incidence. Methods: A retrospective cohort of matched AD and normal patients diagnosed with HTN and taking anti-HTN drugs (n = 1862) from the All of Us database was analyzed. In this hypertensive cohort, obesity was significantly associated with increased AD risk. Genome-wide association studies (GWASs) were conducted on hypertensive AD individuals (n = 1030) and identified six single nucleotide variants (SNVs) that were associated with AD development in this population. Results: Obesity and Area Deprivation Index, a measure of socioeconomic status, were significantly associated with elevated AD risk within the hypertensive cohort. GWAS analysis identified six SNVs significantly associated with AD development among the hypertensive cohort. Conclusions: Our findings suggest that among hypertensive individuals, comorbid obesity and the Area Deprivation Index confer greater AD risk. These results highlight the critical need for obesity prevention and management strategies as part of Alzheimer's risk reduction efforts.},
}

@article {pmid40564185,
year = {2025},
author = {Madhusudhana, R and Boyle, E and Cen, Y},
title = {An Overview of Glutaminyl Cyclase as a Promising Drug Target for Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061467},
pmid = {40564185},
issn = {2227-9059},
support = {5R01GM143176-04/NH/NIH HHS/United States ; 5UM1TR004360-02/NH/NIH HHS/United States ; 241015//CCTR Endowment Fund of Virginia Commonwealth University/ ; },
abstract = {Alzheimer's disease (AD) has become an increasingly pressing concern for the aging population. Current AD treatments mainly focus on cognitive and neuropsychiatric symptoms-with few FDA-approved treatments targeting disease progression itself. The amyloid cascade hypothesis describes the formation and accumulation of β-amyloid (Aβ) oligomers and plaques as a primary event in AD pathogenesis. This hypothesis has served as the foundation of disease-modifying treatment development over the last decade. Recently, glutaminyl cyclase (QC) has been identified as a potential drug target in the amyloid cascade. QC catalyzes the cyclization of Aβ to form pyroglutamated Aβ (pEAβ). pEAβ acts as the seed for the formation of Aβ plaques, thus preventing the formation of pEAβ via QC inhibition, and offers a promising therapeutic strategy against AD. Here, we offer an overview of the pathway QCI research has followed-from the initial testing of imidazole-based inhibitor scaffolds to QCI structural optimization via pharmacophore identification, Varoglutamstat entering clinical trials, and further avenues of bettering specificity and potency for future QCI development.},
}

@article {pmid40564183,
year = {2025},
author = {Boyuklieva, R and Zahariev, N and Simeonov, P and Penkov, D and Katsarov, P},
title = {Next-Generation Drug Delivery for Neurotherapeutics: The Promise of Stimuli-Triggered Nanocarriers.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061464},
pmid = {40564183},
issn = {2227-9059},
support = {BG-RRP-2.004-0007-C01//European Union-NextGenerationEU, National Recovery and Resilience Plan of the Republic of Bulgaria/ ; },
abstract = {Nanotherapeutics have emerged as novel unparalleled drug delivery systems (DDSs) for the treatment of neurodegenerative disorders. By applying different technological approaches, nanoparticles can be engineered to possess different functionalities. In recent years, the developed, stimuli-responsive nanocarriers stand out as novel complex DDSs ensuring selective and specific drug delivery in response to different endogenous and exogenous stimuli. Due to the multifaceted pathophysiology of the nervous system, a major challenge in modern neuropharmacology is the development of effective therapies ensuring high efficacy and low toxicity. Functionalization of the nanocarriers to react to specific microenvironmental changes in the nervous system tissues or external stimulations significantly enhances the efficacy of drug delivery. This review discusses the microenvironmental characteristics of some common neurological diseases in-depth and provides a comprehensive overview on the progress of the development of exogenous and endogenous stimuli-sensitive nanocarriers for the treatment of Alzheimer's and Parkinson's disease.},
}

@article {pmid40564128,
year = {2025},
author = {Drewes, N and Fang, X and Gupta, N and Nie, D},
title = {Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061409},
pmid = {40564128},
issn = {2227-9059},
abstract = {Originally identified as a potential receptor for opioids, the sigma-1 receptor is now recognized as an intracellular chaperone protein associated with mitochondria-associated membranes at the endoplasmic reticulum (ER). Over the past two decades, extensive research has revealed that the sigma-1 receptor regulates many cellular processes, such as calcium homeostasis, oxidative stress responses, protein folding, and mitochondrial function. The various functions of the sigma-1 receptor highlight its role as a central modulator of neuronal health and may be a promising pharmacological target across multiple neurodegenerative conditions. Herein, we provide an overview of the current pharmacological understanding of the sigma-1 receptor with an emphasis on the signaling mechanisms involved. We examine its pathological implications in common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. We then highlight how sigma-1 receptor modulation may influence disease progression as well as potential pharmacological mechanisms to alter disease outcomes. The translational potential of sigma-1 receptor therapies is discussed, as well as the most up-to-date results of ongoing clinical trials. This review aims to clarify the therapeutic potential of the sigma-1 receptor in neurodegeneration and guide future research in these diseases.},
}

@article {pmid40564109,
year = {2025},
author = {Yao, P and Han, H},
title = {Advances in Autophagy-Lysosomal Pathway and Neurodegeneration via Brain-Gut Axis.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061390},
pmid = {40564109},
issn = {2227-9059},
support = {8220141//National Natural Science Foundation of China/ ; },
abstract = {Background/Objectives: The autophagy-lysosomal pathway (ALP) is crucial for neuronal health by clearing misfolded proteins and damaged organelles. While much research has focused on ALP dysfunction in the central nervous system, new evidence shows its importance in the gut, where it affects neurodegeneration via the gut-brain axis. Past reviews have mainly studied the ALP's direct neuroprotective effects or the gut microbiota's role in neurodegeneration separately. However, the two-way relationship between the ALP and the gut microbiota in neurodegenerative diseases is not well understood. We combine the latest findings on the ALP's role in gut health, microbial imbalance, and neuroinflammation, providing a comprehensive view of their combined effects in Alzheimer's, Parkinson's, and Huntington's diseases. Methods: This narrative review synthesizes evidence from preclinical, clinical, and translational studies (2014-2025) to explore the interplay between the autophagy-lysosomal pathway (ALP) and the gut-brain axis in neurodegeneration. The literature was identified via PubMed and Web of Science using search terms including autophagy, lysosome, gut microbiota, neurodegeneration, and gut-brain axis, with additional manual screening of reference lists. The inclusion criteria prioritized studies elucidating molecular mechanisms (e.g., ALP-microbiota crosstalk), while excluding case reports or non-peer-reviewed sources. Results: The gut-brain axis facilitates bidirectional communication between the gut and the brain through neural, immune, and metabolic pathways. Autophagy dysfunction may disrupt intestinal homeostasis, promote gut microbiota dysbiosis, and trigger chronic neuroinflammation, ultimately accelerating neurodegeneration. Notably, strategies targeting the gut microbiota and restoring intestinal barrier function via the ALP have demonstrated promising potential in delaying the progression of neurodegenerative diseases. Conclusions: This review establishes the ALP as a dynamic regulator of gut-brain communication, highlighting microbiota-targeted therapies as promising strategies for neurodegeneration.},
}

@article {pmid40564077,
year = {2025},
author = {Theis, BF and Park, JS and Kim, JSA and Zeydabadinejad, S and Vijay-Kumar, M and Yeoh, BS and Saha, P},
title = {Gut Feelings: How Microbes, Diet, and Host Immunity Shape Disease.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061357},
pmid = {40564077},
issn = {2227-9059},
abstract = {The human gut microbiome is intricately linked to systemic and organ-specific immune responses and is highly responsive to dietary modulation. As metagenomic techniques enable in-depth study of an ever-growing number of gut microbial species, it has become increasingly feasible to decipher the specific functions of the gut microbiome and how they may be modulated by diet. Diet exerts both supportive and selective pressures on the gut microbiome by regulating a multitude of factors, including energy density, macronutrient and micronutrient content, and circadian rhythm. The microbiome, in turn, contributes to local and systemic immune responses by providing colonization resistance against pathogens, shaping immune cell activity and differentiation, and facilitating the production of bioactive metabolites. Emerging research has strengthened the connections between the gut microbiome and cardiometabolic disorders (e.g., cardiovascular disease, obesity, type-2 diabetes), autoimmune conditions (e.g., type-1 diabetes, rheumatoid arthritis, celiac disease), respiratory disease, chronic kidney and liver disease, inflammatory bowel disease, and neurological disorders (e.g., Alzheimer's, Parkinson's disease, depressive disorders). Here, we outline ways in which dietary factors impact host response in diseases through alterations of gut microbiome functionality and composition. Consideration of diet-mediated microbial effects within the context of the diseases discussed highlights the potential of microbiome-targeted treatment strategies as alternative or adjunct therapies to improve patient outcomes.},
}

@article {pmid40564040,
year = {2025},
author = {Amoatika, DA and Absher, JR and Khan, MTF and Miller, MC},
title = {Dementia Deaths Most Commonly Result from Heart and Lung Disease: Evidence from the South Carolina Alzheimer's Disease Registry.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061321},
pmid = {40564040},
issn = {2227-9059},
support = {NA//South Carolina Alzheimer's Disease Research Center/ ; },
abstract = {Background: Cardiovascular disease (CVD) significantly impacts Alzheimer's Disease and Related Dementia (AD/ADRD) mortality. South Carolina has a high incidence of CVD and dementia mortality. The aim of this study, therefore, was to examine the neurological causes of death and the leading causes of death in the South Carolina Alzheimer's Disease Registry (SCADR). Method: Data from 2005-2018 were extracted from the SCADR using ICD-9 and ICD-10 codes. The top 10 leading causes of death (LCOD) were identified using death certificates. Some neurological causes of death were operationalized by combining related ICD codes, such as CVD_C (I219, I251, I500, I64) and chronic obstructive pulmonary disease (COP_C), (J449, C349), and χ2 was used to compare socio-demographic characteristics and mortality. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using extended Cox Proportional Hazard modeling, adjusting for socio-demographic factors. Results: A total of 207,093 registry cases were included in the analysis. About 70% of cases had Alzheimer's Disease (AD) diagnosis, and 40% of all cases were 85 years and older. The LCOD was CVD_C (13.4%). The risk of death among cases with vascular dementia (VaD) was 1.17 times the risk of death among those with AD (aHR: 1.172, 95% CI: 1.148-1.196). Among all deaths, cases with COP_C had a significantly higher likelihood of death compared to those with CVD_C (aHR: 1.06, 95% CI: 1.025-1.090). Conclusions: The study highlights CVD_C as the LCOD in frequency, with survival analysis indicating COP_C risk of death as significantly higher compared to CVD_C deaths. There is a need to prioritize CVD and lung-related comorbidity prevention, assessment, and management programs for individuals living with ADRD.},
}

@article {pmid40563933,
year = {2025},
author = {Kokhan, VS and Levashova, AI and Nesterov, MS and Pikalov, VA and Chicheva, MM},
title = {Combined Ionizing Radiation Caused Cognition and Non-Cognition Behavior Benefits and Modulated Microglial Activity in Wild-Type and Alzheimer's-like Transgenic Mice.},
journal = {Biology},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biology14060682},
pmid = {40563933},
issn = {2079-7737},
support = {22-75-10036//Russian Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is one of the primary causes of disability and dependency among aging populations worldwide. Neuroinflammation may be a potential therapeutic target in AD. Moreover, ionizing radiation may be a tool for modulating neuroinflammation. Here, we used three mouse lines-C57Bl/6 and the transgenic AD models 5xFAD and Tau P301S-to investigate the effects of combined ionizing radiation (γ-rays and carbon-12 nuclei) on emotional state, cognitive abilities, and markers of microglial activation. The obtained data show that combined irradiation results in enhanced exploratory behavior and spatial learning in the C57Bl/6 mice. The same changes, as well as a decrease in anxiety, were found in the Tau P301S mice. Irradiation of the 5xFAD mice resulted in improved welfare and ability to discriminate odors. At the same time, irradiation led to an increase in the level of pro- and anti-inflammatory cytokines in the prefrontal cortex and, to a lesser extent, in the hippocampus of the C57Bl/6 and Tau P301S mice. An increase in macrophage inflammatory protein-1α in the prefrontal cortex and a decrease in interleukin 2β in the hippocampus were found in the 5xFAD mice. Taken together, our data indicate that ionizing radiation exposure is an adequate tool to modulate microglial activity in the brain and may provide cognitive and non-cognitive behavioral benefits in neurodegenerative disease conditions.},
}

@article {pmid40563824,
year = {2025},
author = {Hasan, A and Scuderi, SA and Capra, AP and Giosa, D and Bonomo, A and Ardizzone, A and Esposito, E},
title = {An Updated and Comprehensive Review Exploring the Gut-Brain Axis in Neurodegenerative Disorders and Neurotraumas: Implications for Therapeutic Strategies.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060654},
pmid = {40563824},
issn = {2076-3425},
abstract = {The gut-brain axis (GBA) refers to the biochemical bidirectional communication between the central nervous system (CNS) and the gastrointestinal tract, linking brain and gut functions. It comprises a complex network of interactions involving the endocrine, immune, autonomic, and enteric nervous systems. The balance of this bidirectional pathway depends on the composition of the gut microbiome and its metabolites. While the causes of neurodegenerative diseases (NDDs) vary, the gut microbiome plays a crucial role in their development and prognosis. NDDs are often associated with an inflammation-related gut microbiome. However, restoring balance to the gut microbiome and reducing inflammation may have therapeutic benefits. In particular, introducing short-chain fatty acid-producing bacteria, key metabolites that support gut homeostasis, can help counteract the inflammatory microbiome. This strong pathological link between the gut and NDDs underscores the gut-brain axis (GBA) as a promising target for therapeutic intervention. This review, by scrutinizing the more recent original research articles published in PubMed (MEDLINE) database, emphasizes the emerging notion that GBA is an equally important pathological marker for neurological movement disorders, particularly in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease and neurotraumatic disorders such as traumatic brain injury and spinal cord injury. Additionally, the GBA presents a promising therapeutic target for managing these diseases.},
}

@article {pmid40563811,
year = {2025},
author = {Niazi, NUK and Jiang, J and Ou, H and Chen, R and Yang, Z},
title = {Sleep Deprivation and Alzheimer's Disease: A Review of the Bidirectional Interactions and Therapeutic Potential of Omega-3.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060641},
pmid = {40563811},
issn = {2076-3425},
support = {KCXFZ20240903093925033//the Sustainable Development Program of Shenzhen Science and Technology Major Program/ ; 2022ZDZX2029//Key Project in Higher Education of Guangdong, China/ ; 2024KTSCX199//Guangdong University Featured Innovation Program Project/ ; 2022A1515011419//Guangdong Basic and Applied Basic Research Foundation/ ; R19039 and R19035//the program for scientific research start-up funds of Guangdong Ocean University/ ; },
abstract = {Sleep is essential for physical and mental health, playing a critical role in memory consolidation, behavioral stability, and the regulation of immune and metabolic functions. The incidence of sleep disorders, particularly sleep deprivation (SD), increases with age and is prevalent in neurodegenerative and psychiatric disorders such as Alzheimer's disease (AD). Nearly 40% of AD patients experience significant chronic sleep impairments. The clinical distinction between late-life sleep disorders and AD is often challenging due to overlapping symptoms, including cognitive decline and behavioral impairments. Although the exact causal relationship between SD and AD remains complex and multifaceted, strong evidence suggests a bidirectional link, with AD patients frequently exhibiting disrupted sleep architecture, reduced slow-wave activity, and shorter total sleep duration. On a pathophysiological level, SD contributes to neuroinflammation, amyloid-β plaque deposition, and tau tangles, which are key features of AD. Current treatments, such as sedatives and antidepressants, often have limitations, including inconsistent efficacy, dependency risks, and poor long-term outcomes/recurrence, highlighting the need for safer and more effective alternatives. This review examines the interplay between SD and AD and proposes omega (n)-3 fatty acids (FAs) as a potential therapeutic intervention. Preclinical and clinical studies suggest that n-3 supplementation may improve sleep onset/quality, reduce neuroinflammation, support synaptic function, and decrease amyloid-β aggregation, thereby alleviating early AD-related neurological changes. Given their safety profile and neuroprotective effects, n-3 FAs represent a promising strategy for managing the comorbidity of sleep disorders in AD.},
}

@article {pmid40563810,
year = {2025},
author = {Aracri, F and Bianco, MG and Quattrone, A and Sarica, A},
title = {Bridging the Gap: Missing Data Imputation Methods and Their Effect on Dementia Classification Performance.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060639},
pmid = {40563810},
issn = {2076-3425},
abstract = {Background/Objectives: Missing data is a common challenge in neuroscience and neuroimaging studies, especially in the context of neurodegenerative disorders such as Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). Inadequate handling of missing values can compromise the performance and interpretability of machine learning (ML) models. This study aimed to systematically compare the impacts of five imputation methods on classification performance using multimodal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: We analyzed a dataset including clinical, cognitive, and neuroimaging features from ADNI participants diagnosed with MCI or AD. Five imputation techniques-mean, median, k-Nearest Neighbors (kNNs), Multiple Imputation by Chained Equations (MICE), and missForest (MF)-were applied. Classification tasks were performed using Random Forest (RF), Logistic Regression (LR), and Support Vector Machine (SVM). Models were trained on the imputed datasets and evaluated on a test set without missing values. The statistical significance of performance differences was assessed using McNemar's test. Results: On the test set, MICE imputation yielded the highest accuracy for both RF (0.76) and LR (0.81), while SVM performed best with median imputation (0.81). McNemar's test revealed significant differences between RF and both LR and SVM (p < 0.01), but not between LR and SVM. Simpler methods like mean and median performed adequately but were generally outperformed by MICE. The performance of kNNs and MF was less consistent. Conclusions: Overall, the choice of imputation method significantly affects classification accuracy. Selecting strategies tailored to both data structure and classifier is essential for robust predictive modeling in clinical neuroscience.},
}

@article {pmid40563806,
year = {2025},
author = {Zhang, X and Han, C and Xia, J and Deng, L and Dong, J},
title = {Dynamic Synergy Network Analysis Reveals Stage-Specific Regional Dysfunction in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060636},
pmid = {40563806},
issn = {2076-3425},
support = {ZZKY202203//Key Laboratory of Intelligent Manufacturing and Industrial Internet Technology, Fujian Province University (Xiamen University Tan Kah Kee College)/ ; 82360363//National Natural Science Foundation of China/ ; 82372087//National Natural Science Foundation of China/ ; },
abstract = {Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive neurodegeneration and connectivity deterioration. While resting-state functional magnetic resonance imaging (fMRI) provides critical insights into brain network abnormalities, traditional mutual information-based methods exhibit inherent limitations in characterizing the dynamic synergistic mechanisms between cerebral regions. Method: This study pioneered the application of an Integrated Information Decomposition (ΦID) framework in AD brain network analysis, constructing single-sample network models based on ΦID-derived synergy metrics to systematically compare their differences with mutual information-based methods in pathological sensitivity, computational robustness, and network representation capability, while detecting brain regions with declining dynamic synergy during AD progression through intergroup t-tests. Result: The key finding are as follows: (1) synergy metrics exhibited lower intra-group coefficient of variation than mutual information metrics, indicating higher computational stability; (2) single-sample reconstruction significantly enhanced the statistical power in intergroup difference detection; (3) synergy metrics captured brain network features that are undetectable by traditional mutual information methods, with more pronounced differences between networks; (4) key node analysis demonstrated spatiotemporal degradation patterns progressing from initial dysfunction in orbitofrontal-striatal-temporoparietal pathways accompanied by multi-regional impairments during prodromal stages, through moderate-phase decline located in the right middle frontal and postcentral gyri, to advanced-stage degeneration of the right supramarginal gyrus and left inferior parietal lobule. ΦID-driven dynamic synergy network analysis provides novel information integration theory-based biomarkers for AD progression diagnosis and potentially lays the foundation for pathological understanding and subsequent targeted therapy development.},
}

@article {pmid40563801,
year = {2025},
author = {Hall, SE and White, ZJ and Rohn, TT and Sudasinghe, KH and Young, ME},
title = {Exercise Improves Alzheimer's Disease Phenotype in the TgF344-AD Rat, a Behavioral Time Course Study of Males and Females.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060631},
pmid = {40563801},
issn = {2076-3425},
support = {R03AG065970, P20GM113109, and 2R15AG042781-03//National Institute of Health/ ; },
abstract = {Alzheimer's disease (AD) is the third leading cause of death among older adults with nearly 6 million diagnosed annually. In the race for a cure, one thing is certain-exercise can reduce your risk. However, the mechanisms responsible for this reduced risk are unknown. Several studies have linked exercise to improved memory, reduced amyloid beta plaques, and tau hyperphosphorylation in AD. Background/Objectives: By utilizing a novel rat model of AD, TgF344-AD, we evaluated the time course of behavioral shifts as well as the protective effect of exercise. Methods: TgF344-AD animals (61 total, 31 females and 30 males) were assessed every 3 months from 3 to 12 months of age and then assessments were increased to monthly until they reached 18 months of age. A progressive treadmill protocol was administered at 12 months of age and continued until 18 months. Pre-intervention and post-intervention data were analyzed. Results: Females had greater grip strength relative to body mass compared to males and exercise attenuated the age-related and AD-induced decline. Also, female AD-impaired memory was rescued with exercise, while males had no exercise-induced improvements. Conclusions: There is a sex difference present in the TgF344-AD rat model of Alzheimer's disease and this should be studied further; in addition, sex differences across all models of AD and the human pathology need to be evaluated. Exercise neuroprotection, while more prominent in females, is an important factor in AD research, and further work to understand the mechanisms of neuroprotection is warranted.},
}

@article {pmid40563789,
year = {2025},
author = {Fu, B and Shen, C and Liao, S and Wu, F and Liao, B},
title = {Prediction of Alzheimer's Disease Based on Multi-Modal Domain Adaptation.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060618},
pmid = {40563789},
issn = {2076-3425},
support = {Grant Nos 62362027 and 62362028;No. 2020YFB2104400;//National Nature Science Foundation of China;National Key R and D Program of China;/ ; },
abstract = {Background/Objectives: Structural magnetic resonance imaging (MRI) and 18-fluoro-deoxy-glucose positron emission tomography (PET) reveal the structural and functional information of the brain from different dimensions, demonstrating considerable clinical and practical value in the computer-aided diagnosis of Alzheimer's disease (AD). However, the structure and semantics of different modal data are different, and the distribution between different datasets is prone to the problem of domain shift. Most of the existing methods start from the single-modal data and assume that different datasets meet the same distribution, but they fail to fully consider the complementary information between the multi-modal data and fail to effectively solve the problem of domain distribution difference. Methods: In this study, we propose a multi-modal deep domain adaptation (MM-DDA) model that integrates MRI and PET modal data, which aims to maximize the utilization of the complementarity of the multi-modal data and narrow the differences in domain distribution to boost the accuracy of AD classification. Specifically, MM-DDA comprises three primary modules: (1) the feature encoding module, which employs convolutional neural networks (CNNs) to capture detailed and abstract feature representations from MRI and PET images; (2) the multi-head attention feature fusion module, which is used to fuse MRI and PET features, that is, to capture rich semantic information between modes from multiple angles by dynamically adjusting weights, so as to achieve more flexible and efficient feature fusion; and (3) the domain transfer module, which reduces the distributional discrepancies between the source and target domains by employing adversarial learning training. Results: We selected 639 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and considered two transfer learning settings. In ADNI1→ADNI2, the accuracies of the four experimental groups, AD vs. CN, pMCI vs. sMCI, AD vs. MCI, and MCI vs. CN, reached 92.40%, 81.81%, 81.13%, and 85.45%, respectively. In ADNI2→ADNI1, the accuracies of the four experimental groups, AD vs. CN, pMCI vs. sMCI, AD vs. MCI, and MCI vs. CN, reached 94.73%, 81.48%, 85.48%, and 81.69%, respectively. Conclusions: MM-DDA is compared with other deep learning methods on two kinds of transfer learning, and the performance comparison results confirmed the superiority of the proposed method in AD prediction tasks.},
}

@article {pmid40563783,
year = {2025},
author = {Muhammad, A and Jin, Q and Elwasila, O and Gulzar, Y},
title = {Hybrid Deep Learning Architecture with Adaptive Feature Fusion for Multi-Stage Alzheimer's Disease Classification.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060612},
pmid = {40563783},
issn = {2076-3425},
support = {KFU25xxxx//King Faisal University/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD), a progressive neurodegenerative disorder, demands precise early diagnosis to enable timely interventions. Traditional convolutional neural networks (CNNs) and deep learning models often fail to effectively integrate localized brain changes with global connectivity patterns, limiting their efficacy in Alzheimer's disease (AD) classification.

METHODS: This research proposes a novel deep learning framework for multi-stage Alzheimer's disease (AD) classification using T1-weighted MRI scans. The adaptive feature fusion layer, a pivotal advancement, facilitates the dynamic integration of features extracted from a ResNet50-based CNN and a vision transformer (ViT). Unlike static fusion methods, our adaptive feature fusion layer employs an attention mechanism to dynamically integrate ResNet50's localized structural features and vision transformer (ViT) global connectivity patterns, significantly enhancing stage-specific Alzheimer's disease classification accuracy.

RESULTS: Evaluated on the Alzheimer's 5-Class (AD5C) dataset comprising 2380 MRI scans, the framework achieves an accuracy of 99.42% (precision: 99.55%; recall: 99.46%; F1-score: 99.50%), surpassing the prior benchmark of 98.24% by 1.18%. Ablation studies underscore the essential role of adaptive feature fusion in minimizing misclassifications, while external validation on a four-class dataset confirms robust generalizability.

CONCLUSIONS: This framework enables precise early Alzheimer's disease (AD) diagnosis by integrating multi-scale neuroimaging features, empowering clinicians to optimize patient care through timely and targeted interventions.},
}

@article {pmid40563782,
year = {2025},
author = {Hong, SH and Roh, HW and Nam, YJ and Kim, TW and Cho, YH and Son, SJ and Hong, CH},
title = {Age- and Sex-Specific Gut Microbiota Signatures Associated with Dementia-Related Brain Pathologies: An LEfSe-Based Metagenomic Study.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060611},
pmid = {40563782},
issn = {2076-3425},
support = {2024-ER0505-00//Korea National Institute of Health (KNIH)/ ; GRRCAjou2023-B02//Gyeonggi-do Regional Research Center program of Gyeonggi province/ ; RS-2022-KH130309//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; RS-2021-KH113821//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; },
abstract = {BACKGROUND/OBJECTIVES: Emerging evidence suggests that gut microbiota composition is influenced by both age and sex and may contribute to dementia-related brain pathologies. However, comprehensive microbiome-based biomarker discovery stratified by these factors remains limited.

METHODS: We performed a metagenomic analysis of the gut microbiota of participants stratified by sex (female vs. male) and age (<75 vs. ≥75 years). Alpha diversity (observed operational taxonomic unit, Chao1, Shannon, and Simpson) and linear discriminant analysis effect size analyses were conducted to identify dominant taxa associated with Alzheimer's pathology, vascular pathology, and dementia-related structural brain changes.

RESULTS: Females and non-elderly participants (aged < 75 years) exhibited higher gut microbial diversity, characterized by an increased abundance of Bifidobacterium spp. and Blautia spp., whereas males and elderly participants (aged ≥ 75 years) exhibited increased levels of Bacteroides spp. and Bacteroidia, which have been associated with inflammation and dysbiosis. Several taxa, including Bifidobacterium spp. were consistently identified as potential protective biomarkers, while Bacteroides spp. was linked to a higher risk of dementia-related brain pathologies.

CONCLUSIONS: Our findings demonstrate distinct age- and sex-specific differences in gut microbiota composition that may be closely associated with the pathophysiology of dementia-related brain pathologies. These results demonstrate that gut microbiota may serve as potential biomarkers for monitoring cerebrovascular conditions, potentially contributing to the development of personalized therapeutic strategies.},
}

@article {pmid40563781,
year = {2025},
author = {Alotaibi, MM and De Marco, M and Graham, R and Venneri, A},
title = {Alterations in Olfactory Cortex Volume in Mild Cognitive Impairment and Mild Alzheimer's Disease Dementia: A Study of Sex-Related Differences.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060610},
pmid = {40563781},
issn = {2076-3425},
support = {PE0000006//European Union - NextGenerationEU/ ; },
abstract = {BACKGROUND/OBJECTIVES: Aging is one of the greatest risk factors for neurodegenerative diseases such as Alzheimer's disease (AD). As the disease progresses, neural loss in brain regions, such as the olfactory cortex (OC), i.e., a set of areas including the mediotemporal and orbitofrontal regions, may lead to dysfunction in the sense of smell and affect other brain regions that relate to the olfactory cortex by either afferent or efferent projections.

METHODS: The objective of this study was to assess sex-related differences in olfactory cortex volume using magnetic resonance imaging in individuals with mild cognitive impairment, probable dementia of the AD type and in healthy older adults, using the Mini-Mental Statement Examination score, years of education, and total intracranial volume as correction factors.

RESULTS: Atrophy of the olfactory cortex was observed in patients of both sexes with probable AD dementia. However, at the MCI stage, significant volumetric loss in the OC was detected in females only but not in males.

CONCLUSIONS: This finding indicates greater pathological effects in this region in females at an earlier disease stage than in males. This study suggests that OC volume loss occurs differently between the sexes in older adults, with volumetric loss being greater in females.},
}

@article {pmid40563752,
year = {2025},
author = {Vasileiou, D and Moraitou, D and Diamantaras, K and Papaliagkas, V and Pezirkianidis, C and Tsolaki, M},
title = {Positive Psychology Interventions in Early-Stage Cognitive Decline Related to Dementia: A Systematic Review of Cognitive and Brain Functioning Outcomes of Mindfulness Interventions.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060580},
pmid = {40563752},
issn = {2076-3425},
support = {68/2025//Magda Tsolaki through Association of Alzheimer's Disease and Related Disorders through a scholarship/ ; },
abstract = {Background: Dementia is a global condition affecting over 55 million people. Since there is no treatment, non-pharmacological interventions aim to delay its progression in a safe and cost-effective way. The extant literature suggests that Positive Psychology Interventions (PPIs) can probably be effective for this purpose. The systematic review aims to assess the effectiveness of PPIs as non-pharmacological interventions for mild cognitive decline related to dementia by evaluating their effectiveness in cognitive functions and brain functioning in people with Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and mild Alzheimer's disease dementia (AD). Methods: A comprehensive search conducted in the databases Scopus, PubMed, ScienceDirect and PsychINFO (December 2024-March 2025) published between 2015 and 2025 to identify records that met inclusion criteria: studies included patients with SCD, MCI and mild AD dementia, implemented PPIs, Randomized controlled trials (RCTs) and pre-post intervention studies with measurable outcomes, assess at least one of the following: cognitive functions and brain functioning. Results: The systematic review included 12 studies (N = 669 participants) that can answer the research question. Only mindfulness interventions were identified. Findings suggest that different types of mindfulness interventions, such as the Mindfulness Awareness Program (MAP) and Mindfulness Training (MT), may be efficient for improving specific cognitive functions (e.g., working memory and attention) and influencing biological pathways related to cognitive decline. However, long-term efficacy has not been demonstrated, and results are mixed and unclear. Conclusions: Μindfulness interventions seem promising for enhancing cognition and brain functioning in older adults with cognitive decline, although the data is limited. However, limitations such as the heterogeneity of the studies and the diversity of the interventions make it necessary for more systematic and organized research to be conducted on the implementation of such interventions. At the same time, it is proposed to examine the effectiveness of other constructs of positive psychology, such as character strengths (CS).},
}

@article {pmid40563745,
year = {2025},
author = {Sowa, A and Malicka, M and Biernacka, M and Beszłej, JA and Leszek, J},
title = {VEXAS Syndrome and Alzheimer's Disease-Are There Connections?.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060573},
pmid = {40563745},
issn = {2076-3425},
abstract = {VEXAS syndrome and Alzheimer's disease (AD), though distinct in clinical manifestations, share overlapping pathophysiological mechanisms, including systemic inflammation, protein misfolding, and vascular dysfunction. VEXAS syndrome, a rare autoinflammatory disorder characterized by somatic UBA1 mutations, systemic inflammation, and hematologic abnormalities, presents primarily in older males. Meanwhile, AD, the leading cause of dementia, involves progressive neurodegeneration driven by amyloid-beta plaques, tau tangles, and chronic neuroinflammation. This article explores potential connections between the two conditions, focusing on inflammation, neurovascular changes and cellular stress. Systemic inflammation observed in VEXAS syndrome may potentiate neuroinflammatory processes in Alzheimer's disease (AD), as circulating proinflammatory cytokines have the capacity to cross the blood-brain barrier (BBB), thereby inducing glial activation and promoting neuroinflammation. Additionally, coexisting vascular dysfunctions characteristic of both conditions may synergistically contribute to accelerated cognitive decline. Both conditions involve disruption of the ubiquitin-proteasome system, with UBA1 mutations being specific to VEXAS. Given the established role of UBA1 in maintaining neuronal homeostasis, investigating the overlapping and distinct molecular mechanisms may provide valuable insights into their pathophysiology. The review underscores the need for further research to elucidate these links and improve therapeutic strategies, especially for individuals affected by both disorders.},
}

@article {pmid40563742,
year = {2025},
author = {Lewandowska, J and Majewski, J and Roszek, K},
title = {Extracellular Vesicles and Purinergic Signaling in Alzheimer's Disease-Joining Forces for Novel Therapeutic Approach.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060570},
pmid = {40563742},
issn = {2076-3425},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), are a global problem affecting millions of people. Thanks to years of research and huge efforts, it has been possible to discover the pathophysiological changes accompanying Alzheimer's disease at the cellular level. It turns out that the formation of amyloid-beta plaques and hyperphosphorylation of tau protein in the brain play a key role in disease development. Purinergic signaling (PS) is implicated in the pathophysiology of several disorders in the central nervous system, and recent findings link some disturbances in PS with Alzheimer's disease. The primary objective of our review is to comprehensively explore and identify key purinergic signaling targets that hold therapeutic potential in the treatment of patients suffering from the disease. In particular, we focus on the dual role of purinergic compounds and extracellular vesicles (EVs), which have emerged as critical components in cellular communication and disease modulation. The extracellular vesicles that are naturally released by various cells fulfill the role of communication tools, also by harnessing the purinergic compounds. In this context, our review presents a thorough and integrative analysis of how extracellular vesicles can influence purinergic signaling and how this interaction might be leveraged to develop novel, targeted treatment strategies. Ultimately, this line of research may lead to innovative therapeutic approaches that are not only effective in slowing or halting disease progression but also demonstrate a high degree of biocompatibility and safety for the human organism.},
}